Human and mammal studies finding heritable effects of exposures
- A compilation of studies demonstrating heritable, nongenetic intergenerational effects of exposures
- A few studies on transgenerational effects (not involving a direct germ cell exposure) are also included
- Also noted are selected papers on mechanisms, reviews, perspectives on heritable effects and neurodevelopment, and some studies on zebrafish models
- This is a work in progress and we welcome your input
• Tobacco, nicotine, benzo(a)pyrene
• Cannabis and related components
• Agents of general anesthesia, analgesics, morphine, opioids
• Synthetic steroids—Diethylstilbestrol (DES)
• Synthetic or exogenous steroids—glucocorticoids, estrogens, thyroid hormone
• Environmental endocrine disruptors—pesticides/herbicides/PCBs
• Environmental endocrine disruptors--BPA and plasticizers
• Valproic acid
• Chemotherapeutic agents
• Fear conditioning/habituation
• Immune activation
• Chronic stress/traumatic experience
• Folate metabolism
Tobacco, nicotine, benzo(a)pyrene
Zhu J, et al. Transgenerational transmission of hyperactivity in a mouse model of ADHD. J Neurosci 2014;34:2768–73.
In a mouse model, grandpups of gestating dams exposed to nicotine exhibited behaviors comparable to ADHD.
Rehan VK, et al. Perinatal nicotine-induced transgenerational asthma. Am J Physiol Lung Cell Mol Physiol 2013;305:L501–7.
In a rat model, grandpups of gestating dams exposed to tobacco smoke exhibited higher risk for asthma traits.
Maritz GS, et al. The effect of grand maternal nicotine exposure during gestation and lactation on lung integrity of the F2 generation. Pediatric. Pulmonol. 2014;49:1,67-75.
In a rat model, Grand‐maternal nicotine (F0) resulted in parenchymal deterioration and emphysema in the F2 progeny due to increased numbers of premature senescent cells together with a slower cell proliferation. The transfer of premature aging characteristics from the F1 progeny to the F2 progeny is via the male and female germ cell line.
Meier MJ, et al. In utero exposure to benzo[a]pyrene increases mutation burden in the soma and sperm of adult mice. Environ Health Perspect 2017;125:82–8.
In a mouse model, higher mutation rates were found in offspring sperm and in grand offspring brains (somatic mosaicism), when the pregnant dam was exposed to the tobacco component BaP.
El-Sayed A, et al. The transgenerational impact of benzo(a)pyrene on murine male fertility. Human Reproduction 2010;25(10):2427–2433
In a mouse model, exposure to BaP decreases the fertilization potential of exposed males and has an adverse impact on sperm function and fertility in subsequent generations.
Esakky P, et al. Paternal exposure to cigarette smoke condensate leads to reproductive sequelae and developmental abnormalities in the offspring of mice. Reprod Toxicol. 2016;65:283-294.In a mouse model, cigarette smoke condensate exposure to the male caused DNA damage and cytotoxicity in testes via accumulation of benzo(a)pyrene (B[a]P) and cotinine. Decreased expression of growth arrest and DNA damage inducible alpha (Gadd45a), aryl hydrocarbon receptor (Ahr), and cyclin-dependent kinase inhibitor 1A (P21) was seen in CSC exposed testes. Apoptotic germ cell death was detected by induction of Fas, FasL, and activated caspase-3. The CSC-exposed males displayed reduction in sperm motility and fertilizing ability and sired pups with reduced body weight and crown-rump length, and smaller litter size with higher numbers of resorption.
Csaba G, et al. Transgenerational effect of a single neonatal benzpyrene treatment on the glucocorticoid receptor of the rat thymus. Hum and Experimental Toxicol 1998;17(2).
Singh SP, et al. Gestational Exposure to Sidestream (Secondhand) Cigarette Smoke Promotes Transgenerational Epigenetic Transmission of Exacerbated Allergic Asthma and Bronchopulmonary Dysplasia. J Immunol 2017;https://doi.org/10.4049/jimmunol.1700014.
In mice, effects on lung function and inflammatory phenotype in allergen sensitization model in F2.
McCarthy DM, et al. Nicotine exposure of male mice produces behavioral impairment in multiple generations of descendants. PLOS Biol, 2018;16(10):e2006497 DOI: 10.1371/journal.pbio.2006497
In a mouse model, male mice were exposed to low-dose nicotine in their drinking water. They then bred these mice with females that had never been exposed to nicotine. While the fathers were behaviorally normal, both sexes of offspring displayed hyperactivity, attention deficit, and cognitive inflexibility. When female (but not male) mice from this generation were bred with nicotine-naïve mates, male offspring displayed fewer, but still significant, deficits in cognitive flexibility. Analysis of spermatozoa from the original nicotine-exposed males indicated that promoter regions of multiple genes had been epigenetically modified, including the dopamine D2 gene, critical for brain development and learning, suggesting that these modifications likely contributed to the cognitive deficits in the descendants.
Buck JM, et al. Developmental nicotine exposure precipitates multigenerational maternal transmission of nicotine preference and ADHD-like behavioral, rhythmometric, neuropharmacological, and epigenetic anomalies in adolescent mice. Neuropharmacol 2019:149;66-82.
In mice, gestational exposure to nicotine alters phenotype in first and second generation adolescent descendants. It enhances nicotine preference, elicits hyperactivity and risk-taking behaviors, perturbs the rhythmicity of activity, alters nAChR expression and function, impairs DAT function, and causes DNA hypomethylation in striatum and frontal cortex. The findings recapitulate multiple domains of ADHD symptomatology.
Buck JM et al. Developmental nicotine exposure elicits multigenerational disequilibria in proBDNF proteolysis and glucocorticoid signaling in the frontal cortices, striata, and hippocampi of adolescent mice. Biochem Pharmacol 2019;168:438-451.
Zhang W, et al. Paternal benzo[a]pyrene exposure alters the sperm DNA methylation levels of imprinting genes in F0 generation mice and their unexposed F1-2 male offspring. Chemosphere 2019;228:586-594. In mice, BaP-induced alterations of sperm DNA methylation of imprinting genes were found in F0 and their F1-2 male offspring. Imprinting genes H19, Meg3, Peg1, Peg3, Igf2 and Snrpn were studied. Imprinting genes vulnerability represents a target of environmental toxicants.
Murphy PJ, et al. Oxidative stress underlies heritable impacts of paternal cigarette smoke exposure. BioRxiv https://doi.org/10.1101/750638
In mice, paternal cigarette smoke (CS) exposure changed sperm DNA methylation (DNAme) partially corrected within 28 days of removal from CS exposure. Additionally, paternal smoking causes changes in neural DNAme and gene expression in offspring. Remarkably, the effects of CS exposure are largely recapitulated in oxidative stress-compromised Nrf2-/- mice and their offspring, independent of paternal smoking. These results demonstrate that paternal CS exposure impacts offspring phenotype and that oxidative stress underlies CS induced heritable epigenetic changes.
Goldberg LR, et al. Paternal nicotine enhances fear memory, reduces nicotine administration, and alters hippocampal genetic and neural function in offspring. Addiction Biol 2019
In mice, paternal nicotine exposure was associated with enhanced contextual and cued fear conditioning and spontaneous recovery of extinguished fear memories. Further, nicotine reinforcement was reduced in nicotine‐sired mice, as assessed in a self‐administration paradigm. These behavioral phenotypes were coupled with altered response to nicotine, upregulated hippocampal nicotinic acetylcholine receptor binding, reduced evoked hippocampal cholinergic currents, and altered methylation and expression of hippocampal genes related to neural development and plasticity. Gene expression analysis suggests multigenerational effects on broader gene networks potentially involved in neuroplasticity and mental disorders. The changes in fear conditioning similarly suggest phenotypes analogous to anxiety disorders similar to post‐traumatic stress.
Zhang Q, et al. Reduced testicular steroidogenesis in rat offspring by prenatal nicotine exposure: Epigenetic programming and heritability via nAChR/HDAC4. Food & Chem Toxicol 2019. https://doi.org/10.1016/j.fct.2019.111057
Pregnant Wistar rats were injected subcutaneously with nicotine (2 mg/kg.d) from gestational day 9–20. Some dams were anesthetized to obtain fetal rats, the rest were allowed to spontaneous labor to generate F1 and F2 generation. In utero, PNE impaired testicular development and testosterone production. Meanwhile, the expression of steroidogenic acute regulatory protein (StAR) and 3β-hydroxysteroid dehydrogenase (3β-HSD) were decreased both in F1 and F2 generations. Furthermore, PNE enhanced the expression of fetal testicular nicotinic acetylcholine receptors (nAChRs) and histone deacetylase 4 (HDAC4), while obviously weakened histone 3 lysine 9 acetylation (H3K9ac) level of StAR/3β-HSD promoter from GD20 to postnatal week 12 and even in F2 generation. In vitro, nicotine increased nAChRs and HDAC4 expression, and decreased the StAR/3β-HSD H3K9ac level and expression, as well as the testosterone production in Leydig cells. Antagonism of nAChRs and inhibition of HDAC4 reversed the aforementioned changes. In conclusion, PNE programmed testicular low steroidogenesis and its heritability in male offspring rats. The underlying mechanism was associated to the low-level programming of StAR/3β-HSD H3K9ac via nAChR/HDAC4.
Zhang et al. Paternal nicotine exposure induces hyperactivity in next-generation via down-regulating the expression of DAT. Toxicology 2020, 152367.
In mice, paternal nicotine exposure could induce hyperactivity in the offspring via the hyper-methylation of Dat. Consequently, Dat may be one of the genes that mediate the cross-generation effects of nicotine besides mmu-mmiR-15b.
Cannabis and related components
Levin ED, et al. Paternal THC exposure in rats causes long-lasting neurobehavioral effects in the offspring. 2019; Neurotoxicology and Teratology. https://doi.org/10.1016/j.ntt.2019.04.003
In rats, paternal THC exposure impaired in attentional performance in the offspring; increased in habituation of locomotor activity; generally, can cause deleterious long-term behavioral effects in the offspring.
Andalouss ZL, et al. Behavioural and epigenetic effects of paternal exposure to cannabinoids during adolescence on offspring vulnerability to stress. Int J Dev Neurosci 2019:72:48-54.
Paternal exposure to cannabinoids during adolescence induces stress vulnerability in the offspring. Stress exposure induced an anxiogenic-like effect in the offspring of WIN55,212-2 exposed fathers. Stress exposure increased global DNA methylation and DNMT’s transcription in the offspring prefrontal cortex.
Theodore A Slotkin, Samantha Skavicus, Edward D Levin, Frederic J Seidler, Paternal Δ9-Tetrahydrocannabinol Exposure Prior to Mating Elicits Deficits in Cholinergic Synaptic Function in the Offspring.
Toxicological Sciences 2020, kfaa004, https://doi.org/10.1093/toxsci/kfaa004
In male rats, THC-treated males were mated to drug-naïve females. In offspring was seen a dose-dependent deficit in hemicholinium-3 binding, an index of presynaptic ACh activity, superimposed on regionally selective increases in choline acetyltransferase activity, a biomarker for numbers of ACh terminals. The combined effects produced a persistent decrement in the hemicholinium-3/choline acetyltransferase ratio, an index of impulse activity per nerve terminal. At the low THC dose, the decreased presynaptic activity was partially compensated by upregulation of nicotinic ACh receptors, whereas at the high dose, receptors were subnormal, an effect that would exacerbate the presynaptic defect. Vulnerability to drug exposure is engendered prior to conception, involving the father's sperm, not just gestational exposure via the female.
Agents of general anesthesia, analgesics, morphine, opioids
Chastain-Potts SE et al. Sevoflurane Exposure Results in Sex-Specific Transgenerational Upregulation of Target IEGs in the Subiculum. 2019. Molecular Neurobiology. https://doi.org/10.1007/s12035-019-01752-0.
Neonatal female rats exposed to 6h of the general anesthesia gas sevoflurane had offspring whose brains exhibited epigenetic abnormalities, including reduced DNA methylation, an effect linked to functional decline in learning and memory. An upregulation of Arc and JunB mRNA expression, 71.6% and 74.0%, was seen in the male offspring. Also hypomethylation and modifications to IEGs crucial to synaptic plasticity were observed. The results suggest sevoflurane causes epigenetic modifications in the early rat oocytes.
Ling-Sha Ju, M.D.; Jiao-Jiao Yang, M.D.; Ning Xu, M.D.; Jia Li, M.D.; Timothy E. Morey, M.D.; Nikolaus Gravenstein, M.D.; Christoph N. Seubert, M.D.; Barry Setlow, Ph.D.; Anatoly E. Martynyuk, Ph.D. Intergenerational Effects of Sevoflurane in Young Adult Rats. Anesthesiology 2019.
Adult sevoflurane exposure affects brain development in male offspring by epigenetically reprograming both parental germ cells, while it induces neuroendocrine and behavioral abnormalities only in exposed males. Sex steroids may be required for mediation of the adverse effects of adult sevoflurane in exposed males.
Ju LS, et al. Role of epigenetic mechanisms in transmitting the effects of neonatal sevoflurane exposure to the next generation of male, but not female, rats, Brit J Anesth 2018.
In a rat model, neonatal exposure to the widely used general anesthetic agent sevoflurane can affect the brains and behavior of the next generation of males through epigenetic modification of Kcc2 expression, while F1 females are at diminished risk.
• Also See BJA editorial: Vutskits L, et al. A poisoned chalice: the heritage of parental anaesthesia exposure, Brit. J Anesth, 2018. (“Hence, we are faced with a real possibility that general anaesthetics are not innocuous agents that ‘only put children to sleep’ but rather formidable modulators of chromatin remodeling and function…. The current study extends previous reports of sex differences by showing that anaesthetic exposure itself can alter expression of chloride channels in certain brain regions and that this effect is heritable from exposed male parents to unexposed offspring.”)
Chalon J, et al. Exposure to halothane and enflurane affects learning function of murine progeny. Anesth Analg 1981;60:794–7.
In a mouse model, learning retardation was seen in offspring of murine parents exposed to GA in utero—in other words, mental impairment in the grandpups of the exposed gestating dams.
Tang C-K, et al. Exposure of sires to enflurane affects learning function of murine progeny.
Obstet Anesth Dig 1985;5:2, 67.
In a mouse model, the general anesthetic agent enflurane administered to male mice was found to adversely affected learning function of their offspring.
Rossitto, M, et al, Intergenerational effects on mouse sperm quality after in utero exposure to acetaminophen and ibuprofen. FASEB J. 2018.
In a mouse model, demonstrates that pregnancy exposure to these analgesics during the critical period of sex determination affects the germ-line development and leads to adverse reproductive effects in the grandpups.
Vassoler F, et al. Increased cocaine reward in offspring of females exposed to morphine during adolescence. 2018 Psychopharmacology;1-12.
In rats, morphine in F1 females prior to conception increases the rewarding effects of cocaine in F2 male and female offspring. Sex-specific alterations in endogenous opioids and hypothalamic physiology were observed.
Sabzevari S et al., Morphine exposure before conception affects anxiety-like behavior and CRF level (in the CSF and plasma) in the adult male offspring.
In rats, morphine exposure to the F1 parent before conception induced intergenerational effects via dysregulation of HPA axis which results in anxiety in the adult male offspring.
Rossito M, et cal. In utero exposure to acetaminophen and ibuprofen leads to intergenerational accelerated reproductive aging in female mice. Communications Biology 2019;2;310.
In mice, in utero exposure to therapeutic doses of APAP-ibuprofen combination during sex determination led to delayed meiosis entry and progression in female F1 embryonic germ cells. Consequently, follicular activation was reduced in postnatal ovaries through the AKT/FOXO3 pathway, leading in F2 animals to subfertility, accelerated ovarian aging with abnormal corpus luteum persistence, due to decreased apoptosis and increased AKT-mediated luteal cell survival.
Byrnes JJ et al. Multigenerational effects of adolescent morphine exposure on dopamine D2 receptor function. Psychopharmacology 2013;227(2):263–272.
Toorie AM, et al. A history of opioid exposure in females increases the risk of metabolic disorders in their future male offspring. Addiction Biol 2019. https://doi.org/10.1111/adb.12856
Examination of diet‐induced modifications in F1 male progeny of morphine‐exposed female rats. When fed a high fat‐sugar diet (FSD) for 6 weeks, MORF1 males display features of emerging metabolic syndrome; they consume more food, gain more weight, and develop fasting‐induced hyperglycemia and hyperinsulinemia. In the hypothalamus, proteins involved in energy homeostasis are modified and RNA sequencing revealed down‐regulation of genes associated with neuronal plasticity, coupled with up‐regulation of genes associated with immune, inflammatory, and metabolic processes that are specific to FSD‐maintained MORF1 males. Limited preconception morphine exposure in female rats increases the risk of metabolic syndrome/type 2 diabetes in the next generation.
Killinger CE, Robinson S, Stanwood GD. Subtle biobehavioral effects produced by paternal cocaine exposure. Synapse 2012;66:902–908.
Wimmer ME, Briand LA, Fant B, Guercio LA, Arreola AC, Schmidt HD, Sidoli S, Han Y, Garcia BA, Pierce RC. Paternal cocaine taking elicits epigenetic remodeling and memory deficits in male progeny. Mol Psychiatry 2017;22:1641–1650.
Wimmer ME, Vassoler FM, White SL, Schmidt HD, Sidoli S,
Han Y, Garcia BA, Pierce RC. Impaired cocaine-induced behavioral plasticity in the male offspring of cocaine-experienced sires. Eur J Neurosci 2019;49:1115–26.
Yaw AM, Prosser RA, Jones PC, , Garcia BJ, Jacobson DA,
Glass JD. Epigenetic effects of paternal cocaine on reward stimulus behavior and accumbens gene expression in mice.
Behav Brain Res 2019;367:68–81.
Le Q, Yan B, Yu X, Li Y, Song H, Zhu H, Hou W, Ma D, Wu F,
Zhou Y, Ma L. Drug-seeking motivation level in male rats determines offspring susceptibility or resistance to cocaine-seeking behaviour. Nat Commun 2017;8:
Azadi M, Azizi H, Haghparast A. Paternal exposure to morphine during adolescence induces reward-resistant phenotype to morphine in male offspring. Brain Res Bull 2019;147:124-32.
Moulaei N, Mondanizadeh M, Salmani ME, Palizvan MR,
Khansarinejad B, Sadegh M. Transgenerational consequences of prepregnancy chronic morphine use on spatial learning and hippocampal Mecp2 and Hdac2 expression. NeuroReport 2018;29:739–44.
Luo H, Deng Z, Liu L, Shen L, Kou H, He Z, Ping J, Xu D, Ma L, Chen L, Wang H. Prenatal caffeine ingestion induces transgenerational neuroendocrine metabolic programming alteration in second generation rats.
Toxicol Appl Pharmacol 2014;274:383–92.
Ellis, A.S., Toussaint, A.B., Knouse, M.C. et al. Paternal morphine self-administration produces object recognition memory deficits in female, but not male offspring. Psychopharmacology (2020) doi:10.1007/s00213-019-05450-6
Synthetic steroids—Diethylstilbestrol (DES)
Newbold RR, et al. Adverse Effects of the Model Environmental Estrogen Diethylstilbestrol Are Transmitted to Subsequent Generations. Endocrinology 2006;147(6):s11–s17,
"Interestingly, our data suggest that this increased susceptibility for tumors is passed on from the maternal lineage to subsequent generations of male and female descendants; the mechanisms involved in these transgenerational events include genetic and epigenetic events. Together, our data point out the unique sensitivity of the developing organism to endocrine-disrupting chemicals, the occurrence of long-term effects after developmental exposure, and the possibility for adverse effects to be transmitted to subsequent generations."
Newbold RR, et al. Increased tumors but uncompromised fertility in the female descendants of mice exposed developmentally to diethylstilbestrol. Carcinogenesis 1998;19(9):1655–1663.
Newbold RR, et al. Proliferative lesions and reproductive tract tumors in male descendants of mice exposed developmentally to diethylstilbestrol. Carcinogenesis 2000;21(7):1355–1363.
Walker, BE, et al. Multi-generational carcinogenesis from diethylstilbestrol investigated by blastocyst transfers in mice. Int J Cancer 1995;61(2):249-52.
In mouse model, among 99 offspring derived from DES-exposed germ cells, 6 developed ovarian adenomas and 16 developed uterine adenocarcinomas. DES had a multi-generational effect transmitted through the blastocyst, consistent with fetal germ cell mutation from DES.
Walker, BE, et al. Intensity of multigenerational carcinogenesis from diethylstilbestrol in mice. Carcinogenesis 1997;18(4):791-3.
In mouse model, DES carcinogenic persistence was seen in grandpups by mating DES-lineage female mice to control males. "If this type of carcinogenesis can occur in the human population, it poses a major threat to future generations."
Mahawong, P, et al. Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains. Differentiation 2014;88(0):51–69.
Turusov, VS, et al. Occurrence of tumours in the descendants of CBA male mice prenatally treated with diethylstilbestrol. Int. J. Cancer 1992;50(1):131-135.
Synthetic or Exogenous Steroids—Glucocorticoids, estrogens, thyroid hormone
Moisiadis VG, et al. Prenatal Glucocorticoid Exposure Modifies Endocrine Function and Behaviour for 3 Generations Following Maternal and Paternal Transmission. Sci Rep 2017;7:11814.
In a guinea pig model, gestational treatment with synthetic glucocorticoids (betamethasone) at a clinically relevant dose resulted in various generational pathology including altered cortisol response to stress, altered expression of genes in the prefrontal cortex and hypothalamic paraventricular nucleus. Transgenerational alterations of programming was seen through F3. Transmission was sex- and generation-dependent, occurring through both parental lines.
V.G. Moisiadis, S.G. Matthews, Glucocorticoids and fetal programming part 1: outcomes. Nat. Rev. Endocrinol. 10 (7) (2014) 391–402.
A. Crudo, S. Petropoulos, V.G. Moisiadis, M. Iqbal, A. Kostaki, Z. Machnes, M.Szyf, S.G. Matthews, Prenatal synthetic glucocorticoid treatment changes DNA methylation states in male organ systems: multigenerational effects. Endocrinology 153 (7) (2012) 3269–3283.
Iqbal M, et al. Transgenerational effects of prenatal synthetic glucocorticoids on hypothalamic-pituitary-adrenal function. Endocrinology 2012;153, 3295–3307.
In a guinea pig model, gestational treatment with synthetic glucocorticoids (betamethasone) modified HPA function and behavior in the F2.
Long NM et al. Multigenerational effects of fetal dexamethasone exposure on the hypothalamic-pituitary-adrenal axis of first- and second-generation female offspring. Am J Obstet Gynecol 2013; 208, 217.e1–217.e8.
In a sheep model, the synthetic glucocorticoid dexamethasone administed in the clinical range to gestating ewes have multigenerational effects on HPA activity.
Drake AJ, et al. Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats. Am J Physiol Regul Integr Comp Physiol 2005;288, R34–R38.
In a rat model, pregnant ewes were exposed to the synthetic glucocorticoid dexamethasone, a variety of pathologies (reduced birth weight, glucose intolerance, and elevated hepatic PEPCK activity) were seen in male grandoffspring.
Drake AJ, et al. Multigenerational programming in the glucocorticoid programmed rat is associated with generation-specific and parent of origin effects. Epigenetics 2011;6:1334–43
In a rat model, prenatal glucocorticoid overexposure caused effects on fetal and placental weight in both the F1 and F2 offspring, with marked parent-of-origin effects in F2.
Vaughan OR, et al. Dexamethasone treatment of pregnant F0 mice leads to parent of origin-specific changes in placental function of the F2 generation. Reprod Fertil Dev 2015;27(4):704-11.
In a mouse model, effects of F0 gestating dam dexamethasone exposure are transmitted intergenerationally to the F2 placenta via the maternal, but not paternal, line.
de Assis S, et al. High-fat or ethinyl-oestradiol intake during pregnancy increases mammary cancer risk in several generations of offspring. Nat Commun 2012;3:1053.
In a rat model, fetal exposure to diets high in fat or a large amount of estrogen heightened the risk of breast cancer for three generations of female offspring. Epigenetic changes in the mammary glands of three generations of the rats who had been exposed to increased estrogen were observed.
Petropoulos S, et al. Adult Glucocorticoid Exposure Leads to Transcriptional and DNA Methylation Changes in Nuclear Steroid Receptors in the Hippocampus and Kidney of Mouse Male Offspring. Biology of Reproduction 2014; 90(2):1-10.https://doi.org/10.1095/biolreprod.113.115899
Horan TS, et al. Germline and reproductive tract effects intensify in male mice with successive generations of estrogenic exposure. PLOS Genetics 2017;1006885.
In a mouse model, multiple generations of exposure not only exacerbate germ cell exposure effects, but also increase the incidence and severity of reproductive tract abnormalities.
Rawat A, et al. Hypersensitivity to sertraline in the absence of hippocampal 5-HT1AR and 5-HTT gene expression changes following paternal corticosterone treatment. Env Epigenetics 2018;4(2):doi.org/10.1093/eep/dvy015
In mouse model, varying forms of paternal stress exert different effects on offspring brain serotonergic function.
Short AK, Fennell KA, Perreau VM, Fox A, O’Bryan MK, Kim JH, Bredy TW, Pang TY, Hannan AJ. Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring. Transl Psychiatry 2016; 6:e837.
Preconception male mice were treated by corticosterone. Analysis of the small RNA profile in sperm from CORT-treated males revealed marked effects on the expression of small noncoding RNAs. Sperm from CORT-treated males contained elevated levels of three microRNAs, miR-98, miR-144 and miR-190b, which are predicted to interact with multiple growth factors, including Igf2 and Bdnf. Sustained elevation of glucocorticoids is therefore involved in the transmission of paternal stress-induced traits across generations in a process involving small noncoding RNA signals transmitted by the male germline.
Cartier J, et al. Investigation into the role of the germline epigenome in the transmission of glucocorticoid-programmed effects across generations. Genome Biol 2018:19:50; https://doi.org/10.1186/s13059-018-1422-4
In a rat model, F0 gestational dexamethasone exposure affects birthweight of the F2 generation, though mechanisms through the male germ line are unclear.
Martinez ME, et al. Thyroid hormone influences brain gene expression programs and behaviors in later generations by altering germ line epigenetic information. Mol Psychiatry October 2018.
F2 descendants of mice developmentally overexposed to thyroid hormone due to a Dio3 mutation. Hypothalamic gene expression profiling in postnatal day 15 F2 on the paternal lineage of ancestral male and female T3-overexposed mice revealed, respectively, 1089 and 1549 differentially expressed genes. A large number of them, 675 genes, were common to both sets, suggesting comparable epigenetic effects of thyroid hormone on both the male and female ancestral germ lines. Developmental levels of thyroid hormone influence the epigenetic information of the germ line, disproportionately affecting genes with critical roles in early brain development.
Santos Borges Cd, et al. Betamethasone causes intergenerational reproductive impairment in male rats. Repro Tox 2017 71:108-117. Prenatal betamethasone treatment in rats increased DNA damage and decreased sperm quality and male fertility in F2 generation.
Abrantes MA, Valencia AM, Bany-Mohammed FB, Aranda JV, Beharry KD. Intergenerational Influence of Antenatal Betamethasone on Growth, Growth Factors, and Neurological Outcomes in Rats. Reproductive Sciences 2020;doi:10.1007/s43032-019-00073-w.
Environmental endocrine disruptors, eg, pesticides/herbicides/PCBs
Anway, MD, et al. Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility. Science 2005;308:1466-69.
In rat model, transient exposure of a gestating female during the period of gonadal sex determination to vinclozolin (an antiandrogenic compound) or methoxychlor (an estrogenic compound) induced an adult phenotype in the F1generation of decreased spermatogenic capacity (cell number and viability) and increased incidence of male infertility. These effects were transferred through the male germ line to nearly all males of all subsequent generations examined (that is, F1 to F4).
Anway MD, et al. Endocrine Disruptor Vinclozolin Induced Epigenetic Transgenerational Adult-Onset Disease.
Crews, D, et al. Transgenerational epigenetic imprints on mate preference. PNAS 2007;104 (14):5942-5946.
In rat model, females three generations removed from the original vinclozoiln exposure discriminate and prefer males who do not have a history of exposure.
Skinner MK, et al. Transgenerational epigenetic programming of the brain transcriptome and anxiety behavior. PLoS One 2008;3:e3745.
In a rat model, gestating females were exposed to vinclozolin during fetal gonadal sex determination. Alterations to epigenetic reprogramming of the male germ-line and offspring brain transcriptome (sex-specific) were observed, Several brain signaling pathways were influenced including those involved in axon guidance and long-term potentiation.
Stouder, C, et al. Transgenerational effects of the endocrine disruptor vinclozolin on the methylation pattern of imprinted genes in the mouse sperm. Reproduction 2010;139:373-379.
Guerrero-Bosagna, C, et al. Epigenetic Transgenerational Actions of Vinclozolin on Promoter Regions of the Sperm Epigenome. PLoS ONE 2010;5(9):e13100.
Manikkam M, et al. Pesticide and insect repellent mixture (Permethrin and DEET) induces epigenetic transgenerational inheritance of disease and sperm epimutations. Reprod Toxicol. 2012;34:708–19.
Crews D, et al. Epigenetic transgenerational inheritance of altered stress responses. Proc Natl Acad Sci USA 2012;109:9143–8.
In a rat model, a single exposure to vinclozolin altered the physiology, behavior, metabolic activity, and transcriptome in discrete brain nuclei in descendant males, causing them to respond differently to chronic restraint stress.
Manikkam M, et al. Transgenerational actions of environmental compounds on reproductive disease and identification of epigenetic biomarkers of ancestral exposures. PLoS One 2012;7:1–12, e31901.
(Vinclozolin, permethrin/DEET, plastics, dioxin, jet fuel)
Guerrero-Bosagna, C, et al. Epigenetic transgenerational inheritance of vinclozolin induced mouse adult onset disease and associated sperm epigenome biomarkers. Repro Toxicol 2012;34(4):694-707.
Skinner M, et al. Ancestral dichlorodiphenyltrichloroethane (DDT) exposure promotes epigenetic transgenerational inheritance of obesity. BMC Medicine 2013;11:228.
In rat model, gestating dams were exposed to DDT. A transgenerational transmission of disease was observed through both female (egg) and male (sperm) germlines. F3 generation sperm epimutations, differential DNA methylation regions (DMR), induced by DDT were identified.
Anway, MD, et al. Transgenerational Effect of the Endocrine Disruptor Vinclozolin on Male Spermatogenesis. J. Andrology 2013;27(6):868-879.
Chamorro-Garcia R, et al. Transgenerational inheritance of increased fat depot size, stem cell reprogramming, and hepatic steatosis elicited by prenatal exposure to the obesogen tributyltin in mice. Environ Health Perspect 2013;121:359–66.
Gillette, R, et al. Sexually Dimorphic Effects of Ancestral Exposure to Vinclozolin on Stress Reactivity in Rats. Endocrinol 2014;155(10):3853–3866.
Brieno-Enriquez M, et al. Exposure to endocrine disruptor induces transgenerational epigenetic deregulation of micrornas in primordial germ cells. PLoS One. 2015;10, e0124296.
Mouse model, using vinclozolin.
McBirney M, et al. Atrazine induced epigenetic transgenerational inheritance of disease, lean phenotype and sperm epimutation pathology biomarkers. Plos ONE 2017;12(9): e0184306. https://doi.org/10.1371/journal.pone.0184306
In a rat model, gestating females were exposed to atrazine. The F2 generation (grand-offspring) was found to have increased frequency of testis disease and mammary tumors in males and females, early onset puberty in males, and decreased body weight in females compared to controls.
Gely-Pernot, A, et al. Gestational exposure to chlordecone promotes transgenerational changes in the murine reproductive system of males. Sci Rep 2018;8:10274.
In a mouse model, pregnant females were exposed to chlordecone, an organochlorine insecticide. Subsequent generations suffered reduction in spermatogonia, meiotic defects in spermatocytes and decrease in spermatozoa number. Changes in the expression of genes associated with chromosome segregation, cell division and DNA repair were observed. Altered epigenetic marks were conserved between F1 and F3 generations.
Krishnan K, et al. Effects of the Endocrine-Disrupting Chemicals, Vinclozolin and Polychlorinated Biphenyls, on Physiological and Sociosexual Phenotypes in F2 Generation Sprague-Dawley Rats. Env Health Perspect, September 2018;doi.org/10.1289/EHP3550
Exposure of rats to EDCs at the germ cell stage led to differences in the physiological and behavioral phenotype later in life, especially in males. This finding has implications for multigenerational physiological and reproductive health in wildlife and humans.
Gillette R, et al. Passing experiences on to future generations: endocrine disruptors and transgenerational inheritance of epimutations in brain and sperm. Epigenetics 2018;https://doi.org/10.1080/15592294.2018.1543506
Following gestational exposure to vinclozolin and PCBs, mature sperm of exposed adult F1 and unexposed F3 males was collected, and brain nuclei involved in anxiety and social behaviors were selected for assays of epimutations in CpG islands using reduced representation bisulfite sequencing. In F1 sperm, VIN and PCBs induced differential methylation in 215 and 284 CpG islands, respectively, compared to vehicle. The majority of effects were associated with hypermethylation. Fewer epimutations were detected in the brain. A subset of differentially methylated regions were retained from the F1 to the F3 generation, suggesting a common mechanism of EDC and germline epigenome interaction.
Ben Maamar M, et al. Developmental Origins of Transgenerational Sperm DNA Methylation Epimutations Following Ancestral DDT Exposure 2018 Dev Biol https://doi.org/10.1016/j.ydbio.2018.11.016
Identifies the developmental origins of transgenerational sperm epimutations. Demonstrates a developmental cascade of epigenetic alterations in the germline is required. Demonstrates epimutations are acquired at all spermatogenic and epididymal stages. Elucidates the germline epigenetic programming for environmentally induced epigenetic transgenerational inheritance.
Milesi MM et al. Perinatal exposure to a glyphosate-based herbicide impairs female reproductive outcomes and induces second-generation adverse effects in Wistar rats. Archives of Toxicology 2018;92(8):2629–2643.
Klukovich R, et al. Environmental Toxicant Induced Epigenetic Transgenerational Inheritance of Prostate Pathology and Stromal-Epithelial Cell Epigenome and Transcriptome Alterations: Ancestral Origins of Prostate Disease. Scientific Reportsvolume 9, Article number: 2209 (2019)
Gestating female rats (F0 generation) were exposed to vinclozolin during E8-E14 of gestation. F1 generation offspring were bred to produce the F2 generation, which were bred to produce the transgenerational F3 generation. The transgenerational F3 generation vinclozolin lineage males at 12 months of age had an increased incidence of prostate histopathology and abnormalities compared to the control lineage.
Kubsad D, et al. Assessment of Glyphosate Induced Epigenetic Transgenerational Inheritance of Pathologies and Sperm Epimutations: Generational Toxicology. Sci Rep 2019
Exposure to the herbicide glyphosate (N-(phosphonomethyl)glycine) in a gestating F0 female rats saw dramatic increases in pathologies in the F2 generation grand-offspring, and F3 transgenerational great-grand-offspring. Observations suggest the generational toxicology of glyphosate needs to be considered in the disease etiology of future generations.
Rodriguez DL et al. Endocrine disruptors transgenerationally alters pubertal timing through epigenetic reprogramming of the hypothalamus. Endocrine Abstracts (2019) 63 OC8.3 | DOI: 10.1530/endoabs.63.OC8.3
Female rats (F0 generation) were orally exposed to a mixture of 14 anti-androgenic and estrogenic EDCs or corn oil for 2 weeks before and throughout gestation and until weaning. The results show multiple multi- and transgenerational effects after ancestral EDC exposure. While F2 and F3 females showed delayed vaginal opening, decreased percentage of regular estrous cycles, decreased GnRH interpulse interval and altered folliculogenesis, no such changes were detected in F1 animals.
He QL, et a. 2019. Effects of 2,3′,4,4′5-pentachlorobiphenyl exposure during pregnancy on epigenetic imprinting and maturation of offspring’s oocytes in mice. Arch Toxicol:1-18.
Gestating mice were exposed to PCB118. In the fetal oocytes, the PCB118 altered the DNA methylation status of differentially methylated regions in some imprinted genes, and the expression levels of Dnmt1, 3a, and 3l, Uhrf1 and Tet3 were also changed. In addition, PCB118 disturbed the maturation process of progeny mouse oocytes in a dose-dependent manner.
Krishnan et al. Endocrine-disrupting chemicals alter the neuromolecular phenotype in F2 generation adult male rats. Physiol &Behav 2019. 112674.
Sprague-Dawley rat dams were treated on pregnancy days 8 to 18 with one of three treatments: a PCB) mixture, Aroclor 1221, or vinclozolin. F1 male and female offspring were bred with untreated partners to generate F2 offspring. The brains of F2 males were examined for molecular changes in the hypothalamus related to behavioral outcomes. Of the genes assessed, steroid hormone receptors (estrogen receptor α, androgen receptor, progesterone receptor) but not dopamine receptors 1 and 2 or DNA methyltransferase 3a expression were altered, particularly in the VIN males. Several significant correlations between behavior and gene expression were also detected. These results suggest that preconceptional exposure of male rats to EDCs at the germ cell stage alters the neuromolecular phenotype in adulthood in a lineage-dependent manner.
Lessard M, et al. Prenatal Exposure to Environmentally-Relevant Contaminants Perturbs Male Reproductive Parameters Across Multiple Generations that are Partially Protected by Folic Acid Supplementation. Sci Rep 2019;9:13829.
In rats, gestating dams (F0)were given POPs or corn oil and fed basal or supplemented folic acid diets, then used to yield four generations of litters. Altered sperm parameters were seen in F1, which were partly rescued by FA supplementation. Paternal exposure to POPs reduced sperm quality in F2 males, and the fertility of F3 males was modified by both POPs and FA. Ancestral FA supplementation improved sperm parameters of F4 males, while the POPs effect diminished. Intriguingly, F3 males had the poorest pregnancy outcomes and generated the embryos with the most significantly differentially expressed genes. Early-life exposure to POPs harms male reproduction across multiple generations. FA supplementation partly mitigated the impact of POPs.
Ben Maamar et al. Epigenetic transgenerational inheritance of parent-of-origin allelic transmission of outcross pathology and sperm epimutations. Dev Biol 2019: https://doi.org/10.1016/j.ydbio.2019.10.030
In rats, vinclozolin and DDT induce transgenerational sperm epimutations involving DNA methylation, ncRNA, and histone modifications or retention. There was increased pathology incidence in the maternal outcross F4 generation male prostate, kidney, obesity, and multiple diseases through a maternal allelic transmission. The paternal outcross F4 generation female offspring had increased pathology incidence for kidney, obesity and multiple types of diseases through the paternal allelic transmission. Some disease such as testis or ovarian pathology appear to be transmitted through the combined actions of both male and female alleles. Analysis of the F4 generation sperm epigenomes identified differential DNA methylated regions (DMRs) in a genome-wide analysis. DDT and vinclozolin have the potential to promote the epigenetic transgenerational inheritance of disease and sperm epimutations to the outcross F4 generation in a sex specific and exposure specific manner. The parent-of-origin allelic transmission observed appears similar to the process involved with imprinted-like genes.
Environmental endocrine disruptors--BPA and plasticizers
Wolstenholme JT, et al. Gestational exposure to bisphenol A produces transgenerational changes in behaviors and gene expression. Endocrinology 2012;153:3828–38.
In a mouse model, gestational exposure to BPA produces multigenerational alterations in genes and behavior.
Manikkam M, et al. Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. PLoS One 2013;8:1–18, e55387
Iqbal K, et al. Deleterious effects of endocrine disruptors are corrected in the mammalian germline by epigenome reprogramming. Genome Biol 2015;16:59.
In a mouse model, gestating mice were treated with endocrine-disrupting chemicals vinclozolin, bisphenol A, or di-(2-ethylhexyl)phthalate, resulting in changes in transcription and methylation in the F1 germline. Though intergenerational changes were observed, transgenerational (no direct exposure) were not.
Chen, J et al. The mechanism of environmental endocrine disruptors (dehp) induces epigenetic transgenerational inheritance of cryptorchidism. PLoS One 2015;10, e0126403.
In a rat model, the incidence of cryptorchidism in F2 (offspring of exposed germ cells) was 12.5%. Conception rate was also decreased in F2 generation.
Ziv-Gal, A, et al. The effects of in utero bisphenol a exposure on reproductive capacity in several generations of mice. Toxicol. Appl. Pharmacol. 2015;284:354–362.
In mouse model, in utero BPA reduced the ability of F2 female mice to maintain pregnancies. (Also found generational effects in DES-exposed mice.)
Berger A, et al. 2016. The effects of in utero bisphenol a exposure on the ovaries in multiple generations of mice. Reprod Toxicol 2016;60:39–52.
Drobná Z, et al. Transgenerational effects of bisphenol A on gene expression and DNA methylation of imprinted genes in brain. Endocrinology 2018;159:1132–144.
In a mouse model, gestational exposure to BPA produces multigenerational alterations in brain tissues. BPA-caused changes at two imprinted genes in the brain were observed.
Horan TS, et al. Replacement Bisphenols Adversely Affect Mouse Gametogenesis with Consequences for Subsequent Generations. Curr Biol 2018;doi.org/10.1016/j.cub.2018.06.070
In mice, exposure to BPS (a common BPA replacement) from damaged polysulfone cages induces germline effects affecting the F2 generation.
Małgorzata M, et al. Reproductive and developmental F1 toxicity following exposure of pubescent F0 male mice to bisphenol A alone and in a combination with X-rays irradiation. Toxicology 2018. https://doi.org/10.1016/j.tox.2018.10.007
In a mouse model, pubescent F0 males were exposed to bisphenol A and irradiation for 8-weeks. An increased mortality of pups F1 generation and its obesity were observed; disturbance in the sex ratio and diminished sperm quality of F1 generation were seen.
Bansal A, et al. Transgenerational effects of maternal bisphenol: a exposure on offspring metabolic health. J Dev Origins of Health and Disease, October 2018; https://doi.org/10.1017/S2040174418000764
In a maternal C57BL/6J mice (F0) exposure model using BPA doses that are relevant to human exposure levels (10 μg/kg/day, LowerB; 10 mg/kg/day, UpperB), we showed male- and dose-specific effects on pancreatic islets of the first (F1) and second generation (F2) offspring relative to controls.
Shi M, et al. Prenatal exposure to bisphenol A, E and S induces transgenerational effects on male reproductive functions in mice. Toxicol Sci. 2019 Sep 18. pii: kfz207. doi: 10.1093/toxsci/kfz207.
In mice, gestational exposure to (BP)A analogues, BPE and BPS, with examination of transgenerational effects on male reproductive functions. In F3 males, exposure to BPA, BPE and BPS decreased sperm counts and/or motility and disrupted the progression of germ cell development as morphometric analyses exhibited an abnormal distribution of the stages of spermatogenesis in F3 males. Dysregulated serum levels of estradiol-17β and testosterone, as well as expression of steroidogenic enzymes in F3 adult testis were also observed. The results suggest that prenatal exposure to BPA, BPE and BPS induces transgenerational effects on male reproductive functions probably due to altered epigenetic modification following disruption of DNMTs and histone marks in the neonatal and/or adult testis.
Sadler-Riggleman I, et al. Epigenetic transgenerational inheritance of testis pathology and Sertoli cell epimutations: generational origins of male infertility. Environ Epigenet. 2019 Aug 29;5(3):dvz013. doi: 10.1093/eep/dvz013.
In rats, gestating females were transiently exposed to DDT, vinclozolin. DNA and RNA were obtained from purified Sertoli cells isolated from postnatal 20-day-old male testis of F3 generation rats. Transgenerational alterations in DNA methylation, noncoding RNA, and gene expression were observed in the Sertoli cells from vinclozolin and DDT lineages when compared to the control lineage, suggesting ancestral exposures to environmental toxicants promote the epigenetic transgenerational inheritance of Sertoli cell epigenetic and transcriptome alterations that associate with testis abnormalities.
Manikkam M, et al. Dioxin (TCDD) Induces Epigenetic Transgenerational Inheritance of Adult Onset Disease and Sperm Epimutations. PLoS One 2012:e46249.
In a rat model, gestating females were exposed to dioxin, increasing the incidences of multiple diseases in subsequent generations, including kidney disease in males, pubertal abnormalities in females, ovarian primordial follicle loss and polycystic ovary disease. Analysis of the F3 sperm epigenome identified 50 differentially DNA methylated regions in gene promoters.
Bruner-Tran KL, et al. Developmental exposure to TCDD reduces fertility and negatively affects pregnancy outcomes across multiple generations. Reprod Toxicol. 2011;31:344–50.
Bruner-Tran KL, et al. Developmental exposure of mice to dioxin promotes transgenerational testicular inflammation and an increased risk of preterm birth in unexposed mating partners. PLoS One 2014;9, e105084.
Bruner-Tran, KL, et al. Developmental toxicant exposure is associated with transgenerational adenomyosis in a murine model. Biol Reprod. 2016;95 (4), 73.
Sanabria, M, et al. Sperm quality and fertility in rats after prenatal exposure to low doses of tcdd: a three-generation study. Reprod. Toxicol. 2016;65:29–38.
In rat model, fetal exposure to low doses of TCDD negatively effected epididymal processes, sperm quality and fertility in subsequent generations.
Choi CS, et al. The transgenerational inheritance of autism-like phenotypes in mice exposed to valproic acid during pregnancy. Sci Rep 2016; 6:36250.
In a mouse model, valproic acid (an anti-convulsant drug) induced epigenetic inheritance of autism-like neurobehavioural phenotype in mice through the paternal germline in first and second generation.
Cipriani C, et al. High expression of Endogenous Retroviruses from intrauterine life to adulthood in two mouse models of Autism Spectrum Disorders. Sci Rep 2018 8(1):629
In a mouse model, findings of a transgenerational effect of prenatal valproic acid exposure. In the second and third generation, more marked transcriptional effects were seen in offspring from females, compared to paternal lineages.
Tartaglione AM, et al. Early Behavioral Alterations and Increased Expression of Endogenous Retroviruses Are Inherited Across Generations in Mice Prenatally Exposed to Valproic Acid. Mol Neurobiol 2018, 1-15, https://doi.org/10.1007/s12035-018-1328-x
Ibi D, et al. Paternal valproic acid exposure in mice triggers behavioral alterations in offspring. Neurotox Toxicol 2019. https://doi.org/10.1016/j.ntt.2019.106837.
Paternal VPA exposure increased the levels of acetylated histone H3 in the testicular tubules of sires; down-regulated the levels of acetylated histone H3 in the brain in adult offspring; caused behavioral abnormalities in adult offspring.
Glen CD, et al. Exposure to anticancer drugs can result in transgenerational genomic instability in mice. Proc Natl Acad Sci 2012;109(8):2984–2988.
In a mouse model, paternal exposure to a commonly used chemotherapeutic agents resulted in increased mutation rates and transgenerational instability. (De novo mutagenesis, not epigenetic per se, was investigated.)
Chan D et al. Epigenetic alterations in sperm DNA associated with testicular cancer treatment. Toxicol Sci 2012;125(2):532–543.
In a rat model, treatment with chemotherapeutic agent resulted in DNA methylation alterations in sperm. This study did not investigate resulting phenotype in offspring borne of the epigenetically altered sperm.
Prokopuk, L, Hogg K, Western PS. 2018. Pharmacological inhibition of EZH2 disrupts the female germline epigenome. Clin Epigenetics 10:33.
In mice, inhibition of EZH1/2 with the clinically relevant drug, tazemetostat, severely depletes H3K27me3 in growing oocytes of adult female mice. Moreover, EZH2 inhibition depleted H3K27me3 in primary oocytes and in fetal oocytes undergoing epigenetic reprogramming. Once depleted, H3K27me3 failed to recover in growing oocytes or in fetal oocytes. Together, these data demonstrate that drugs targeting EZH2 significantly affect the germline epigenome and, based on genetic models with oocyte-specific loss of EZH2 function, are likely to affect outcomes in offspring.
Stefansdottir A, et al. Etoposide damages female germ cells in the developing ovary. BMC Cancer 2016;16(1):482.
(Note: This is an F1 germ cell study, not an F2 phenotype study.) In a mouse model, the anti-cancer drug and topoisomerase II inhibitor etoposide was examined for effect on germ cells in the developing fetal ovary. Exposure of pre-follicular ovaries, in which topoisomerase IIα expression was germ cell-specific, resulted in a near-complete elimination of germ cells prior to follicle formation, with the remaining germ cells going on to form unhealthy follicles by the end of culture. In contrast, exposure to follicle-enclosed oocytes, which no longer expressed topoisomerase IIα in the germ cells, had no effect on total follicle numbers or health, the only effect seen specific to transitional follicles.
Adams PM, et al. Cyclophosphamide induced spermatogenetic effects detected in the Fl generation by behavioral testing. Science 1981; 211:80-83.
Postmeiotic exposure of the male rat gamete to cyclophosphamide led to behavioral abnormalities in the prepubertal progeny.
Adams PM, et al. Active avoidance behavior in the Fl progeny of male rats exposed to cyclophosphamide prior to fertilization. Neurobehav Toxicol Teratol 1982; 4:531-534.
Postmeiotic exposure of the male rat gamete to cyclophosphamide led to behavioral abnormalities in the prepubertal progeny.
Fabricant JD, et al. Post-meiotic cell mediation of behavior in progeny of male rats treated with cyclophosphamide. Mutat Res 1983; 119:185-190.
Postmeiotic exposure of the male rat gamete to cyclophosphamide led to behavioral abnormalities in the prepubertal progeny.
Auroux M, et al. Cyclophosphamide in the male rat: behavioral effects in the adult offspring. Behav Brain Res 1985;16:25-36.
When mating of male rat exposed to cyclophosphamide occurred 100 days after the end of the treatment, only learning impairment, and not learning impairment and postnatal death, was observed.
Auroux M, et al. Antimitotic drugs (cyclophosphamide and vinblastine) in the male rat: deaths and behavioral abnormalities in the offspring. J Androl 1986; 7:378-386.
A premeiotic exposure of male rat gamete to cyclophosphamide. Deleterious effects seemed more obvious when the treated male rats were mated soon after the treatment period; when mating occurred 60 days after the end of the treatment, they observed postnatal deaths in the offspring and the survivors later exhibited decreased spontaneous activity as well as decreased learning ability .
Auroux MR, et al. Antimitotic drugs in the male rat. Behavioral abnormalities in the second generation. J. Androl. 1988;9, 153–159.
Auroux MR, et al. Cyclophosphamide in the male rat: cerebral biochemical changes in progeny. Biomed Pharmacother 1990;44:519–523.
Dulioust EJ, et al. Cyclophosphamide in the male rat: new pattern of anomalies in the third generation. J Androl 1989;10:296–303.
Taylor JD, Baumgartner A, Schmid TE, Brinkworth MH. Responses to genotoxicity in mouse testicular germ cells and epididymal spermatozoa are affected by increased age. Toxicol Letters 2019; 310:1-6. Acute 150 mg/kg CP treatment increased SCSA-detectable chromatin damage in mouse sperm. Old animals were more susceptible to CP-induced sperm chromatin damage than young.
Acute 150 mg/kg CP treatment increased apoptosis more in young animals than in old.
Vaisheva F, Delbes G, Hales BF, Robaire B. (2007). Effects of the chemotherapeutic agents for non-Hodgkin lymphoma, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), on the male rat reproductive system and progeny outcome. J Androl 28:578–87
[Google Scholar] (Note: not a phenotypic outcome study)
Tracey R, et al. Hydrocarbons (jet fuel JP-8) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. Reprod Toxicol. 2013;36:104–16.
Stockard CR, et al. Further studies on the modification of the germ-cells in mammals: the effect of alcohol on treated Guinea pigs and their descendants. J Exp Zool 1918;26:119–226.
Abbott CW, et al. Prenatal ethanol exposure and neocortical development: a transgenerational model of FASD. Cereb Cortex 2017;1–14, bhx168.
Govorko D, et al. Male germline transmits fetal alcohol adverse effect on hypothalamic proopiomelanocortin gene across generations. Biol Psychiatry 2012;72:378–88.
In a rat model, fetal alcohol-induced gene methylation, expression, and functional defects persisted in the F2 and F3 male but not in female germline.
Chang RC, et al. Preconception paternal alcohol exposure exerts sex-specific effects on offspring growth and long-term metabolic programming. Epigenetics & Chromatin 2019:12:9.
Preconception paternal alcohol exposure induced a prolonged period of fetal gestation and an increased incidence of intrauterine growth restriction, which affected the male offspring to a greater extent than the females. Growth deficits associated with insulin hypersensitivity in the male offspring. These metabolic defects were associated with an up-regulation of genes within the pro-fibrotic TGF-β signaling pathway and increased levels of cellular hydroxyproline within the livers of the male offspring. We observed suppressed cytokine profiles within the liver and pancreas of both the male and female offspring, which correlated with the up-regulation of genes in the LiverX/RetinoidX/FarnesoidX receptor pathways.
Bedi Y, et al. Alterations in sperm-inherited noncoding RNAs associate with late-term fetal growth restriction induced by preconception paternal alcohol use. Reproductive Toxicology 2019; https://doi.org/10.1016/j.reprotox.2019.04.006.
Chronic preconception paternal alcohol exposure associates with late-term fetal growth restriction and a loss of placental efficiency in the offspring. The model of chronic alcohol consumption employed in this study did not impact macro-measures of male reproductive physiology or negatively affect fertility. Chronic alcohol use alters the ratio of transfer RNA-derived small RNAs to Piwi-interacting RNAs, which has recently been identified as a core facet of the epigenetic maturation of sperm. Chronic alcohol exposure induces a 30% increase in the abundance of sperminherited miRNAs, with miR21, miR30 and miR142 exhibiting the greatest changes. Although our data share some similarities to recent work examining stressinduced changes in paternally-inherited miRNAs, we did not observe any differences in the levels of plasma corticosterone, indicating a novel mechanism underlies the observed changes.
Chastain LG, Sarkar DK. Alcohol effects on the epigenome in the germline: role in the inheritance of alcohol-related pathology. Alcohol 2017;60:53–66.
Abel EL. Paternal alcohol consumption affects grooming response in rat offspring. Alcohol 1991;8:21–23.
Wozniak DF, Cicero TJ, Kettinger L 3rd, Meyer ER. Paternal alcohol consumption in the rat impairs spatial learning performance in male offspring. Psychopharmacology 1991;105:289–302
Pentinat T, et al. Transgenerational inheritance of glucose intolerance in a mouse model of neonatal overnutrition. Endocrinology 2010;151:5617–5623.
Ng, SF, et al. Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 2010;467:963-6.
In a rat model, a paternal high-fat-diet programs β-cell ‘dysfunction’ in rat F1 female offspring. Chronic HFD consumption in Sprague–Dawley fathers induced increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had an early onset of impaired insulin secretion and glucose tolerance that worsened with time, and normal adiposity. Many genes were found to be dysregulated in offspring.
Carone, BR, et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 2010;143, 1084-96.
In a mouse model, offspring of males fed a low-protein diet exhibited elevated hepatic expression of many genes involved in lipid and cholesterol biosynthesis and decreased levels of cholesterol esters, relative to the offspring of males fed a control diet. Epigenomic profiling of offspring livers revealed numerous modest (∼20%) changes in cytosine methylation depending on paternal diet, including reproducible changes in methylation over a likely enhancer for the key lipid regulator Ppara.
Dunn, GA et al. Maternal high-fat diet effects on third-generation female body size via the paternal lineage. Endocrinology 2011;152, 2228–2236.
In a mouse model, a high-fat diet in gestation resulted in larger F3 female offspring. A potential dynamic pattern of paternally expressed genes from the paternal lineage was seen at an imprinted locus, thereby providing sex specificity to both the transmission and inheritance of traits related to disease predisposition.
Radford, E.J. et al. In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 2014;345,1255903.
In a mouse model, prenatal undernutrition could compromise male germline epigenetic reprogramming and permanently alter DNA methylation in the sperm of adult offspring at regions resistant to zygotic reprogramming. However, persistence of altered DNA methylation into late-gestation somatic tissues of the subsequent generation was not observed.
Cissé O, et al. Effect of diet in females (F1) from prenatally undernourished mothers on metabolism and liver function in the F2 progeny is sex-specific. Eur J Nutr 2018;1–13. https://doi.org/10.1007/s00394-018-1794-y
Sarker G, et al. Transgenerational transmission of hedonic behaviors and metabolic phenotypes induced by maternal overnutrition. Translat Psych 2018;8:195.
In a mouse model, maternal HFD insult causes sustained alterations of the mesolimbic dopaminergic system suggestive of a predisposition to develop obesity and addictive-like behaviors across multiple generations.
Rea J et al. Intrauterine hyperglycemia exposure results in intergenerational inheritance via DNA methylation reprogramming on F1 PGCs. Epigenetics & Chromatin 2018; 11:20.
In mice, intrauterine hyperglycemia exposure per se contributes to intergenerational metabolic changes in the F2 but not F3 generation. And the aberrant DNA methylation reprogramming occurs as early as day 13.5 in PGCs of the F1 generation. Our findings suggest that intrauterine exposure alone is sufficient to cause the epigenetic inheritance in F2 offspring, and the epigenetic memory carried by DNA methylation pattern could be erased by the second wave of methylation reprogramming in F2 PGCs during fetal development.
Zhang Z et al. Intrauterine Growth Restriction Programs Intergenerational Transmission of Pulmonary Arterial Hypertension and Endothelial Dysfunction via Sperm Epigenetic Modifications. Hypertension 2019;74:1160–1171. https://doi.org/10.1161/HYPERTENSIONAHA.119.13634
Using a model of maternal caloric restriction to induce IUGR, first and second generations exhibited elevated pulmonary arterial pressure, myocardial, and vascular remodeling after prolonged exposure to hypoxia. Primary pulmonary vascular endothelial cells (PVECs) from both first and second generations of IUGR exhibited greater proliferation, migration, and angiogenesis. The results suggested that IUGR permanently altered epigenetic signatures of ET-1 from the sperm and PVECs in the first generation, which was subsequently transferred to PVECs of offspring. This mechanism would yield 2 generations with endothelial dysfunction and pulmonary arterial hypertension–like pathophysiological features in adulthood.
Fusco S, et al. Maternal insulin resistance multigenerationally impairs synaptic plasticity and memory via gametic mechanisms. Nat Commun 2019:10;4799.
Maternal high-fat diet-dependent insulin resistance multigenerationally impairs descendants' synaptic plasticity, learning and memory via gametic mechanisms.
Dias, BG et al. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci 2014;17, 89–96.
In a mouse model, pre-conception adult mice were subjected to odor fear conditioning, with behavioral, neuroanatomical, and epigenomic consequences in unexposed pups and grandpups.
Schell CJ, et al. Parental habituation to human disturbance over time reduces fear of humans in coyote offspring. Ecol and Evol 2018. doi: 10.1002/ece3.4741
Human-observed captive coyote parents demonstrated habituation to risk in second litters. Second‐litter pups were also less risk‐averse than their first‐litter siblings, suggesting parental habituation may be an ecological cue for offspring to reduce their fear response, thus emphasizing the role of parental plasticity in shaping their pups’ behavioral and hormonal responses toward humans.
Weber-Stadlbauer, U. et al. Transgenerational transmission and modification of pathological traits induced by prenatal immune activation. Mol Psychiatry 2017; 22:102-112.
In a mouse model, prenatal immune activation by the viral mimetic poly(I:C) resulted in alterations in brain and behavioral functions in multiple generations. Reduced sociability and increased cued fear expression in first- and second-generation offspring were observed, in addition to other sex-specific effects. Genome-wide transcriptional changes were also seen.
Chronic stress/traumatic experience
Morgan, CP, et al. Early Prenatal Stress Epigenetically Programs Dysmasculinization in Second-Generation Offspring via the Paternal Lineage. J Neurosci. 2011,:31(33):11748-11755.
Rodgers, AB, et al. Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation. J Neurosci 2013;33:9003–9012.
In a mouse model, males were exposed to six weeks of chronic stress before breeding. Offspring displayed significantly reduced HPA stress axis responsivity. Changes in transcription were seen in the brain, suggestive of epigenetic reprogramming and consistent with altered offspring stress responsivity, including increased expression of glucocorticoid-responsive genes in the PVN. In examining potential epigenetic mechanisms of germ cell transmission, robust changes in sperm microRNA were found.
Rodgers, AB, et al. Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. Proc Natl Acad Sci USA 2015;112,13699–13704.
In a mouse model, after males were exposed to chronic stress, sperm miRNAs were found postfertilization to alter offspring stress responsivity. Also zygote microinjection of the miRs, demonstrated a recapitulation of the offspring stress dysregulation phenotype.
Gapp, K. et al. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat Neurosci 2014;17, 667–669.
In a mouse model, traumatic stress in early life altered mouse microRNA expression, and behavioral and metabolic responses in the progeny. Injection of sperm RNAs from traumatized males into fertilized wild-type oocytes reproduced the behavioral and metabolic alterations in the resulting offspring.
Franklin, TB, et al. Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry 2010; 68, 408–15.
In a mouse model, mice were exposed to chronic and unpredictable maternal separation from postnatal day 1 to 14. Alterations in the profile of DNA methylation in the promoter of several candidate genes in the germline of the separated males were observed. Comparable changes in DNA methylation are also present in the brain of the offspring and are associated with altered gene expression.
Weiss, IC, et al. Inheritable effect of unpredictable maternal separation on behavioral responses in mice. Front Behav Neurosci 2011; 5,3.
In a mouse model, unpredictable maternal separation from birth to postnatal day 14 in C57Bl/6J mice has mild behavioral effects in the animals when adult, but that its combination with maternal stress exacerbates this effect. Further, the behavioral deficits are transmitted to the following generation through females, an effect that is independent of maternal care and is not affected by cross-fostering. The combined manipulation does not alter basic components of the hypothalamic–pituitary–adrenal axis but decreases the expression of the corticotropin releasing factor receptor 2 (CRFR2) in several nuclei of the amygdala and the hypothalamus in the brain of maternal-separated females.
Bohacek, J. et al. Pathological brain plasticity and cognition in the offspring of males subjected to postnatal traumatic stress. Mol. Psychiatry 2014; doi:10.1038/mp.2014.80
In a mouse model, males subjected to postnatal traumatic stress have offspring with defects associated with impaired long-term memory. The expression in offspring of brain-specific signaling component in the hippocampus is reduced in the offspring, and DNA methylation at its promoter is altered both in the hippocampus of the offspring and the sperm of fathers.
Razoux, F. et al. Transgenerational disruption of functional 5-HT1AR-induced connectivity in the adult mouse brain by traumatic stress in early life. Mol. Psychiatry 2016. doi:10.1038/mp.2016.146
In a mouse model, traumatic stress in postnatal life alters 5-HT1A receptor-evoked local and global functions in progeny of the exposed animals. Disrupted functional connectivity is consistent across generations and match limbic circuits implicated in mood disorders.
Kinnally EL, et al. Paternal line effects of early experiences persist across three generations in rhesus macaques. Dev Psychobiol. 2018. https://doi.org/10.1002/dev.21771
Dumeige L, et al. Epigenetic programming of transgenerational hypertension in preterm birth mice. Endocrine Abstracts (2019) 63 OC12.2 | DOI: 10.1530/endoabs.63.OC12.2
In mice, significant increased blood pressure was found in the F2 and F3 males, descendants of the preterm birth group, concomitantly with increased renal Gilz mRNA expression, despite similar MR or GR expression, and plasma aldosterone or corticosterone levels. Gilz promoter methylation was reduced in preterm offspring with a negative correlation between methylation and expression (P=0.008), highly suggestive of an epigenetic Gilz regulation. Our study demonstrates prematurity-related alterations of renal corticosteroid signaling pathways, with a transgenerational inheritance of blood pressure dysregulation and epigenetic Gilz regulation up to the third generation. This study should allow a better understanding of molecular mechanisms involved in essential hypertension, which could partly be due to perinatal epigenetic programming from previous generations.
Folate metabolism/ Folic acid
Padmanabhan N, Jia D, Geary-Joo C, Wu X, Ferguson-Smith AC, Fung E, Bieda M, Snyder FF, Gravel RA, Cross JC, Watson ED, (2013), Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development, Cell, 155(1): 81-93
Patel, N.J., Hogan, K.J., Rizk, E. et al. Ancestral Folate Promotes Neuronal Regeneration in Serial Generations of Progeny. Mol Neurobiol (2020) doi:10.1007/s12035-019-01812-5.
Toschi P. et a. Maternal peri-conceptional undernourishment perturbs offspring sperm methylome.
• Tobacco impacts on germ cell integrity
• Diethylstilbestrol (DES)
• Chemotherapeutic agents
• Chronic stress/trauma
• Food supply/obesity
Golding J, et al. Grand-maternal smoking in pregnancy and grandchild’s autistic traits and diagnosed autism. Sci Rep 2017;7:46179.
This study of the ALSPAC cohort found significantly higher risk of autism and autism-related traits in the grandchildren of women who smoked cigarettes during pregnancy, through the exposed females.
Accordini S, et al. A three-generation study on the association of tobacco smoking with asthma, Int. J. Epidemiology 2018;dyy031, https://doi.org/10.1093/ije/dyy031
Based on data from the European Community Respiratory Health Survey III, fathers’ smoking before the age of 15 was associated with an increased risk of asthma without nasal allergies in their offspring, suggesting an effect of paternal pre-adolescent environment on the next generation. Grandmothers’ smoking during pregnancy was associated with an increased risk of asthma with nasal allergies in their grandchildren within the maternal line, suggesting a multi-generation effect of tobacco smoking.
Li YF, et al. Maternal and grandmaternal smoking patterns are associated with early childhood asthma. Chest. 2005;127:1232–41.
In a case-controlled study from Southern California, grandmaternal smoking during the mother’s fetal period was associated with increased asthma risk in her grandchildren.
Magnus MC, et al. Grandmother's smoking when pregnant with the mother and asthma in the grandchild: the Norwegian Mother and Child Cohort Study. Thorax 2015;70:237-243.
The grandmother's smoking when pregnant with the mother increased the risk of asthma in the grandchild independent of the mother's smoking status.
Lodge CJ, et al. Grandmaternal smoking increases asthma risk in grandchildren: a nationwide Swedish cohort. Clin. Exp. Allergy. 2018;48:167–74.
Children had an increased risk of asthma in the first 6 years of life if their grandmothers smoked during early pregnancy, independent of maternal smoking. This exhibited a dose‐response relationship and was associated with a persistent childhood asthma phenotype.
Miller LL, et al. Do Grandmaternal Smoking Patterns Influence the Etiology of Childhood Asthma? Chest 2014;145(6)1213-1318.
In ALSPAC cohort, no association with asthma in relation to maternal prenatal exposure. Some evidence of an increase in asthma risk with paternal prenatal exposure when the study mother was a nonsmoker, a finding particularly strong for girls.
Wu C-C, et al. Paternal Tobacco Smoke Correlated to Offspring Asthma and Prenatal Epigenetic Programming. 2019. Frontiers in Genetics doi: 10.3389/fgene.2019.00471
Preconception paternal tobacco smoking increases CG methylation contents of immune genes, such as LMO2 and IL-10, which significantly retained from newborn stage to 6 years of age and correlated to development of childhood asthma. Modulation of the LMO2 and IL-10 CG methylation and/or their gene expression may provide a regimen for early prevention of PTS-associated childhood asthma.
Williams et al. Grandmothers’ smoking in pregnancy is associated with a reduced prevalence of early-onset myopia. Sci Rep 2019:9; 15413.
Hall A, Northstone K, Iles-Caven Y, Ellis G, Gregory S, Golding J, et al. (2020) Intolerance of loud sounds in childhood: Is there an intergenerational association with grandmaternal smoking in pregnancy? PLoS ONE 15(2): e0229323. https://doi.org/10.1371/journal.pone.0229323
We hypothesised that there would be sex differences in the effects of grandmaternal prenatal smoking, based on previous intergenerational studies. For 6-year-old children maternal report of intolerance to loud noise was more likely in grandsons if the maternal grandmother had smoked.
Tobacco impacts on germ cell integrity (selected)
Cheng SF, et al. Nicotine exposure impairs germ cell development in human fetal ovaries cultured in vitro. Aging 2018 Jul 12;10(7):1556-1574. Exposure to nicotine in vitro resulted in the marked increase of apoptosis in the ovaries in a time and dose-dependent manner. Evidence that adverse nicotine effects are potentially due to an increased level of reactive oxygen species (ROS) and consequent DNA damage, both in the ovarian somatic cells and germ cells, are reported.
Jenkins TG, et al. Cigarette smoking significantly alters sperm DNA methylation patterns. Andrology 2017 Nov;5(6):1089-1099.
Asare-Anane H, et al. Tobacco smoking is associated with decreased semen quality. Reprod Health. 2016 5;13(1):90.
Results demonstrated a decline in semen quality in a dose dependent tobacco smoking manner. Smokers had significantly lower semen volume, sperm concentration, sperm motility, total spermcount, sperm morphology, free testosterone and follicle stimulating hormone (p <0.05 respectively), compared with non-smokers. Smokers were at a higher risk of developing oligospermia, asthenozoospermia and teratozoospermia than non-smokers.
Marczylo EL, et al. Smoking induces differential miRNA expression in human spermatozoa: a potential transgenerational epigenetic concern? Epigenetics 2012;7:432–39.
Cigarette smoke was found to induce specific differences in the spermatozoal microRNA content of human smokers compared with non-smokers. The altered microRNAs appeared to predominantly mediate pathways vital for healthy sperm and normal embryo development, particularly cell death and apoptosis.
Mamsen LS, et al. Cigarette smoking during early pregnancy reduces the number of embryonic germ and somatic cells. Human Reproduction 2010;25(11):2755–2761.
Hammadeh, ME, et al. Protamine contents and P1/P2 ratio in human spermatozoa from smokers and non-smokers. Human Reproduction 2010;25(11);2708–2720.
Rahman R et al. Semen quality of young men in Switzerland: a nationwide cross-sectional population-based study. Andrology. 2019 May 21. doi: 10.1111/andr.12645. [Epub ahead of print]
A larger proportion of men with poor semen quality had been exposed in utero to maternal smoking. Overall, a significant proportion of Swiss young men display suboptimal semen quality with only 38% having sperm concentration, motility, and morphology values that met WHO semen reference criteria.
Northstone K, Golding J, Davey Smith G, Miller LL, Pembrey M. Prepubertal start of father's smoking and increased body fat in his sons: further characterisation of paternal transgenerational responses. Eur J Hum Genet 2014;22:1382–6.
Titus L, et al. Reproductive and hormone-related outcomes in women whose mothers were exposed in utero to diethylstilbestrol (DES): A report from the US National Cancer Institute DES Third Generation Study. Report Toxic 2019;84:32-38.
Assessed DES exposure in relation to outcomes in a cohort of F2s whose F1 mothers were prenatally DES-exposed and unexposed. The F2 women have increased risks of menstrual aberrations, preterm birth, and possibly ectopic pregnancy, suggesting an intergenerational effect of endocrine disrupting chemicals in humans.
Kioumourtzoglou M, et al. Association of Exposure to Diethylstilbestrol During Pregnancy With Multigenerational Neurodevelopmental Deficits. JAMA Pediatr published online May 2018.
This study of 47,450 women in the Nurses’ Health Study II found significantly elevated odds for ADHD in the grandchildren of women who took the toxic synthetic hormone drug DES (diethylstilbestrol) during pregnancy.
• Also see JAMA Peds commentary: Nigg, J Toward an Emerging Paradigm for Understanding Attention Deficit Hyperactivity Disorder and Other Neurodevelopmental, Mental, and Behavioral Disorders: Environmental Risks and Epigenetic Associations, JAMA Pediatr. 2018;172(7):619-621. (“If disorders like ADHD are epigenetic conditions [that is, dependent on or heavily modulated by discoverable epigenetic changes that are traceable to preventable environmental exposures], it would have powerful implications for where national research dollars should focus to find ways to reduce the incidence of ADHD and other mental disorders.”)
Tournaire M, et al. Birth defects in children of men exposed in utero to diethylstilbestrol (DES), Therapie, March 3, 2018.
The study suggests an increased incidence of two male genital tract defects in sons of men prenatally exposed to DES. This intergenerational effect had already been observed in animals and in the offspring of women prenatally exposed to DES.
Tournaire, M, et al. Adverse health effects in children of women exposed in utero to diethylstilbestrol (DES) Effets indésirables chez les enfants de femmes exposées au diéthylstilbestrol (DES) in utero. Thérapie 2016;71(4):395-404.
A global increase of defects in children born to women exposed to DES in utero when compared with those born to unexposed and with the general population. Increased defects were observed in male genital tract, esophagus, lip or palate, musculoskeletal and circulatory systems.
Kalfa N, et al. Prevalence of hypospadias in grandsons of women exposed to diethylstilbestrol during pregnancy: a multigenerational national cohort study. Fertil Steril 2011;95(8):2574-2577.
This nationwide cohort study in collaboration with a French association of DES-exposed women studied 529 families and showed that a significant proportion of boys born to DES daughters exhibited hypospadias.
Titus-Ernstoff L, et al. Birth defects in the sons and daughters of women who were exposed in utero to diethylstilbestrol (DES). Int J Androl 2010;33:377–84.
Data suggest a possible association between the mother’s prenatal DES exposure and birth defects in their offspring, particularly in daughters. We cannot, however, rule‐out the possible influence of reporting bias. In particular, the exposed daughters’ elevated risk of cardiac defects may be as a result of the underreporting of these conditions by unexposed mothers.
Brouwers MM, et al. Hypospadias: a transgenerational effect of diethylstilbestrol? Hum Reprod 2006;21(3):666-669.
An increased risk of hypospadias was observed when mothers were exposed to DES in utero. However, the excess risk appears to be of much smaller magnitude than in the 2002 study (below).
Titus-Ernstoff L, et al. Menstrual and reproductive characteristics of women whose mothers were exposed in utero to diethylstilbestrol (DES). Int J Epidemiol 2006;35 (4):862-868.
Found menstrual irregularity and possible infertility in granddaughters of women who took DES in pregnancy. "
Titus-Ernstoff L, et al. Offspring of women exposed in utero to diethylstilbestrol (DES): a preliminary report of benign and malignant pathology in the third generation. Epidemiology 2008;19:251–7.
Based on a small number the risk of ovarian cancer was higher in daughters of women prenatally exposed to DES.
Klip H, et al. Hypospadias in sons of women exposed to diethylstilbestrol in utero: a cohort study. Lancet 2002;359(9312):1102-1107.
Found an increased risk of hypospadias in the sons of women exposed to DES in utero, though the absolute risk was small.
Shnorhavorian, M, et al. Differential DNA methylation regions in adult human sperm following adolescent chemotherapy: potential for epigenetic inheritance, PloS One 2017;12(2)journal.pone.0170085.
Adolescent chemotherapy exposure promoted epigenetic alterations that persisted approximately ten years after exposure. A signature of statistically significant DMRs was identified in the exposed males, found in CpG desert regions of primarily 1 kilobase size. This study did not investigate phenotypic outcomes in the next generation.
Patel B, et al. Transgenerational effects of chemotherapy: Both male and female children born to women exposed to chemotherapy have fewer children. Cancer Epidemiology October 2018;56:1-5.
The sons and daughters (F1 generation) of chemotherapy-exposed women have fewer (74-77% fewer) live births when compared to both matched, unexposed general population and cousin controls.
Sundquist et al. Autism and attention-deficit/hyperactivity disorder among individuals with a family history of alcohol use disorders. eLife 2014. https://doi.org/10.7554/eLife.02917.001
Examination whether the risks of autism and ADHD are increased among individuals with a family history of alcohol use disorders (AUDs). The standardized incidence ratios (SIRs) of autism and ADHD among individuals with a biological parental history of AUDs were 1.39 (95% CI 1.34–1.44) and 2.19 (95% CI 2.15–2.23), respectively, compared to individuals without an affected parent. Among offspring whose parents were diagnosed with AUDs before their birth, the corresponding risks were 1.46 (95% CI 1.36–1.58) and 2.70 (95% CI 2.59–2.81), respectively.
Sen A, et al. Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren Sci Rep 2015;5:14466.
Lead exposure in pregnant mothers can have an epigenetic effect on the DNA methylation pattern in the grandchildren.
Serpeloni F, et al. Grandmaternal stress during pregnancy and DNA methylation of the third generation: an epigenome-wide association study. Transl Psychiatry 2017;7(8):e1202.
In small study from a Brazilian cohort, grandmaternal exposure to psychosocial stress during pregnancy affected DNA methylation of the grandchildren.
Pembrey ME, et al. Sex-specific, male-line transgenerational responses in humans.
Eur J Hum Genet. 2006;14(2):159-66.
Study of Överkalix cohorts, Sweden showed paternal grandfather’s food supply was linked to the mortality of grandsons; paternal grandmother’s food supply was associated with the granddaughters’ mortality.
Bygren LO, et al. Change in paternal grandmothers' early food supply influenced cardiovascular mortality of the female grandchildren. BMC Genet. 2014;15:12.
Sex-linked increased risk for cardiovascular mortality associated with change in food availability of paternal grandmother.
Vågerö D, et al. Paternal grandfather’s access to food predicts all-cause and cancer mortality in grandsons. Nat Comms 2018 9;5124.
Pre-pubertal nutritional experience may trigger a sex-specific transgenerational response along the male line. Harvest data in G0 (n = 9,039) was examined for association with mortality in children (G1, n = 7,280) and grandchildren (G2, n = 11,561) in the Uppsala Multigeneration Study. We find support for the main Överkalix finding: paternal grandfather’s food access in pre-puberty predicts his male, but not female, grandchildren’s all-cause mortality. In our study, cancer mortality contributes strongly to this pattern. We are unable to reproduce previous results for diabetes and cardiovascular mortality.
Johannessen et al. Overweight in childhood, puberty or early adulthood: changing the asthma risk in the next generation? J Allergy and Clinical Immunol 2019. https://doi.org/10.1016/j.jaci.2019.08.030
Selected mechanism papers
Sharma U, et al. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 31 January 2015.
Grandjean V, et al. RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders. Sci Rep 2015;5:18193.
Mitchell, E, et al. Behavioural traits propagate across generations via segregated iterative-somatic and gametic epigenetic mechanisms. Nat Comms 2016;7: 11492 (2016)
Huypens P, et al. Epigenetic germline inheritance of diet-induced obesity and insulin resistance. Nat Genetics 2016;48:497-499.
Dickson DA, et al. Reduced levels of miRNAs 449 and 34 in sperm of mice and men exposed to early life stress. Translational Psychiatry May, 2018.
Zhang Y, et al. Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs. Nat Cell Biol 2018; 20(5):535-540.
Benito E, et al. RNA-Dependent Intergenerational Inheritance of Enhanced Synaptic Plasticity after Environmental Enrichment. Cell Rep 2018; 23(2):546-554.
Gapp K, et al. Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma, BioRxiv 2018;
McCarrey, JR, et al. Tertiary Epimutations – A Novel Aspect of Epigenetic Transgenerational Inheritance Promoting Genome Instability. PLoS ONE 2016;11(12):e0168038.
Lesch BJ, et al. Intergenerational epigenetic inheritance of cancer susceptibility in mammals. eLife 2019;8:e39380. DOI: https://doi.org/10.7554/eLife.39380
Soubry A, Hoyo C, Butt CM, Fieuws S, Price TM, Murphy. SK, Stapleton HM. Human exposure to flame-retardants is associated with aberrant DNA methylation at imprinted genes in sperm.
Environ Epigenet 2017;3:13.
Diaz-Castillo C, et al. Transgenerational Self-Reconstruction of Disrupted Chromatin Organization After Exposure To An Environmental Stressor in Mice. Sci Rep 2019: 9;13057.
Great-great-grandsons of female mice exposed to tributyltin (TBT) throughout pregnancy and lactation were predisposed to obesity due to altered chromatin organization that subsequently biased DNA methylation and gene expression.
DiTroia SP, et al. Maternal vitamin C regulates reprogramming of DNA methylation and germline development. Nature 2019; https://doi.org/10.1038/s41586-019-1536-1.
And, why not throw in some zebrafish?
Kalichak F, et al. Persistent and transgenerational effects of risperidone in zebrafish 2019; Environmental Science and Pollution Research pp 1–11
Knecht AL, et al. Transgenerational inheritance of neurobehavioral and physiological deficits from developmental exposure to benzo[a]pyrene in zebrafish.
Toxicol Appl Pharmacol 2017;329:148–57.
Corrales J, et al. Multigenerational effects of benzo[a]pyrene exposure on survival and developmental deformities in zebrafish larvae. Aquat Toxicol 2014;148:16-26.
Baker TR, et al. Dioxin induction of transgenerational inheritance of disease in zebrafish
Mol Cell Endocrinol 2014;398:36-41.
Xu, N, et al. Early Embryonic Androgen Exposure Induces Transgenerational Epigenetic and Metabolic Changes. Molec Endocrinol 2014;28(8):1329–1336.
Vera-Chang MN, et al. Transgenerational hypocortisolism and behavioral disruption are induced by the antidepressant fluoxetine in male zebrafish Danio rerio. PNAS 2018; https://doi.org/10.1073/pnas.1811695115
A 6-day fluoxetine (antidepressant drug) exposure during early zebrafish development induces hypocortisolism for at least three generations. Gene expression analysis indicates that pathways controlling cortisol synthesis are altered in the descendants in the third generation. This FLX-induced low-cortisol phenotype is more prominent in males and is associated with significantly reduced exploratory behaviors for two generations.
Alfonso S, et al. Examining multi- and transgenerational behavioral and molecular alterations resulting from parental exposure to an environmental PCB and PBDE mixture. Aquat Toxicol. 2018 Dec 28;208:29-38. doi: 10.1016/j.aquatox.2018.12.021
Narod SA et al. Human mutagens: Evidence from paternal exposure? Environ Mol Mutagen 1988.https://doi.org/10.1002/em.2850110311
McLachlan, JA. Commentary: Prenatal exposure to diethylstilbestrol (DES): a continuing story
Int J Epidemiol 2006;35(4):868–870.
Jirtle, RL, et al. Environmental epigenomics and disease susceptibility. Nat Rev Gen 2007; 8:253–262.
Gluckman, PD, et al. Non‐genomic transgenerational inheritance of disease risk
Dunn, GA ,et al. Sex-specificity in transgenerational epigenetic programming. Horm Behav 2011;59:290–295.
Bohacek J, et al, Transgenerational Epigenetic Effects on Brain Functions, Biol Psych 2013;73(4) 313-320.
Bohacek J, et al. Epigenetic Inheritance of Disease and Disease Risk. Neuropsychopharmacology 2013;38:220–236.
Noble, D. Physiology is rocking the foundations of evolutionary biology. Exper Physiol 2014;1235-1243.
Skinner, M. Endocrine disruptor induction of epigenetic transgenerational inheritance of disease. Mol. Cell. Endocrinology 2014;398:4–12.
Barlow DP, et al. Genomic imprinting in mammals. CSH Perspect Biol 2014;6(2).
Soubry A, et al. A paternal environmental legacy: evidence for epigenetic inheritance through the male germ line. Bioessays 2014;36:359–71.
Pembrey, M, et al. Human transgenerational responses to early-life experience: potential impact on development, health and biomedical research. J Med Genet 2014;51:563–572.
Rissman, EF et al. Minireview: Transgenerational Epigenetic Inheritance: Focus on Endocrine Disrupting Compounds. Endocrinology 2014;155(8):2770–2780.
Chamorro-García R, et al. Transgenerational effects of obesogens and the obesity epidemic. Curr Opinion Pharmacol. 2014;19:153-158.
Szyf M. Nongenetic inheritance and transgenerational epigenetics.
Ozgyin, L, et al. Nuclear receptors in transgenerational epigenetic inheritance. Prog Biophys Mol Biol 2015;118:34–43.
Xin, F, et al. Multigenerational and transgenerational effects of endocrine disrupting chemicals: A role for altered epigenetic regulation? Semin Cell Dev Biol 2015;43:66–75.
Bale, TL. Epigenetic and transgenerational reprogramming of brain development. Nat Rev Neurosci 2015;16:332–344.
Hogg et al. Refurbishing the germline epigenome: Out with the old, in with the new. Sem Cell Dev Biol 2015;45:104-113.
Bohacek, J. & Mansuy, I.M. Molecular insights into transgenerational non‐genetic inheritance of acquired behaviours. Nat Rev Genet 2015;16:641–652.
Trerotola M et al., Epigenetic inheritance and the missing heritability. Human Genomics 2015;9:17
Schaefer S and Nadeau JH. The Genetics of Epigenetic Inheritance: Modes, Molecules, and Mechanisms. Quarterly Rev Biol. 2015;9-(4).
Rando, OJ, Intergenerational Transfer of Epigenetic Information in Sperm. Cold Spring Harb Perspect Med. 2016;6(5)
Alonso-Magdalena, P, et al. Bisphenol-A and metabolic diseases: epigenetic, developmental and transgenerational basis. Environ Epigenetics 2016:2.
Marczylo EL et al, Environmentally induced epigenetic toxicity: potential public health concerns. Crit. Rev. Toxicol. 2016;46:8,676-700.
Miska, E. & A. Ferguson-Smith. Transgenerational Inheritance: Models and Mechanisms of non-DNA Sequence-based Inheritance. Science 2016; 354: 59.
Beal MA, et al. From sperm to offspring: Assessing the heritable genetic consequences of paternal smoking and potential public health impacts. Mut. Research/Rev in Mut. Research. 2017;773:26-50.
Fullston, T, et al. The most common vices of men can damage fertility and the health of the next generation. J Endocrinol. 2017;234(2):F1-F6.
Jishi TA, et al. Current perspective of diethylstilbestrol (DES) exposure in mothers and offspring. Repro Toxicol 2017;71:71-77.
Roy, M-C, C. Dupras & V. Ravitsky. The Epigenetic Effects of Assisted Reproductive Technologies: Ethical Considerations. J Dev Orig Health Dis 2017; 8: 436
Sales VM, Ferguson-Smith AC, Patti ME, 2017. Epigenetic mechanisms of transmission of metabolic disease across generations. Cell Metabolism 2017;25(3):559-571.
Gapp K, et al. . Epigenetic germline inheritance in mammals: looking to the past to understand the future. Genes, Brain and Beh 2018;17:3,e12407.
Soubry A. POHaD: why we should study future fathers. Environ Epigenetics 2018; 4:2.
Barouki R, et al. Epigenetics as a mechanism linking developmental exposures to long-term toxicity. Environ Int. 2018;114:77-86.
Knudsen TM, et al. Trans- and inter-generational epigenetic inheritance in allergic diseases. J Allergy and Clinical Immun. 2018;doi.org/10.1016/j.jaci.2018.07.007
Gold HB, et al. Not just heads and tails: the complexity of the sperm epigenome. J Biol Chem. 2018. pii: jbc.R117.001561. doi: 10.1074/jbc.R117.001561.
Nilsson, EE, et al. Environmentally induced epigenetic transgenerational inheritance of disease. Environ Epigenetics. 2018;4(2)
De Felici, et al. Epigenetic Reprogramming in the Mammalian Germ Line: Possible Effects by Endocrine Disruptors on Primordial Germ Cells. Open Biotech J 2018;12, 2018.
Latchney, SE, et al. Linking inter-individual variability to endocrine disruptors: insights for epigenetic inheritance. Mammalian Genome 2018;29(1-2):141-152.
For those seeking an even longer read, a newly published book: Bonduriansky and Day, Extended Heredity, Princeton 2018.
Arah OA, Tobacco smoking and asthma: multigenerational effects, epigenetics and multilevel causal mediation analysis.
Int J Epidem 2018, dyy193, https://doi.org/10.1093/ije/dyy193
Coppola M, et al. Are physicians fully aware of the potential transgenerational and multigenerational effects of a large opioid misuse in the population? J Opioid Management 2018;14(4):237.
Morgan CP, et al. Driving the next generation: Paternal lifetime experiences transmitted via extracellular vesicles and their small RNA cargo. Biol Psychiatry 2018; https://doi.org/10.1016/j.biopsych.2018.09.007.
Hammer B, et al. In utero exposure to cigarette smoke and effects across generations: a conference of animals on asthma. Clin & Exper Allergy 2018; https://doi.org/10.1111/cea.13283
Zimmet P, et al. Epidemic T2DM, early development and epigenetics: implications of the Chinese Famine. Nat Rev Endocrinol (2018)
Siddeek B, et al., Sperm epigenome as a marker of environmental exposure and lifestyle, at the origin of diseases inheritance. Mutation Research 2018;778:38-44.
Kexin Z, et al. Current Advance in Research of Gamete and Embryo-fetal Origins of Adult Diseases. Science China Life Sciences 2018 10.1007/s11427-018-9427-4
Skvortsova K, et al. Functions and mechanisms of epigenetic inheritance in animals. Nat Rev Molec Cell Biol 2018;19:774–790.
Shukla A, et al. Air pollution associated epigenetic modifications: Transgenerational inheritance and underlying molecular mechanisms. Science of the Total Environment 2018. https://doi.org/10.1016/j.scitotenv.2018.11.381Exposure to airborn particulate matter induces derailment of mitochondrial machinery and irreversible changes to the epigenome. These covalent changes may affect diverse range of cell signaling mechanisms and are heritable in nature. Transmission of these epimutations from gametes to zygotes may primarily involve mitochondrial DNA, parental allele imprinting, histone withholding and non coding RNAs.
Lønnebotn M, et al. Environmental Impact on Health across Generations: Policy Meets Biology. A Review of Animal and Human Models. Challenges 2018 9(2), 42; https://doi.org/10.3390/challe9020042
Western P. Epigenomic drugs and the germline: Collateral damage in the home of heritability? Molec Cell Endocrinol 2018;468,:121-133.
Jarred EG, et al. Out of sight, out of mind? Germ cells and the potential impacts of epigenomic drugs. F1000Research 2018, 7(F1000 Faculty Rev):1967 Last updated: 21 DEC 2018
Gilardi F, Augsburger M and Thomas A (2018) Will Widespread Synthetic Opioid Consumption Induce Epigenetic Consequences in Future Generations? Front. Pharmacol. 9:702. doi: 10.3389/fphar.2018.00702
Blake GET, Rakoczy J, Watson ED, (2018) Epigenetics of transgenerational inheritance of disease in T. Tollefsbol (Ed.) Epigenetics in Human Disease, 2nd Edition (pp. 805-836). London: Academic Press, Elsevier
Norouzitallab P, et al. Can epigenetics translate environmental cues into phenotypes? Science Tot. Environ. 2019;647;1281-1293.
Perez MF, et al. Intergenerational and transgenerational epigenetic inheritance in animals. Nature Cell Biology 2019.
Baxter FA, Drake AJ. 2019 Non-genetic inheritance via the male germline in mammals. Phil. Trans. R. Soc. B 374: 20180118.
Patel BV, Hotaling JM,
Impact of chemotherapy on subsequent generations,
Urologic Oncology: Seminars and Original Investigations,
Lewens, T. Blurring the Germline: Genome Editing and Transgenerational Epigenetic Inheritance. Bioethics https://doi.org/10.17863/CAM.37499
Ying Zhang, Qi Chen. The expanding repertoire of hereditary information carriers.
Development 2019 146: dev170902 doi: 10.1242/dev.170902
Escher J and Robotti S. Pregnancy drugs, fetal germline epigenome, and risks for next‐generation pathology: A call to action. Env Mol Mutagen 2019
Brehm E and Flaws AJ. Transgenerational effects of endocrine disrupting chemicals on male and female reproduction. Endocrinology. 2019 Apr 18. pii: en.2019-00034. doi: 10.1210/en.2019-00034. [Epub ahead of print]
Wasserzug-Pash P and Klutstein M. Epigenetic changes in mammalian gametes throughout their lifetime: the four seasons metaphor. 2019;Chromosoma 1-19. Here
Rattan S and Flaws JA. The epigenetic impacts of endocrine disruptors on female reproduction across generations. Biol Reprod. 2019 May 11. pii: ioz081. doi: 10.1093/biolre/ioz081.
JA Camacho, P Allard. Germline and Transgenerational Impacts of Toxicant Exposures. Chapter in Toxicoepigenetics Core Principles and Applications, 2019. Here
Bonde JPE et al. Paternal Environmental Exposure And Offspring Health. 2019. Current Opinion in Endocrine and Metabolic Research here
Nieto SJ and Kosten A. Who’s your daddy? Behavioral and epigenetic consequences of paternal drug exposure. 2019. Int J Dev Neurosci. https://doi.org/10.1016/j.ijdevneu.2019.07.002
Reece AS and Hulse GC. Impacts of cannabinoid epigenetics on human development: reflections on Murphy et. al. ‘cannabinoid exposure and altered DNA methylation in rat and human sperm’ epigenetics 2018; 13: 1208-1221.: Epigenetics: Vol 0, No 0
Rodriguez JB and Sanchez CC. Genetic Damage in Human Spermatozoa: Epigenetic Transgenerational Inheritance 2019. pp 57-74
Konkel L. All in the Family: What Multigenerational Cohorts Are Revealing about Potential Environmental Impacts on Neurodevelopment 2019. Env Health Perspect 127:7.
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