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

项目总结

Project Summary Increasing numbers of children are being 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 exhibited by 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. Both males and females developmentally exposed to BPA go on to become poor parents as adults. We 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. The first goal will be to ascertain whether early exposure to BPA, G, and the combination of the two EDCs results in behavioral deficits observed in ASD patients. The second goal will be to determine whether males and females exposed to these chemicals show gene expression/DNA methylation/miRNA (miR) 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 of male and female F1 California mice to BPA, G, and BPA + G affects behavioral domains disrupted in ASD children, such as social-sexual-communicative, cognitive, anxiety/neuro-affective, and repetitive behaviors. 2) Test whether these individual and combined EDCs affect global transcriptomic profiles in the amygdala, hippocampus and hypothalamus in F1 males and females that may underpin the EDC-induced behavioral disruptions. 3) Determine whether these treatments induce DNA methylation and miR changes in the amygdala, hippocampus and hypothalamus in both F1 sexes and perform a comprehensive correlation analysis to link the various bio-molecular and behavioral disturbances. Data will likely provide novel candidate biomarkers that can be used to diagnose and in potential preventative/remediation strategies in children at-risk for ASD due to early exposure to these EDCs.