Bisphenol A causes reproductive toxicity, decreasesdnmt1transcription, and reduces global DNA methylation in breeding zebrafish(Danio rerio)

Abstract

Bisphenol A (BPA) is a commercially important high production chemical widely used in epoxy resins and polycarbonate plastics, and is ubiquitous in the environment. Previous studies demonstrated that BPA activates estrogenic signaling pathways associated with adverse effects on reproduction in vertebrates and that exposure can induce epigenetic changes. We aimed to investigate the reproductive effects of BPA in a fish model and to document its mechanisms of toxicity. We exposed breeding groups of zebrafish (Danio rerio) to 0.01, 0.1, and 1 mg/L BPA for 15 d. We observed a significant increase in egg production, together with a reduced rate of fertilization in fish exposed to 1 mg/L BPA, associated with significant alterations in the transcription of genes involved in reproductive function and epigenetic processes in both liver and gonad tissue at concentrations representing hotspots of environmental contamination (0.1 mg/L) and above. Of note, we observed reduced expression of DNA methyltransferase 1 (dnmt1) at environmentally relevant concentrations of BPA, along with a significant reduction in global DNA methylation, in testes and ovaries following exposure to 1 mg/L BPA. Our findings demonstrate that BPA disrupts reproductive processes in zebrafish, likely via estrogenic mechanisms, and that environmentally relevant concentrations of BPA are associated with altered transcription of key enzymes involved in DNA methylation maintenance. These findings provide evidence of the mechanisms of action of BPA in a model vertebrate and advocate for its reduction in the environment.

Bisphenol A: Understanding Its Health Effects from the Studies Performed on Model Organisms

“…BPA activates this pathway by increasing phosphorylation of Mapk3/1and cAMP concentrations in zebraish oocytes. Activation of this pathway prevents the resumption of meiotic maturation in ish oocytes [83]. Study showed that BPA downregulated oocyte maturation-promoting signals through changes in the chromatin structure mediated by histone modiications in zebraish [85].…”

“…Structurally distorted and less developed oocytes were also observed [82]. A study by Laing et al [83] documented signiicant increase in egg production, together with a reduced rate of fertilization in zebraish exposed to BPA, associated with considerable alterations in the transcription of genes involved in reproductive function and epigenetic processes in both liver (vtg1, esr2b, hdac3, mbd2, mecp2 and dnmt1) and gonad tissue (esr2a, cyp19a1a and amh). Their study demonstrated how BPA disrupts reproductive processes in zebraish.…”

Zebrafish in Toxicology and Environmental Health

“…BPA is suggested to act through epigenetic mechanisms through histone modification and alteration of DNA methylation (Faulk et al, 2016; Kundakovic & Champagne, 2011; Santangeli et al, 2016), and zebrafish studies have provided key mechanistic insights. The effect of BPA on histone methylation patterns and DNA methylation has recently been shown in adult zebrafish (Laing et al, 2016; Santangeli et al, 2016). Global DNA methylation has also recently been shown to be reduced in the ovaries and testes of adult zebrafish exposed to 15 μg/L BPA for 7 days (Liu, Zhang, et al, 2016) and 1 mg/L BPA for 15 days (Laing et al, 2016).…”

“…The effect of BPA on histone methylation patterns and DNA methylation has recently been shown in adult zebrafish (Laing et al, 2016; Santangeli et al, 2016). Global DNA methylation has also recently been shown to be reduced in the ovaries and testes of adult zebrafish exposed to 15 μg/L BPA for 7 days (Liu, Zhang, et al, 2016) and 1 mg/L BPA for 15 days (Laing et al, 2016). Adult female zebrafish exposed to environmentally relevant concentrations of BPA, from 5 to 20 μg/L, displayed nonmonotonic effects in that the lowest dose tested led to a complete block in ovulation, accompanied by more significant reduction in gene expression of the estrogen receptors esr1 and esr2a , and induction of apoptosis markers caspase3 and p53 (Santangeli et al, 2016).…”

An old culprit but a new story: bisphenol A and “NextGen” bisphenols

“…Epigenetic modifications include changes in DNA methylation, histone post-translational modifications, and noncoding RNAs, and the mechanism(s) through which BPA induces transgenerational phenotypes remain unknown. Although several reports suggest that BPA exposure can induce changes in DNA methylation patterns in somatic tissues ([27–29]; reviewed in Xin et al [14]), and a single study (26) has reported DNA methylation changes in mature sperm two generations after exposure, at present no study has demonstrated the induction of specific germline changes and their persistence across generations.…”