Germ Cell Exposures

Winter 2019 Newsletter from Escher Fund for Autism Contents: Research Highlights : 2018 a Banner Year in Germline Exposures

Now Accepting Nominations for Escher Prizes in Germ Cell Exposures

2019 Conferences Relating to Germ Cell Exposure Germ Cell Exposure 2018 Research Highlights 2018 was a banner year for the field of heritable impacts of germ cell exposures.

An unprecedented number of studies were published demonstrating how toxicant exposures during critical windows of germline programming can induce adverse impacts in offspring borne of those cells. Not just dose, but timing makes the poison, and few windows of development are more sensitive than a reprogramming germ cell. Some 2018 highlights:



(1) Smoking can leave a toxic legacy in germ cells In animals, McCarthy et al . showed that nicotine exposure in male mice produces behavioral impairment (hyperactivity, attention deficit, and cognitive inflexibility) in multiple generations of descendants here. Promoter regions of multiple genes had been epigenetically modified, including the dopamine D2 gene, critical for brain development and learning. In a similar vein, Andaloussi et al . showed that paternal exposure to cannabinoids during rat adolescence induces stress vulnerability in the offspring here.



. showed that nicotine exposure in male mice produces behavioral impairment (hyperactivity, attention deficit, and cognitive inflexibility) in multiple generations of descendants here. Promoter regions of multiple genes had been epigenetically modified, including the dopamine D2 gene, critical for brain development and learning. In a similar vein, . showed that paternal exposure to cannabinoids during rat adolescence induces stress vulnerability in the offspring here. In humans, Accordini et al. showed fathers’ smoking before the age of 15 was associated with an increased risk of asthma without nasal allergies in their offspring, and grandmothers’ smoking during pregnancy was associated with an increased risk of asthma with nasal allergies in their grandchildren within the maternal line here. Similarly, Lodge et al. showed that grandmaternal smoking increases asthma risk in grandchildren in a nationwide Swedish cohort here. Cheng et al. indicated that nicotine exposure impairs germ cell development in human fetal ovaries cultured in vitro here. And from late 2017 we also saw Jenkins et al. reporting that cigarette smoking significantly alters sperm DNA methylation patterns here. Please note that another 2017 study by Golding et al. linked grandmaternal smoking to autism risk in grandchildren through the female line here. (2) Germ cell exposure to synthetic/exogenous steroids can lead to impaired brain development Diethylstilbestrol (DES). News from America’s greatest medical catastrophe keeps getting worse. Kioumourtzoglou et al . found significantly elevated odds for ADHD in the grandchildren of women who took DES during pregnancy, adding to growing literature demonstrating germline impacts of the toxic pseudo-estrogen, published in Jama Peds here. In an accompanying editorial, Joel Nigg stressed the “implications for where national research dollars should focus to find ways to reduce the incidence of ADHD and other mental disorders.” Here. And another DES study, by Tournaire et al . suggested an increased incidence of two male genital tract defects in sons of men prenatally exposed to DES here. And a study by Titus et al . showed granddaughters of DES prenatally exposed women have increased risks of menstrual aberrations, preterm birth, and possibly ectopic pregnancy here.



News from America’s greatest medical catastrophe keeps getting worse. . found significantly elevated odds for ADHD in the grandchildren of women who took DES during pregnancy, adding to growing literature demonstrating germline impacts of the toxic pseudo-estrogen, published in Jama Peds here. In an accompanying editorial, stressed the “implications for where national research dollars should focus to find ways to reduce the incidence of ADHD and other mental disorders.” Here. And another DES study, by . suggested an increased incidence of two male genital tract defects in sons of men prenatally exposed to DES here. And a study by . showed granddaughters of DES prenatally exposed women have increased risks of menstrual aberrations, preterm birth, and possibly ectopic pregnancy here. Glucocorticoids . Okay this one’s from 2017 but as someone exposed in utero to prednisolone and other synthetic steroids in utero, and who has two kids with malfunctioning prefrontal cortices (read "Bugs in the Program" here), I can’t help myself. Moisiadis et al . used a guinea pig model to show that gestational treatment with betamethasone at a clinically relevant dose resulted in various generational (through F3) pathology including altered cortisol response to stress, altered expression of genes in the prefrontal cortex and hypothalamic paraventricular nucleus. Transmission was sex- and generation-dependent, occurring through both parental lines. Read it here. In another fetal germline exposure study, Cartier et al. used a rat model, to show gestational dexamethasone exposure affects birthweight of the grandpup generation here. And Rawat et al . used a mouse model to show paternal corticosterone treatment exerted effects on offspring brain serotonergic function here.



. Okay this one’s from 2017 but as someone exposed in utero to prednisolone and other synthetic steroids in utero, and who has two kids with malfunctioning prefrontal cortices (read "Bugs in the Program" here), I can’t help myself. . used a guinea pig model to show that gestational treatment with betamethasone at a clinically relevant dose resulted in various generational (through F3) pathology including altered cortisol response to stress, altered expression of genes in the prefrontal cortex and hypothalamic paraventricular nucleus. Transmission was sex- and generation-dependent, occurring through both parental lines. Read it here. In another fetal germline exposure study, used a rat model, to show gestational dexamethasone exposure affects birthweight of the grandpup generation here. And . used a mouse model to show paternal corticosterone treatment exerted effects on offspring brain serotonergic function here. Thyroid hormone. Again, the brains of germline-disrupted offspring prove vulnerable to abnormal steroid exposure. Martinez et al. demonstrated that thyroid hormone influences brain gene expression programs and behaviors in later generations by altering germ line epigenetic information here. (3) General anesthesia, analgesics, morphine change next-gen brains via germ cells Ah, all those things we take to dull or extinguish the pain—they may exert durable germline impacts if given during critical windows of germline development. Ju et al. used a rat model to show 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, here. In an accompanying editorial, "A poisoned chalice: the heritage of parental anaesthesia exposure," Vutskits et al. noted that “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….” here.



Even common analgesics seems to exert intergenerational effects when delivered during early gametogenesis. Rossitto et al. used a mouse model to 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, here. Considering we are in the midst of a opioid epidemic, perhaps we should be concerned about generational effects via exposed germ cells. Vassoler et al. used rats to show that morphine in F1 adolescent 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, here. Also, Sabzevari et al., show in rats that 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, here.



Indeed a wise M. Coppola of Italy asked explicitly, "Are physicians fully aware of the potential transgenerational and multigenerational effects of a large opioid misuse in the population?" here.



(4) Generational impacts of chemotherapy Germline effects of chemo drugs have long been the subject of concern. Prokopuk et al. from Down Under observed that tazemetostat significantly affects the female germline epigenome and, based on genetic models with oocyte-specific loss of EZH2 function, are likely to affect outcomes in offspring, here. Perhaps consistent with this finding, Patel et al. found that both male and female children born to women exposed to chemotherapy have fewer children, here. The exposed males should also be concerned. Shnorhavorian et al. showed that adolescent chemotherapy exposure promoted epigenetic alterations that persisted approximately ten years after exposure. While this study did not investigate phenotypic outcomes in the next generation, the finding was suggestive of possible impairment in offspring. See it here.



Patrick Western and colleagues deserve high praise for two reviews sounding the alarm about potential germline and adverse heritable impacts of epigenomic drugs here and here.



(5) Valproic acid changes germ cells, too The Italians deserve a big Congratulazioni for investigating the generational effects of valproic acid (depakote). Cipriani et al. used a mouse mode to find 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, here. And Tartaglione et al. found behavioral alterations and increased expression of endogenous retroviruses are inherited across generations in mice prenatally exposed to valproic acid, here.



(6) And that's just the drugs, studies also confirmed germline-disrupting effects of environmental chemicals Again and again, environmental toxicants such as pesticides and plasticizers were seen to exert adverse germ cell effects in mammal models.



Here are some studies on pesticides. Krishnan et al. demonstrated exposure of rats to EDCs vinclozolin and polychlorinated biphenyls at the germ cell stage led to differences in the physiological and socio-sexual phenotype in offspring, especially in males here. McBirney et al. used a rat model to expose gestating females 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, here. Gely-Pernot et al used a mouse model to expose pregnant females 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 here. Gillette et al. showed in rats how gestational exposure to vinclozolin and PCBs resulted in transgenerational inheritance of epimutations in brain and sperm here. Ben Maamar et al. showed that early exposure to DDT in rats results in a developmental cascade of epigenetic alterations in the germline here. Plasticizers were also repeatedly found to exert adverse generational consequences. For example, Drobná et al. found transgenerational effects of BPA on gene expression and DNA methylation of imprinted genes in the mouse brain here. Horan et al. showed that replacement bisphenols adversely affect mouse gametogenesis with consequences for subsequent generations here. Małgorzata et al. found reproductive and developmental F1 toxicity following exposure of pubescent F0 male mice to BPA alone and in a combination with X-rays irradiation here. Bansal et al. used mice to show a grand offspring effects of maternal BPA exposure on offspring metabolic health here.



(7) With all this toxicant-induced nongenetic inheritance at play, what are we doing to protect future generations?



Alarmingly, not much. Heritable effects of germ cell exposure is still off the radar of U.S. regulatory agencies as far as I can tell (the FDA, for example, has no intention to explore fetal germline effects of pregnancy drugs, see, eg, its response to my petitioning here), while almost all research on heritability of disease, including neurodevelopmental pathology, remains stubbornly devoted to gene hunting, in spite of decades of rather thin results. This is a disappointing state of affairs to say the least, but I'm optimistic that we will evolve past our state of biological naïveté in the coming years.



In an attempt to accelerate this process, in 2018 I asked the NIH to implement a program on heritable effects of general anesthesia here, nominated germline effects of anesthetic gases for evaluation by the NIEHS National Toxicology Project here, petitioned for an NIEHS OHAT scoping review germline effects of chemical and drugs here, funded four research grants, and gave many other grants to support meetings and conferences, among other endeavors. I was also elected to the governing council of the Environmental Mutagenesis and Genomics Society here, a great honor for which I am very thankful. —JE See compilation of 100+ studies demonstrating heritable impacts of germline exposures in humans and mammals Now Accepting Nominations for Escher Prizes in Germ Cell Exposures Escher Fund for Autism is pleased to announce its 2019 inaugural Escher Prizes in Germ Cell Exposures , recognizing researchers whose work shines a light on the heritable hazards of germline exposures to drugs or other chemicals. We invite you to nominate yourself or a colleague for one of these awards. Awardees will receive a $2,000 donation to help further their endeavors through their respective nonprofit institutions, as well as certificates of recognition. Please help us recognize those who are breaking ground in revealing how germ cell exposure, particularly during early stages of reprogramming, to exogenous toxicants plays a non-genetic heritable role in the etiology of certain diseases and disorders, including but not limited to neurodevelopmental disorders, metabolic disorders, reproductive and socio-sexual disorders, asthma, allergies, and cancer. Areas of research may include, but are not limited to: epidemiology, animal models, in vitro assays, genomics, epigenomics and chromatin, toxicology, reproductive biology, chemical and pharmaceutical history, medical anthropology, and public health.



Deadline to submit a nomination is March 31, 2019. Depending on the quality of the submissions, 2 to 4 prizes will be awarded. To submit a nomination, simply email us: (1) name, email address and institutional affiliation of the individual making the nomination; (2) name, email address and institutional affiliation of the nominee; and (3) up to 500 words explaining the reasons you believe the nominee deserves an award, providing citations to any relevant papers.



Questions are welcome and may be directed here.



Thank you! 2019 Conferences Relating to Germ Cell Exposure May 19-24: Germinal Stem Cell Biology , Gordon Research Conference, Hong Kong , Gordon Research Conference, Hong Kong here

This meeting focuses on the “stem cells of the species” which provide the link between generations—how can they be recognized, how they are regulated at the genetic and epigenetic levels, and how their properties and behavior affect resulting embryos. July 18-21: Society for the Study of Reproduction , San Jose , San Jose here

The meeting features talks on germ cell imprinting, DNA methylation, fetal and placental biology, embryo development, reproductive plasticity, and regenerative medicine. July 21-26: Epigenetics , Gordon Research Conference, New Hampshire , Gordon Research Conference, New Hampshire here

This meeting covers fundamental aspects of epigenetic memory and inheritance, genome evolution, and the regulatory impact of repetitive elements, as well as our current understanding of the principles of nuclear organization and gene regulation. August 26-28: Epigenetic Inheritance: Impact for Biology and Society , Zurich here

This symposium is dedicated to the theme of epigenetic inheritance, a novel discipline at the interface between biology, medicine and environmental science that studies how life experiences and environmental factors can modify the organism across generations. The event is a follow-up of the Latsis Symposium 2017 held at ETHZ. September 17-24: Environmental Mutagenesis and Genomics Society, Washington DC here

This meeting is a milestone— the 50th anniversary of the EMGS. It will feature several workshops and symposia devoted to the question of heritable impacts of germ cell exposure to toxicants.

September 19: EMGS Workshop on Heritable Hazards of Smoking , Washington DC