Autism spectrum disorder is defined by deficits in social behavior and communication as well asrepetitive stereotyped behaviors. The incidence of this disorder is increasing, and higher rates in malesindicate that endocrine disruptors in the environment may be major contributors. Of note, young males withautism often have an enlarged cortex, particularly in the prefrontal cortex with greater numbers of neurons andglia (Courchesne et al., 2010; Edmonson et al., 2014). Interestingly, we have also found that pre- andpostnatal exposure to BPA results in an increased number of neurons in the rat medial prefrontal cortex(mPFC) (Sadowlski et al., 2014). In this proposal, the effects of the widespread endocrine disruptor, bisphenolA (BPA), will be examined during the development of the rat mPFC. The central hypothesis is that BPA altersapoptosis and/or neurogenesis early in mPFC development by changing gene expression and its effectspersist through epigenetic methylation. Because there are sex differences in the timing and amount of theseearly cellular processes, the sexes are differentially vulnerable. Aim 1 will first delineate when apoptosis occurs in the male and female rat mPFC. Next, on the dayssurrounding the highest rates of apoptosis and/or when the sexes diverge significantly, pups will orally ingestBPA. Following exposure, apoptotic markers and the number of neurons and glia will be stereologicallyassessed before puberty and in adulthood. Next, fetal pups will be gestationally exposed to BPA on days ofpeak cortical neurogenesis. BrdU, a marker of dividing cells, will also be administered to test whether BPAalters the rate of neurogenesis. A subset of animals from all groups will be tested for their conspecific affiliativebehavior before weaning age as an indicator of early deficits in social behavior. Overall, this aim will identifythe cellular mechanism during development by which BPA can bias the cortex toward an excess of neuronsand glia and autistic characteristics. Changes in gene expression that are concomitant with cellular changes following BPA exposure in themPFC will be characterized in Aim 2. Genes that have been implicated in autism, such as FOXG1 and Pten,as well as those associated with hormone receptors and apoptosis will be included. Epigenetic changes whichindicate long-term effects of BPA exposure will also be examined. The long-term goal is to know the specific timing and mechanisms of vulnerability to this ubiquitousendocrine disruptor so that exposure can be avoided or ameliorated.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
