Last weekend I delivered a talk at an autism conference, among the openers for keynote speaker Temple Grandin (sitting with me at left). After the conference we got to chatting and I mentioned my "time bomb" hypothesis of autism and the idea that grandmaternal smoking, for example, increased the risk of autism in grandoffspring via glitches induced in vulnerable fetal germline. "Well," said the legendary author and new inductee to the Women's Hall of Fame, "my mother's mother smoked like a chimney!"

I have lost count of the number of times I've heard this sort of information about autism grandmothers. When I first started interviewing autism parents about their own prenatal exposures about five years ago, my sole focus was the synthetic steroid hormone "anti-miscarriage" treatments like those to which I had been exposed in utero. Yes I found those hormone stories, but most of the responses went something like this: "No, I doubt my mom took any drugs like that, but she was a heavy smoker," or "My mom smoked a pack a day back when she was pregnant with me," or "Both my mom and mother-in-law were smokers," or "My mother-in-law smoked like crazy," or, of course, "My mother smoked like a chimney."

At first I thought nothing of the information, I considered cigarette smoke a mundane and uninteresting fetal exposure compared to the fake hormone protocols my mother was given. But after hearing the smoking story for what seemed like the bazillionth time I did some research to try to connect the dots. And what I found hit me with a wallop: cigarette smoke harbored a long list of toxicants such as benzo[a]pyrene and nicotine, induced mutagenesis and somatic mosaicism, damaged germ cells on many levels, had adverse epigenomic effects on fetal cells, and, from a phenotypic point of view, did direct damage to the fetus, including low birth weight and some evidence of behavioral differences such as ADHD. And there was new evidence from animal models of intergenerational adverse effects of gestational tobacco exposure, including what I would call "mousie ADHD" resulting from nicotine given to the gestating grandma mouse. When paired with the temporality of the autism increase (decades after the parental in utero exposures), the strange socio-demographics of autism, recurrence of ASDs and related pathologies among siblings, and the much-replicated findings of heterogenous de novo mutations, not to mention my somewhat casual surveying of autism families, grandmaternal smoking struck me as a rather formidable hypothesis.

When we ponder tobacco toxicity we tend to think of lung cancer, heart disease and stroke, among other somatic pathologies. And sometimes we even think of the millions of fetuses who were heavily exposed in those decades when pregnancy smoking was not only common, but at times prescribed for the purposes of appetite control or anxiety relief. But what about the vulnerable fetal germ cells simultaneously exposed back then during this critical window of germline synthesis? Had anyone looked?

To my amazement, the answer was pretty much no. And no autism studies were considering the question either. So I decided to make this question a priority even though it was absent from radar when I began my research quest in 2012. I'm happy to report that some of our projects are now looking at neurodevelopmental outcomes in grandoffspring of women who smoked during pregnancy. Knowing this could be a question of national, or international, importance, I have also contacted about a half dozen PIs of various autism cohorts asking (well, let's be honest, begging) them to inquire about grandmaternal smoking as they do their work evaluating either genomics or proximal fetal exposures, and though I don't yet have any takers, I detect growing openness to the question.

One more thing for autism research to consider—the so-called "broader autism phenotype." Are we seeing the BAP in sibs and parents because of natural genetic variation, or at least in part because of acute but forgotten prenatal exposures suffered by us autism parents born during the Mad Men era of maternal medicine? Born in 1965, I was a young subject in a landmark 1977 study finding what we today would call "Aspie traits" in offspring exposed to heavy doses of synthetic progestins. (See the study here: Reinisch and Karow (1977) Prenatal Exposure to Synthetic Progestins and Estrogens: Effects on Human Development). Could the same induced variation hold true of autism parents exposed as fetuses to developmental toxicants such as cigarette smoke (and/or alcohol or drugs or meds)? Well, again, no one has asked. The BAP has so far been presumed to be all natural, a bit of dogma and assumption-making perhaps rooted in ignorance of biological history.

In sum, might there be at least one "smoking gun" behind a subset of the autism increase? Perhaps in autism research we should start not with the autistic kids, or even their parents, but with the grandmothers.

Jill Escher
February 27, 2017

Note: Sometimes I need to pinch my arm to remind myself that it's 2017. You know, it's easy to forget! Because so much of our world is lost in a time warp. Take, for example, the FDA, which seems to be completely — and I mean completely — oblivious to the fact (1) that fetuses have germ cells, and (2) that fetal germ cells are tissues of interest for pharmaceutical toxicology. Basic high school biology stuff. Oh, people of the United States, I weep for all of you, and for all our successive generations. —JE

Escher Fund for Autism

Division of Dockets Management
Food and Drug Administration
Department of Health and Human Services
5630 Fishers Lane, rm. 1061
Rockville, MD 20852

February 8, 2017

Re: Docket Number FDA-2015-P-0876—Re Citizen Petition to Withdraw Approval for 17α-Hydroxyprogesterone Caproate (“17-OHPC,” Including Brand “Makena”) as a Drug Used in Pregnancy, Pending Fetal Germline Impact Assessment

To the Commissioner of the Food and Drug Administration:

The FDA received the undersigned’s above-referenced petition on March 19, 2015. Nearly two years later, the agency has taken no action on the petition, which seeks immediate action to withdraw approval for the pregnancy drug 17-OHPC, pending fetal germline impact assessment. The synthetic compound at issue is an endocrine disrupting chemical (“EDC”) widely administered to pregnant women, exposing simultaneously their fetuses and those fetuses’ early germ cells to that chemical and/or its metabolites, as the chemicals easily pass the placenta and enter fetal tissues, including gonadal tissues. EDCs are documented to interfere with healthy germ cell development.

By sitting on the petition, the FDA is acting in reckless disregard for the gametic health of countless exposed offspring, and risking the developmental integrity of their offspring, and in so doing, continuing its indefensible and outdated policy of ignoring outright the pharmaceutical risks to vulnerable fetal germline. The petitioner asks that the FDA act expeditiously to grant the petition.

• There is little question that germ cells are direct targets of endocrine disruptors from the very early stages of fetal gonad formation. Epigenetic pathways are crucial for germline development and EDCs can interfere with epigenetic mechanisms, including DNA methylation, histone modifications, changes of chromatin structure and microRNA expression, resulting in the transmission of deranged genetic information to the following generation.

• In genes subject to fine dosage control such as imprinted genes, for example, geno-affective exposures such as EDCs may easily cause small molecular glitches with catastrophic, life-long neurodevelopmental consequences.

• In June 2015, the world’s most esteemed hormone biologists, the Endocrine Society, issued a public statement that EDCs must be assessed for fetal germline impacts. Petitioner is not presenting a “fringe” or novel question, but rather a fundamentally critical issue for drug toxicology and generational public health.

• The drug at issue has only a most minimal impact on preterm birth, and patients can receive natural progesterone analogues instead of 17-OHPC where preterm birth is a consideration, while the drug is undergoing safety review.

• As an alternative to removing the drug from the market, the FDA can require the vendors of this drug to warn all consumers of the possibility for germline damage to their babies, and to their eventual grandchildren.

• In the event that adequate safety assessments reveal no adverse molecular effects on fetal germline, the vendors of 17-OHPC may resume marketing and selling the drug.

It is tragedy that the FDA, which is commissioned with the duty to assess damaging effects of pregnancy drugs, seems to possess neither the ability nor interest to contemplate the manifest, unequivocal drug vulnerabilities of fetal germline, even to intentional, high-dose persistent EDC exposures such as 17-OHPC. Given the potential germline consequences of the drug as outlined in the petition, the petitioner implores the agency to act responsibly and grant the petition without further delay.

The petitioner wishes again to thank FDA staff for its consideration.

Very truly yours,

Jill Escher
Escher Fund for Autism