Bisphenol A impairs the double-strand break repair machinery in the germline and causes chromosome abnormalities

Abstract

Bisphenol A (BPA) is a highly prevalent constituent of plastics that has been associated with diabetes, cardiovascular disease, and an increased risk of miscarriages in humans. In mice, BPA exposure disrupts the process of meiosis; however, analysis of the affected molecular pathways is lagging and has been particularly challenging. Here we show that exposure of the nematode Caenorhabditis elegans to BPA, at internal concentrations consistent with mammalian models, causes increased sterility and embryonic lethality. BPA exposure results in impaired chromosome synapsis and disruption of meiotic double-strand break repair (DSBR) progression. BPA carries an anti-estrogenic activity in the germline and results in germline-specific down-regulation of DSBR genes, thereby impairing maintenance of genomic integrity during meiosis. C. elegans therefore constitutes a model of remarkable relevance to mammals with which to assess how our chemical landscape affects germ cells and meiosis.toxicology | oogenesis

High Intake of Dietary Sugar Enhances Bisphenol A (BPA) Disruption and Reveals Ribosome-Mediated Pathways of Toxicity

“…They showed that the set of genes that is downregulated with the BPA/high-sugar diet displays a substantial increase in the number of genes highly expressed in testis ( Figure 4B and Table S2; P = 1.05e-13, Fisher's exact test). These results are in agreement with the observation that BPA impairs germline tissues (Allard and Colaiacovo 2010;Lawson et al 2011;Hunt et al 2012) and suggest that excess sugar might contribute to these toxic effects.…”

“…The effects of BPA exposure on the impairment of chromosome synapsis and double-strand DNA break repair have previously been observed during Caenorhabditis elegans oogenesis (Allard and Colaiacovo 2010), and similar observations were noted in rhesus monkey females (Hunt et al 2012). Hunt et al (2012) further observed abnormal centromere associations, although the mechanisms have remained unclear.…”

“…BPA exposure knocks down the expression of testis-expressed genes BPA has been implicated in the disruption of a variety of reproductive traits in humans and model organisms (Allard and Colaiacovo 2010;Lawson et al 2011;Hunt et al 2012).…”

“…Several studies using animal models and humans have indicated that BPA exposure might produce a broad range of adverse effects, including cancer (Weber Lozada and Keri 2011; Pupo et al 2012), disruption of meiosis and other reproductive anomalies (Allard and Colaiacovo 2010;Hunt et al 2012), impairment of genes that control brain development (Itoh et al 2012), and behavior (Kundakovic et al 2013). In some cases, the phenotypes are accompanied by disrupted expression of DNA methyltransferase 1 and 3A, two enzymes responsible for the incorporation of methyl marks on the DNA (Doherty et al 2010;Itoh et al 2012;Kundakovic et al 2013).…”

“…As observed for acute exposure, the combined exposure suggests that BPA and sugar generate a distinct gene regulatory response. Interaction in the combined exposure might happen either through the independent disruption of functionally related pathways or through the enhancement of the disruption of a single pathway targeted by each individual component in the mixture.BPA exposure knocks down the expression of testis-expressed genes BPA has been implicated in the disruption of a variety of reproductive traits in humans and model organisms (Allard and Colaiacovo 2010;Lawson et al 2011;Hunt et al 2012).To address the issue in Drosophila, we investigated the consequence of the BPA/sugar interaction on gene expression levels in the testis. In agreement with expectations, chronic BPA exposure showed a statistically significant increase in the prevalence of testis-expressed genes in the set of candidates that were downregulated ( Figure 4A; P , 0.001, Fisher's exact test).…”