Autism spectrum disorder is defined by deficits in social behavior and communication as well as repetitive stereotyped behaviors. The incidence of this disorder is increasing, and higher rates in males indicate that endocrine disruptors in the environment may be major contributors. Of note, young males with autism often have an enlarged cortex, particularly in the prefrontal cortex with greater numbers of neurons and glia (Courchesne et al., 2010; Edmonson et al., 2014). Interestingly, we have also found that pre- and postnatal 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, bisphenol A (BPA), will be examined during the development of the rat mPFC. The central hypothesis is that BPA alters apoptosis and/or neurogenesis early in mPFC development by changing gene expression and its effects persist through epigenetic methylation. Because there are sex differences in the timing and amount of these early 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 days surrounding the highest rates of apoptosis and/or when the sexes diverge significantly, pups will orally ingest BPA. Following exposure, apoptotic markers and the number of neurons and glia will be stereologically assessed before puberty and in adulthood. Next, fetal pups will be gestationally exposed to BPA on days of peak cortical neurogenesis. BrdU, a marker of dividing cells, will also be administered to test whether BPA alters the rate of neurogenesis. A subset of animals from all groups will be tested for their conspecific affiliative behavior before weaning age as an indicator of early deficits in social behavior. Overall, this aim will identify the cellular mechanism during development by which BPA can bias the cortex toward an excess of neurons and glia and autistic characteristics. Changes in gene expression that are concomitant with cellular changes following BPA exposure in the mPFC 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 which indicate 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 ubiquitous endocrine disruptor so that exposure can be avoided or ameliorated.

Public Health Relevance

The recent rise in the incidence of autism, as well as the larger number of males who are affected, has led to speculation that chemicals that disrupt hormones may be playing a role. We propose to examine the effects of a widespread hormone disruptor, bisphenol A, on the early development of the cells and on gene expression in the rat prefrontal cortex.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Lawler, Cindy P
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University of Illinois Urbana-Champaign
Schools of Arts and Sciences
United States
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