Endocrine Disrupting Chemicals, Epigenetic Alterations, and Autism-like Behaviors in the Highly Social California Mouse Model

University Of Missouri-Columbia, Columbia MO

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Abstract

? DESCRIPTION (provided by applicant): Increasing numbers of children have been diagnosed with autism spectrum disorders (ASD) and related neurobehavioral disorders. Based on the rising incidence that is not explained by genetics alone, it has been postulated that in utero exposure to environmental chemicals may increase the risk for these disorders. Perinatal exposure of children through the mother to endocrine disrupting chemicals (EDCs), including bisphenol A (BPA), has been linked to ASD. To establish potential causation and underlying mechanisms, it is important to test these chemicals in a relevant animal model species, where the clinical core behavioral symptoms of ASD children can be replicated. Most ASD animal model studies to date have employed transgenic mice. However, these animals often fail to replicate all of the core ASD-like behaviors. The monogamous, biparental, and highly communicative California mouse (Peromyscus californicus) provides a complementary animal model for ASD research. We have previously demonstrated that neurobehavioral programming in California mice is especially vulnerable to BPA. Developmentally exposed males demonstrate compromised socio-sexual behaviors, and their female siblings exhibit heightened anxiety, reminiscent of children with ASD. The project will test the hypothesis that early exposure to BPA and genistein (G), a phytoestrogen present in soy products- including baby formulas, results in ASD-like behavioral disorders in California mice. An internationally recognized ASD expert will provide guidance on how findings in this model translate to children afflicted with these disorders. The first goal will thus be to ascertain whether early exposure to BPA, G, and the combination of the two EDCs affects later behavioral patterns. The second goal will be to examine the EDC-induced gene expression/DNA methylation changes in the brain sub-regions (amygdala, hypothalamus and hippocampus) governing these traits that may underlie the disrupted behavioral phenotypes. Specific Aims are to: 1) Test whether developmental exposure to BPA, G, and BPA + G affects later male and female California mouse behavioral domains (social-sexual-communicative, cognitive, anxiety/neuro-affective, and repetitive behaviors) that resemble ASD. 2) Test whether these individual and combined EDCs affect transcripts in the amygdala, hippocampus and hypothalamus in male and female California mice that may underpin these EDC-induced behavioral disruptions. 3) Determine whether these diets induce DNA methylation changes in the amygdala, hippocampus and hypothalamus in both sexes and perform a comprehensive correlation analysis to link the behavioral changes with DNA methylation/gene expression alterations. Data will likely provide novel candidate biomarkers that can be used to diagnose and potentially for preventative/remediation strategies in children at-risk for ASD due to exposure to these EDCs.