Abstract
Our recent study has shown that prenatal exposure to bisphenol A (BPA) altered the expression of genes associated with autism spectrum disorder (ASD). In this study, we further investigated the effects of prenatal BPA exposure on ASD-related genes known to regulate neuronal viability, neuritogenesis, and learning/memory, and assessed these functions in the offspring of exposed pregnant rats. We found that prenatal BPA exposure increased neurite length, the number of primary neurites, and the number of neurite branches, but reduced the size of the hippocampal cell body in both sexes of the offspring. However, in utero exposure to BPA decreased the neuronal viability and the neuronal density in the hippocampus and impaired learning/memory only in the male offspring while the females were not affected. Interestingly, the expression of several ASD-related genes (e.g. Mief2, Eif3h, Cux1, and Atp8a1) in the hippocampus were dysregulated and showed a sex-specific correlation with neuronal viability, neuritogenesis, and/or learning/memory. The findings from this study suggest that prenatal BPA exposure disrupts ASD-related genes involved in neuronal viability, neuritogenesis, and learning/memory in a sex-dependent manner, and these genes may play an important role in the risk and the higher prevalence of ASD in males subjected to prenatal BPA exposure.
Highlights
Our recent study has shown that prenatal exposure to bisphenol A (BPA) altered the expression of genes associated with autism spectrum disorder (ASD)
Regarding the samples used for the RNA-seq analysis, RNA samples were isolated from hippocampal tissues of neonatal rat pups whose mothers were exposed to BPA at 5000 μg/kg maternal body weight daily (BPA n = 6, male pups n = 3 and female pups n = 3) or to vehicle control from gestational day 0 (GD0) until parturition as shown in Supplementary Fig. S1
We found that certain neurological traits exhibited sex-dependent relationships with the expression of these selected genes. An example of those neurological traits is the number of neurite branches that showed a positive correlation with the expression of these genes (i.e. Mief[2], Eif3h, Cux[1], Kdm5c, Arhgap[32], Itga[4], and Atp8a1) in the male offspring but exhibited an inverse correlation in the female. These results suggest that dysregulation of the genes induced by prenatal BPA exposure is correlated with the impairment of neurological functions and with learning and memory behaviors in a sex-dependent manner, suggesting that BPA may exert its effects on neuronal viability, neuritogenesis, and learning/memory of offspring through sex-specific molecular mechanisms
Summary
Our recent study has shown that prenatal exposure to bisphenol A (BPA) altered the expression of genes associated with autism spectrum disorder (ASD). We further investigated the effects of prenatal BPA exposure on ASD-related genes known to regulate neuronal viability, neuritogenesis, and learning/memory, and assessed these functions in the offspring of exposed pregnant rats. The reanalysis of transcriptome profiling data from previously published BPA studies showed that BPA-responsive genes were significantly associated with ASD-related genes[17] These findings strongly support that prenatal BPA exposure may increase the risk and involve in the male bias of ASD. They found that maternal BPA exposure reduced neuron quantities and spine densities in the hippocampus of offspring, and impaired the learning and memory ability of male offspring These studies provided supporting evidence that BPA exposure can disrupt neurological functions and behaviors related to ASD, the link between the dysregulations of ASD-related genes and the altered neurological functions resulting from BPA exposure has never been investigated. Inasmuch as ASD is known to be an early-onset disorder and its pathobiology is thought to occur as early as in the embryonic s tage[66,67], it is important to focus on the prenatal effects to understand the role of BPA in ASD susceptibility
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