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Environmental Epigenetics: New Frontiers in Autism Research took place March 22-23, 2013 at the UC Davis MIND Institute in Sacramento, California, co-sponsored by Autism Speaks, the MIND Institute, and the Escher Fund for Autism. The meeting brought together leading scientists from multiple disciplines to consider how environmental epigenetics may play a role in the causes of some forms of neurodevelopmental disability, including autism spectrum disorders.

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An autism mom asks: Who says you can’t have a genetic epidemic?

Presenter: Jill Escher

Affiliation: Escher Fund for Autism

Date: March 22, 2013

Length: 13:04

Summary: A mother of two children with autism poses the question whether past exposures, particularly prenatal exposures to popular mid-20th century prenatal pharmaceutical drugs, such as synthetic steroid hormones and sedatives, may have impacted vulnerable fetal germline epigenetics, resulting in a surge of developmental abnormalities in the grandchild generation.

Environment, neurodevelopment, and opportunities for prevention

Presenter: Tracey Woodruff, Ph.D., MPH

Affiliation: Program on Reproductive Health and the Environment, UCSF

Date: March 22, 2013

Length: 22:47

Summary: We are experiencing a sharp upward trend in autism that cannot be fully explained by factors such as younger ages at diagnosis, migration patterns, changes in diagnostic criteria. Interaction among environmental factors, including a glut of novel and untested synthetic chemicals known to cause disturbances in CNS development, may be contributing to the problem. Dr. Woodruff explains the history of environmental chemical exposures and efforts that were successful in reducing exposures and improving child health.

Perinatal environmental exposures and lifecourse health effects

Presenter: Dana Dolinoy, Ph.D.

Affiliation: University of Michigan School of Public Health

Date: March 22, 2013

Length: 30:00

Summary: Molecular level epigenetic “switches” can influence the expression of protein-coding genes. Periods of particular epigenetic susceptibility include gametogenesis, pre-implantation stage of embryogenesis, fetal and neonatal periods of development, puberty, ad old age. Lab studies have shown endocrine-disrupting chemicals can have non-monotonic effects, differentially methylate DNA (both hyper- and hypo), and have different effects in different succeeding generations. Epigenomic studies can decipher the role of the environment on the epigenome, identify epigenetically labile genes, and link epigenetically labile loci with biological pathways and phenotypes/human health outcomes.

Evolutionary implications for a new world of contamination

Presenter: David Crews, Ph.D.

Affiliation: Section of Integrative Biology, University of Texas at Austin

Date: March 22, 2013

Length: 27:45

Summary: As an evolutionary biologist, Dr. Crews’ research focuses on how exposures change adaptation across generations in a sex-dependent way. He describes two types of ways in which the environment sculpts the phenotype of individuals: 1) context dependent which is due to a direct exposure and manifests in each generation and 2) germline dependent. This manifests in the absence of a causative agent since it is cumulative across generations. He describes experiments where changes to the environment can affect social and sexual behavior, as well as response to stress, when the exposures was ancestral.

Environmental induced epigenetic transgenerational inheritance of disease

Presenter: Michael Skinner, Ph.D.

Affiliation: Washington State University

Date: March 22, 2013

Length: 40:32

Summary: Biological science is undergoing a paradigm shift away from the fixed genetic determinism of the 20th century and toward an understanding that environmental factors can alter gene expression and activity. Genetics works together with the environment to contribute to disease risk. In some cases, changes to gene expression in future generations can occur when the germ cell (sperm or egg) is reprogrammed via an abnormal exposure such as an endocrine-disrupting compound, and these alterations may persist for generations. This transgenerational exposure to environmental factors represents an example of epigenetic inheritance. Various pathologies may result from certain germline exposures, including cancer, infertility, polycystic ovary disease, obesity, and behavioral abnormalities. Assays find clusters of altered gene expression dependent on the original exposure, or dependent on the generation studied.

A remodeled germline epigenome: the ultimate gift to our children and grandchildren

Presenter: Amander Clark, Ph.D.

Affiliation: UCLA

Date: March 22, 2013

Length: 19:12

Summary: During pregnancy, three generations of DNA coexist in the woman’s body: hers, that of her fetus, and the primordial germ cells growing within the fetus. Those germ cells decades later contribute to the grandchild generation. Human gametogeneis begins in early gestation, with the male fetus’s germline developing differently than the female fetus’s germline. The proper reprogramming of the germline is essential for proper child development, and molecular perturbations can lead to developmental disorders. Environmental exposures can interfere with the molecular process of germline programming.

How might epigenetics relate to the etiology of ASD?

Presenter: M. Danielle Fallin, Ph.D.

Affiliation: Johns Hopkins Bloomberg School of Public Health

Date: March 22, 2013

Length: 26:24

Summary: Various epigenetic mechanisms may contribute to ASD traits and there is growing evidence for environmental susceptibility of epigenetic marks. Studies show that phenotype and epigenetic marks can be modified by factors such as maternal diet, pharmaceuticals, and smoking, and metals and behavior. The epigenome may be the intermediary between genetics and the environment, mediating disease outcome. Existing research supports a role for epigenetics in ASD etiology, for example with ASD-related disorders with known epigenetic mechanisms, parent-of-origin effects, differences of expression in ASD-related genes, and differences in methylation patterns.

Epigenetic inheritance of complex behaviors and their alteration by traumatic stress in mammals

Presenter: Prof. Isabelle Mansuy

Affiliation: Brain Research Institute, University of Zurich

Date: March 22, 2013

Length: 30:34

Summary: Disease arises via a combination of genotype and epigenotype. Over the human lifecycle, there are different environmental influences on epigenotype. Early trauma is a risk factor for psychiatric and cognitive disorders, and involve epigenetic factors. Animal studies show early trauma can alter social behavior across generations. Multiple molecular mechanisms appear to be involved with the induced differences in gene expression, including DNA methylation, histone/protamines posttranslational modifications, and small noncoding RNAs.

Neuroendocrine disruptors, epigenetics and neurodevelopment

Presenter: Andrea Gore, Ph.D.

Affiliation: University of Texas at Austin

Date: March 22, 2013

Length: 43:34

Summary: Hormones play a critical role in sculpting the entire nervous system and brain. Endocrine disrupting chemicals can adversely affect fetal brain development and may have lifelong consequences. Psychiatric disorders are influenced by gonadal steroid hormones. EDCs perturb hypothalamic development and therefore hormonal regulation. Studies of PCBs, which persist in the environment and bioaccumulate in tissue demonstrate lifelong changes in physiology, brain development and behaviors. Multigenerational adverse impacts of exposure to the antimiscarriage synthetic hormone DES is also discussed.

Prenatal exposures: An unrecognized multigenerational epidemic

Presenter: June Reinisch, Ph.D. and Erik L. Mortensen, CanD

Affiliation: University of Copenhagen Prenatal Development Project

Date: March 22, 2013

Length: 31:39

Summary: Historically, the placenta was viewed as a barrier preventing passage of harmful substances to the fetus. However, today we know that organ acts more like a sieve, with most maternally ingested substances reaching fetal tissues. Prenatal use of synthetic medications goes back a century, beginning with barbiturates and then synthetic hormones, including synthetic estrogens (including the catastrophic drug DES) progesterones, and corticosteroids. In the mid 20th century, synthetic hormone drugs were widely used in pregnancies deemed to be “at risk,” and as a result millions of offspring were exposed to augmented levels of synthetic or natural hormones. The exposures are associated with a variety of disruptions of typical development; however, drug impacts on fetal germ tissues (grandchild, or F2, generation) have not yet been assessed. A study using the Danish Prenatal Development Project, which is unusually rich with prenatal exposure data, will be the first to examine potential germline/F2 impacts of prenatal drug use.

A role for assisted reproduction technology (ART) in the etiology of ASD?

Presenter: Rosanna Weksberg, M.D., Ph.D.

Affiliation: University of Toronto

Date: March 22, 2013

Length: 23:58

Summary: Exposures are most likely to have a significant impact only during certain stages of development, including gamete development and early embryonic development. Assisted reproduction, such as ovulation stimulation, in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), expose gametes and the early embryo to unusual environmental factors coinciding in time with critical windows of epigenetic programming. Exposures that may cause epigenetic perturbations include: ovulation stimulation (FSH/clomid) (causing maturation and ovulation of oocytes with incomplete/aberrant DNA methylation); IVF (in vitro embryo culturing may disrupt proper imprinting maintenance in oocyte and embryo during global genome demethylation); ICSI (sperm with incomplete/aberrant methylation bypass natural selection). The increased incidence of imprinting disorders associated with ART appears to arise from epigenetic rather than genetic defects. Methylation patterns in ART children appear to be slightly but significantly reduced. Study of children conceived through ART offer a unique opportunity to study exposure and epigenetic factors in development.

BPA, social behavior, and epigenetics in juvenile mice

Presenter: Emilie Rissman, Ph.D.

Affiliation: University of Virginia

Date: March 22, 2013

Length: 23:58

Summary: Studies on exposure-induced changes in social behavior in mice may shed light on human neurobehavioral disorders. A study found that low-dose endocrine disrupting chemical BPA changes juvenile interactions in female mice; some changes in gene expression were also found. Multigenerational effects were identified, with different effects in different generations. Environmentally induced epigenetic modification of the X chromosome may have implications for the sex difference seen in ASD.

PBDE exposure, sex differences and epigenetics in an animal model of ASD

Presenter: Janine LaSalle, Ph.D.

Affiliation: Medical Microbiology and Immunology, UC Davis School of Medicine

Date: March 22, 2013

Length: 30:21

Summary: A study on PBDEs (flame retardant chemical) and PCBs (industrial chemical) examined the effects of environmental pollutants on epigenetics of neurodevelopment in both a mouse model and with human brain tissue. Perinatal BDE-47 exposure adversely affected reproductive success in this genetically susceptible mouse model, consistent with adverse effects on human fecundity. PBDE exposure adversely affected two measurements of social behavior in the mouse model, and resulted in reduced global DNA methylation in the adult brain specifically in females, correlating with deficits in sociability. Gene by environment interactions at the epigenetic interface are complex, involving sexual dimorphism, epigenetic dysregulation, compensatory molecular mechanisms, and specific behavioral deficits. The study of PCBs in human brain samples suggested a possible environmental contributor to 15q duplications through an epigenetic mechanism. An integrative approach to understanding environmental impacts on the brain methylome is suggested.

Counseling the pregnant woman: Focus on SSRI antidepressants

Presenter: Adam Urato, M.D.

Affiliation: Chairman, Dept. of OB/GYN, MetroWest Medical Center, Assistant Professor, Tufts Medical Center

Date: March 23, 2013

Length: 29:23

Summary: Medication use during pregnancy is common and has been steadily increasing since the 1970s; typical pharmaceuticals include antidepressants, anti-nausea drugs, and heartburn medications. This represents a dramatic change in the chemical environment from the perspective of evolutionary biology: mammals have evolved for 200 million years without the interference of synthetic drugs in gestation. In spite of clear warning signs, the synthetic estrogen drug DES was used on pregnant women for 33 years before the harmful effects were acknowledged. Today, prenatal use of SSRI drugs has surged since their introduction in the 1980s. Studies in animal models and human cohorts suggest that fetal SSRI exposure may long-term neurodevelopmental outcome, including reports of an increased risk for ASD.