We are in the midst of an opioid epidemic, and, worryingly, evidence is emerging that opiates could have neurobehavioral impacts on the next generation via exposed germline (Vassoler et al., 2018; Sabzevari et al., 2018; reviewed generally in Gilardi et al., 2018).
While we have focused on brain and behavior in this discussion, other studies have demonstrated how drug, smoking or chemical exposures to germ cells can increase risks for other pathologies as well, including cancer, metabolic dysfunction and obesity, asthma and allergies, even differences in sexual behavior. Research has reported some perplexing links between autism and these conditions, and perhaps the quasi-genetic phenomenon will help explain some of them.
[Another note to biology buffs: See here for a compilation of more than 100 studies demonstrating non-genetic inheritance in humans and mammals.]
Intriguing consistencies with patterns seen in autism
It’s not every day that a hypothesis of autism comes along that can help explain many of the baffling patterns seen in the research literature. But we think this quasi-genetic hypothesis packs an unusual punch when it comes to potential explanatory power. Here are some examples:
Temporal associations. The start of the autism increase, observed to have begun with births in the 1980s, comes roughly a generation after early germ cell exposures to these novel synthetic pregnancy drugs and the peak of maternal smoking (1950s and 60s).
The 4:1 male:female sex ratio. The hypothesis is consistent with the sex-specific intergenerational responses to exposures detected in human and animal studies. Several studies in hormonal disruption of germ cells, for example, have found male offspring more likely suffer adverse effects.
Autism heterogeneity and the “broader autism phenotype.” Toxicant exposures to male or female germ cells over different times, in different doses, in different combinations, against a backdrop of varying genomic susceptibilities, would likely not cause uniform effects. This roulette-wheel mix could help explain the heterogeneity of the autisms and “broader autism phenotype” seen among other family members. Also the personalities and cognitive traits of parents themselves could have been influenced by their direct in utero exposures, as was the documented case with co-author JE who was a subject in this landmark study on developmental impacts of synthetic steroid hormone pregnancy drugs (Reinisch and Karow, 1977).
Regional, socioeconomic, and ethnic disparities. Higher rates of autism in some regions, ethnicities and socioeconomic strata may coincide with higher rates of drug exposures of the parents, for example, pregnancy smoking in the grandmother generation.
Arising in early brain development. It has been frequently observed that autism arises from brain mis-wiring during early development in the womb. What drives this mis-wiring? Increasingly it looks like chromatin and epigenomic factors may contribute, suggesting that “epigenetic dysfunction is a fundamental contributor to brain development and disease pathogenesis of neurodevelopmental disorders, including ASD” (Tremblay and Jiang, 2019).
Quasi-genetics as a new priority for autism research
Though we feel this hypothesis is strong, we do not remotely suggest that all autisms are quasi-genetic, or that other hypotheses are not worth exploring. Of course many are. But if we ever want to solve the mystery of autism’s heritability, research must embrace a greater degree of biological and historical authenticity. Today, we see too many researchers sitting in offices thinking in the abstract about even the weakest of genetic associations, while remaining unconcerned with any other information transmitted by germ cells, and totally disconnected from actual autism families and their complicated exposure histories. We continue to pour hundreds of millions of taxpayer dollars looking under the lamppost of gene sequencing, although it’s clear we’re in the land of diminishing returns chasing ultra-ultra rare variants with precious little relevance for families, prevention or public health. Meanwhile we spend pretty much nothing investigating heritable effects of exposures.
These questions could be researched in various ways. For example, rodent models can provide a rough idea of impacts of various drugs, such as those discussed in this article, on the next generation’s gene expression, brain function, and behavior. In humans, retrospective studies in populations with documented drug and smoking exposures could be conducted, even though of course researchers would need to be careful of “confounds,” or other factors that could be intervening to change outcomes. We suggest that the question of quasi-genetic inheritance is of such relevance and importance that our National Institutes of Health should consider funding at least 50 studies on this subject in the next three years. We dropped the ball in the 1980s when this idea first percolated. Let’s make up for all that lost time.
It is a heartbreaking possibility that errors of brain development could be an unforeseen legacy of certain benign-seeming actions that occurred very long ago. But given the potentially significant public health implications, and the emerging science demonstrating biological plausibility, it’s time to reconsider the history of our germ cells, and what those histories mean for our children.
La Donna Ford, MD is a former anesthesiologist. She is the mother of a son with idiopathic autism and lives in the San Francisco Bay Area.
Jill Escher is a research philanthropist (GermlineExposures.org), president of the National Council on Severe Autism, president of Autism Society San Francisco Bay Area, and a councilor-elect of the Environmental Mutagenesis and Genomics Society, where she also serves as chair of the Germ Cell and Heritable Effects special interest group. A former lawyer, she is the mother of two children with idiopathic autism and lives in the San Francisco Bay Area.
Correspondence may be directed to firstname.lastname@example.org.
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