Abstract
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with complex, multifactorial etiologies that are incompletely understood. Over the last decade, numerous genomic studies have led to the identification of hundreds of genes linked to ASD, but identification of environmental factors that confer risk of ASD has lagged behind. Environmental chemicals are one class of environmental factor of concern due to 1) the limited toxicological analysis on existing chemicals, and 2) the extent to which humans come in contact with these chemicals. Bisphenol A (BPA) is a chemical used in the synthesis of plastics that is found in a wide variety of food and personal care items that humans come in contact with every day. There is extensive data showing BPA functions as an endocrine disruptor, but recent studies have indicated that it may also affect neurodevelopment. Here, I investigated the neurodevelopmental toxicity of BPA and its potential as an ASD risk factor, using Drosophila melanogaster as a model organism. Drosophila have a high degree of conservation with humans with respect to the genes and molecular pathways that govern neurodevelopment. As such, fruit flies are increasingly being used as a model of human neurodevelopmental disorders. The aim of this research was to determine if developmental exposure to BPA affects two neurodevelopmental processes relevant to ASD: axon outgrowth and neural stem cell (NSC) proliferation. Importantly, this study also addressed if the effect of BPA exposure varies in the presence of a significant ASD risk gene. To do so, wild-type Drosophila and Drosophila carrying a mutation in fragile X mental retardation 1 (fmr1)—the most common single gene cause of autism—were exposed to BPA during development and consequent axon outgrowth and NSC proliferation phenotypes were compared. Axon outgrowth was examined by imaging the mushroom body of adult flies. Data was generated from these images through scoring the degree of aberrant midline crossing by axons in this structure. This approach showed that BPA increased the severity and frequency of midline crossing in wild-type flies, but exhibited a neuroprotective effect in fmr1 flies. To assess NSC proliferation, images were taken of larval brains and the number of NSCs and intermediate neural progenitor cells (INPs) undergoing mitosis was directly counted. This analysis showed that BPA significantly decreased the number of mitotically active NSCs and INPs in wild-type flies, but not in fmr1 mutant flies.