Understanding the epigenetic consequences of gene/environment interactions through animal models

Background: The epigenetics revolution provides mechanisms by which gene transcription can be modulated by the environment.   The focus of this presentation will be to investigate the hypothesis that that certain environmental compounds, specifically, endocrine disruptors, act epigenetically to modify transcription of important neurodevelopmental genes. Two of the most widely used compounds are Bisphenol A (BPA), which increases rigidity and di(2-ethylhexyl) phthalate (DEHP) which enhances flexibility of plastics. Correlational data provide evidence that exposure to one or both of these compounds during gestation is associated with a variety of suboptimal behaviors in children including anxiety, IQ, and executive function (Braun et al., Braun et al., 2013).  In addition to direct actions on the developing brain both of these EDCs have transgenerational effects on testes organization (Doyle et al 2013) and behavior (Wolstenholme et al 2012; 2013).

Objectives: In order to establish causal relationships between EDC exposures in utero, and juvenile behavior, we are using a mouse model. We focus on human relevant doses of BPA and DEHP that are consumed by dams during pregnancy. We assess behaviors in juvenile mice that are either the first generation or several generations removed form EDC exposure. In this manner we can make causal statements about gestational exposures to EDCs and behavior.

Methods: Female mice were exposed to BPA-in chow or control chow throughout gestation in one study. In a second study females received , DEHP or vehicle for a week in mid-pregnancy.  Sibling pairs were bred to the third generation with no further BPA or DEHP exposure. First (F1) and third (F3) generation juveniles were tested for social interactions, recognition and in the open field in the BPA experiment. In the DEHP study we tested the same behaviors and examined stress responses.

Results: Bisphenol A exposure during gestation increases social interactions in both male and female juvenile mice interacting with adult females confined to a small holding cell, on the other hand BPA-exposed mice are less willing to interact with other juveniles in an unrestrained test.  Interestingly 3-4 generations later juvenile mice in the BPA lineage are more interactive in both tasks and fail to distinguish novel from unfamiliar testing partners. Testing of DEHP-exposed mice is going on at the present time with a focus on stress-responses and anxiety.  Target genes in brains of BPA linage mice do not exhibit differences in DNA methylation and other mechanisms are under investigation.

Conclusions: Two commonly used EDCs given to mice at low doses during gestation have short and long term effects on behavior and gene expression. How and which neurodevelopmental genes are modified by these compounds has yet to be determined.