Prenatal exposure to bisphenol A alters the transcriptome-interactome profiles of genes associated with Alzheimer's disease in the offspring hippocampus

Abstract

Our recent study revealed that prenatal exposure to bisphenol A (BPA) disrupted the transcriptome profiles of genes in the offspring hippocampus. In addition to genes linked to autism, several genes associated with Alzheimer's disease (AD) were found to be differentially expressed, although the association between BPA-responsive genes and AD-related genes has not been thoroughly investigated. Here, we demonstrated that in utero BPA exposure also disrupted the transcriptome profiles of genes associated with neuroinflammation and AD in the hippocampus. The level of NF-κB protein and its AD-related target gene Bace1 were significantly increased in the offspring hippocampus in a sex-dependent manner. Quantitative RT-PCR analysis also showed an increase in the expression of Tnf gene. Moreover, the reanalysis of transcriptome profiling data from several previously published BPA studies consistently showed that BPA-responsive genes were significantly associated with top AD candidate genes. The findings from this study suggest that maternal BPA exposure may increase AD risk in offspring by dysregulating genes associated with AD neuropathology and inflammation and reveal a possible relationship between AD and autism, which are linked to the same environmental factor. Sex-specific effects of prenatal BPA exposure on the susceptibility of AD deserve further investigation.

Figure 1

Interactome analysis of genes differentially expressed in the hippocampus of offspring rats prenatally exposed to BPA when using rat offspring consisting of both sexes (a), only males (b), and only females (c), as predicted by Ingenuity Pathway Analysis. Red = up-regulation; Green = down-regulation.

Figure 2

NF-κB and inflammatory cytokines associated with Alzheimer’s disease were increased in the hippocampi of rats prenatally exposed to BPA. The protein level of NF-κB (a–c) and the expression of Tnf (d,e), Il1b (f,g), and Il6 (h,i) were determined in both sexes and separately in the hippocampus of offspring rats prenatally exposed to BPA (male n = 6; female n = 6) or vehicle control (male n = 6; female n = 6). The differences between two groups were analyzed by two-tailed Student’s t-test. P-value < 0.05 is considered as significant.

Figure 3

Prenatal BPA exposure increased the expression of Bace1 in the rat hippocampus. The expression levels of Bace1 (a,b) and the protein levels of APP (c,e) and Aβ (f–h) were determined in the hippocampus of rats prenatally exposed to BPA (male n = 6; female n = 6) or vehicle control (male n = 6; female n = 6). The differences between two groups were analyzed by two-tailed Student’s t-test. P-value < 0.05 is considered as significant.