Many endocrine disrupting compounds (EDCs) have immediate effects on exposed individuals, but more complex concerns surround their long term actions on subsequent generations. The limited data from humans concur with the animal work suggesting that exposure to EDCs, particularly exposure during development, produce subtle increases in disease states, along with evidence for transgenerational effects. The precise epigenetic and/or genetic actions of EDCs on specific target genes, which produce stable modifications in subsequent generations, are unknown. The first goal of this program is to understand the mechanisms underlying transgenerational inheritance produced by human-relevant levels of the ubiquitous EDC, Bisphenol A (BPA). The work proposed is the first to test transgenerational actions of human-relevant exposures of BPA on brain and behaviors. Pregnant inbred mice are exposed to EDCs via voluntary ingestion of maternal diet. At birth, control and BPA pups are fostered to dams on control diet to isolate the actions of BPA to gestation and control for any consequences of these compounds on maternal behavior. We have shown that several social behaviors in the first and fourth generation (F4) of mice the BPA lineage differ significantly from control mice. Moreover, mRNA for two genes that regulate social behavior, vasopressin (Avp) and oxytocin (Oxt), are decreased in brains of the F4 BPA-exposed mice. Experiment one will determine the parent of origin for transmission of BPA's actions. In addition we will assess a number of cognitive and emotional behaviors in these mice to improve our ability to predict which human diseases may be sensitive to BPA. In the next study brains regions are probed with next generation sequencing techniques to establish target genes. Brains from F3 mice will be dissected into the nuclei that compose the social behavior network. A combination of Chromatin Immunoprecipitation (ChiP-) and RNA-sequencing will be conducted. These data provide targets for the epigenetic modifications found in brain. The mechanisms revealed will be applicable to other target tissues and thus a variety of diseases. This research plan will provide the field with a model for transgenerational actions of BPA and an epigenomic map of the consequences of these exposures.

Public Health Relevance

Endocrine disrupting compounds (EDCs), such as Bisphenol A, are in widespread use and are now present in water, wildlife and humans. This compound has both endocrine- like actions and more complex epigenetic properties. In the proposed program of research we will use state of the art high throughput genomic and epigenomic methods to examine genes that underlie transgenerational properties of BPA acting on brain and behavior. The proposed research is highly relevant to the mission of NIEHS pertaining to discovering the genetic and epigenetic bases for diseases exacerbated by EDCs.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Chadwick, Lisa
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University of Virginia
Schools of Medicine
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Goldsby, Jessica A; Wolstenholme, Jennifer T; Rissman, Emilie F (2017) Multi- and Transgenerational Consequences of Bisphenol A on Sexually Dimorphic Cell Populations in Mouse Brain. Endocrinology 158:21-30
Quinnies, Kayla M; Harris, Erin P; Snyder, Rodney W et al. (2017) Direct and transgenerational effects of low doses of perinatal di-(2-ethylhexyl) phthalate (DEHP) on social behaviors in mice. PLoS One 12:e0171977
Harris, Erin P; Allardice, Heather A; Schenk, A Katrin et al. (2017) Effects of maternal or paternal bisphenol A exposure on offspring behavior. Horm Behav :
Rissman, Emilie F (2016) The Endocrine Society Centennial: No Longer a Surprise: Estrogenic Chemicals in a Multitude of Places. Endocrinology 157:2969-71
Quinnies, Kayla M; Cox, Kimberly H; Rissman, Emilie F (2015) Immune deficiency influences juvenile social behavior and maternal behavior. Behav Neurosci 129:331-8
Quinnies, Kayla M; Doyle, Timothy J; Kim, Kwan Hee et al. (2015) Transgenerational Effects of Di-(2-Ethylhexyl) Phthalate (DEHP) on Stress Hormones and Behavior. Endocrinology 156:3077-83
Rissman, Emilie F; Adli, Mazhar (2014) Minireview: transgenerational epigenetic inheritance: focus on endocrine disrupting compounds. Endocrinology 155:2770-80