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The Weismann barrier has long been regarded as a basic tenet of biology. However, upon close examination of its historical origins and August Weismann’s own writings, questions arise as to whether such a status is warranted. As scientific research has advanced, the persistence of the concept of the barrier has left us with the same dichotomies Weismann contended with over 100 years ago: germ or soma, gene or environment, hard or soft inheritance. These dichotomies distract from the more important questions we need to address going forward. In this review, we will examine the theories that have shaped Weismann’s thinking, how the concept of the Weismann barrier emerged, and the limitations that it carries. We will contrast the principles underlying the barrier with recent and less recent findings in developmental biology and transgenerational epigenetic inheritance that have profoundly eroded the oppositional view of germline vs. soma. Discarding the barrier allows us to examine the interactive processes and their response to environmental context that generate germ cells in the first place, determine the entirety of what is inherited through them, and set the trajectory for the health status of the progeny they bear.

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All the cells in our bodies are derived from the germ cells of our parents, just as our own germ cells become the bodies of our children. The integrity of the genetic information inherited from these germ cells is of paramount importance in establishing the health of each generation and perpetuating our species into the future. There is a large and growing body of evidence strongly suggesting the existence of substances that may threaten this integrity by acting as human germ cell mutagens. However, there generally are no absolute regulatory requirements to test agents for germ cell effects. In addition, the current regulatory testing paradigms do not evaluate the impacts of epigenetically mediated intergenerational effects, and there is no regulatory framework to apply new and emerging tests in regulatory decision making. At the 50th annual meeting of the Environmental Mutagenesis and Genomics Society held in Washington, DC, in September 2019, a workshop took place that examined the heritable effects of hazardous exposures to germ cells, using tobacco smoke as the example hazard. This synopsis provides a summary of areas of concern regarding heritable hazards from tobacco smoke exposures identified at the workshop and the value of the Clean Sheet framework in organizing information to address knowledge and testing gaps.

Bisphenol A (BPA) is an industrial plasticizer widely found in consumer products such as plastic bottles and canned foods. Human and murine studies have shown strong associations between prenatal exposures to endocrine disruptors such as BPA during early development and the prevalence of various diseases including cardiovascular diseases, type 2 diabetes, and obesity. Previous studies have found that the liver tissue is a sensitive BPA target site, and BPA alters the microbial diversity in exposed mice. To understand whether and how the gut microbiome mediates the effects of BPA on liver gene expression to influence metabolic phenotypes, we conducted a multi-dimensional systems biology study. We treated pregnant C57BL/6 mice with a low dose of BPA at 5ug/kg/day during gestation and evaluated metabolic phenotypes, fecal microbial composition and liver transcriptome of both male and female offspring. Prenatal exposure to low dose BPA significantly not only affected liver genes involved in oxidative phosphorylation, PPAR signaling and fatty acid metabolism, but also affected the gut microbial composition in an age-dependent manner, with the most pronounced effect observed at week 20. Bacteria belonging to the S24-7 and Lachnospiraceae families were correlated to offspring body weight and differentially expressed liver genes such as Fabp1, Acadl and Dgat1. This study provides insights into the relationship between gut bacteria and host liver genes that could contribute to metabolic disease risks upon BPA exposure. Future studies will test whether the gut microbiota identified in this study play a direct causal role on the host genomic and phenotypic responses using fecal transplant and bacteria colonization experiments. Disclosure G. Diamante: None. I.C. Cely: None. J. Lang: None. A. Bline: None. Z.O. Zamora: None. M. Singh: None. A. Lusis: None. X. Yang: None. Funding American Diabetes Association (1-19-PDF-007-R to G.D.)