Abstract
Exposure to bisphenol A (BPA) has been related to male reproductive disorders. Since this endocrine disruptor also displays genotoxic and epigenotoxic effects, it likely alters the spermatogenesis, a process in which both hormones and chromatin remodeling play crucial roles. The hypothesis of this work is that BPA impairs early embryo development by modifying the spermatic genetic and epigenetic information. Zebrafish males were exposed to 100 and 2000 μg/L BPA during early spermatogenesis and during the whole process. Genotoxic and epigenotoxic effects on spermatozoa (comet assay and immunocytochemistry) as well as progeny development (mortality, DNA repairing activity, apoptosis and epigenetic profile) were evaluated. Exposure to 100 µg/L BPA during mitosis slightly increased sperm chromatin fragmentation, enhancing DNA repairing activity in embryos. The rest of treatments promoted high levels of sperm DNA damage, triggering apoptosis in early embryo and severely impairing survival. Regarding epigenetics, histone acetylation (H3K9Ac and H3K27Ac) was similarly enhanced in spermatozoa and embryos from males exposed to all the treatments. Therefore, BPA male exposure jeopardizes embryonic survival and development due to the transmission of a paternal damaged genome and of a hyper-acetylated histone profile, both alterations depending on the dose of the toxicant and the temporal window of exposure.
Highlights
Bisphenol A (BPA; 2,2-bis(4-hydroxyphenyl)propane] was firstly used to enhance the growth of cattle and poultry due to its estrogenic activity, but its actual future would be in epoxy resins and plastic industry[1]
Around 46% of sperm cells from males treated with 100 μg/L bisphenol A (BPA) showed less than 10% of DNA fragmentation, whereas 27% of cells from males exposed to 2000 μg/L BPA had between 40 and 50% of their DNA fragmented (Fig. 1A)
As for long exposure to 100 μg/L BPA, there was a decrease in the percentage of low-damaged sperm cells: 30% had less than 10% of fragmented DNA, whereas all the spermatozoa from males exposed to 2000 μg/L BPA exhibited DNA fragmentation higher than 40%; 29% of these cells had between 70 and 80% of fragmented DNA (Fig. 1B)
Summary
Bisphenol A (BPA; 2,2-bis(4-hydroxyphenyl)propane] was firstly used to enhance the growth of cattle and poultry due to its estrogenic activity, but its actual future would be in epoxy resins and plastic industry[1]. It is widely known that BPA affects male reproduction owing to its endocrine disruptive capacity[13,14,15], little is known about the mechanisms of inheritance to subsequent generations non-exposed to the toxicants In that regard, both genotoxic and epigenotoxic effects on the germline cells might well lie behind the paternal transmission of the toxic effects to the progeny that have been previously reported[16]. Throughout the spermatogenesis, the different cell populations suffer an intense remodelling of the epigenetic information, which involves inheritable modifications altering gene expression that do not change primary DNA sequence, such as DNA methylation, post-translational histone modifications as well as coding and non-coding RNAs28,33 Therein lies another important target of BPA, whose epigenetic toxicity has already been associated with reproductive disorders[34]. Some environmentally-induced epigenetic defects can be inherited through paternal via by subsequent generations when these changes occur in elements escaping from remodelling, such as imprinted genes, or when the enzymes in charge of the epigenetic reprogramming are affected[39,40,41]
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