Human and mammal studies finding heritable effects of exposures
A compilation of more than 70 studies demonstrating heritable effects of exposures in mammals and humans. Also noted are selected papers on mechanisms, reviews, perspectives on heritable effects and neurodevelopment, and some studies on zebrafish models.
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 when the pregnant dam was exposed to the tobacco component BaP. Okay slightly off topic, but let’s not forget the importance of de novo mutagenesis in germ cells, which can be precipitated by exposure to mutagenic substances such as BaP. Now back to our program.
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.
Agents of general anesthesia and analgesics
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.
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.
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 sheep 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.
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.
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."
Environmental endocrine disruptors/pesticides/plasticizers
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.
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. Pesticide and insect repellent mixture (Permethrin and DEET) induces epigenetic transgenerational inheritance of disease and sperm epimutations. Reprod Toxicol. 2012;34:708–19.
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.
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.
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 the endocrine disrupting fungide 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.
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.
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.
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)
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
McBirney M, et al. Atrazine induced epigenetic transgenerational inheritance of disease, lean phenotype and sperm epimutation pathology biomarkers. PLoS One 2017;12:e0184306–37.
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.
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.
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.
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.
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.
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.
Odor fear conditioning
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.
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
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.
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.
Tobacco impacts on germ cell integrity (selected)
Jenkins TG, et al. Cigarette smoking significantly alters sperm DNA methylation patterns. Andrology 2017 Nov;5(6):1089-1099.
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.
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.
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. [Yes, some studies I list in this response are new and I know Mitchell is not clairvoyant. Nevertheless they help paint the larger picture.]
• 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.
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.
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).
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.
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. 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.
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.
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, but the topic, and suggestion of possible impairment of offspring, is of such tremendous social importance I felt the need to include it here.
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.
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.
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
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.
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;
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.
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.
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.
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.
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.
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)
For those seeking an even longer read, a newly published book: Bonduriansky and Day, Extended Heredity, Princeton 2018.
Norouzitallab, P, et al. Can epigenetics translate environmental cues into phenotypes? Science Tot. Environ. 2019;647;1281-1293.
And what the heck, why not throw in some zebrafish?
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
Perspectives on Generational Effects and Neurodevelopment
Escher, J. Bugs in the Program: can pregnancy drugs and smoking disturb molecular reprogramming of the fetal germline, increasing heritable risk for autism and neurodevelopmental disorders? Environ Epigenetics 2018;4(2), dvy001.
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.
Gialloreti, EL, et al. Autism Spectrum Disorder: Why Do We Know so Little? Front. Neurol. | doi: 10.3389/fneur.2018.00670