Transgenerational Actions of Endocrine Disrupting Compounds On Brain and Behavior: Implications for Autism

Background: Prevalence of Autism Spectrum Disorder (ASD) has increased dramatically over the past few decades. According to the CDC, the incidence of ASD in 2000 was 1:150; now the level is 1:88. While candidate gene mutations, SNPs and CNVs have been discovered, no one gene accounts for more than 1% of ASD. Our lab is asking how environmental factors, particularly via epigenetic regulation of gene transcription, may contribute to changes in social behavior.  Exposure to endocrine disrupting compounds (EDC) is widespread through many sources including; food can linings, plastic products, cosmetics and paper to name a few. The actions of these compounds 

Objectives: Our goal was to assess effects of Bisphenol A on a set of social behavior and expression of neural genes over the course of 3-4 generations in laboratory mice.

Methods: We exposed mice to BPA only during gestation. We employed doses of BPA that produce blood levels comparable to those found in humans; to date we have used three different doses. Our behavioral data illustrate the non-monotonic effects of BPA. To ask if the actions of BPA are transgenerational we compared gene expression and behavior in mice from the first, second, third, and/or fourth generations. 

Results: Juveniles exposed to in the first generation displayed fewer social interactions as compared with control mice, whereas in later generations (F₃ and F₄), the effect of BPA was to increase general activity. Brains from embryonic day 18.5 had lower gene transcript levels for several estrogen receptors, oxytocin and vasopressin as compared to controls; decreased vasopressin mRNA persisted into the F₄generation, at which time oxytocin expression was also reduced but only in males. 

Conclusions: Thus, exposure to a low dose of BPA, only during gestation, has immediate and long lasting, trans-generational, effects on mRNA in brain and social behaviors. These heritable effects of exposure to an endocrine disrupting compound have implications for complex diseases, which are likely the result of gene-environment interactions.