Abstract
BackgroundBisphenol S (BPS) is increasingly used as a replacement for bisphenol A in the manufacture of products containing polycarbonates and epoxy resins. However, further studies of BPS exposure are needed for the assessment of health risks to humans. In this study we assessed the potential harmfulness of low-dose BPS on reproduction in male mice.MethodsTo simulate human exposure under experimental conditions, 8-week-old outbred ICR male mice received 8 weeks of drinking water containing a broad range of BPS doses [0.001, 1.0, or 100 μg/kg body weight (bw)/day, BPS1–3] or vehicle control. Mice were sacrificed and testicular tissue taken for histological analysis and protein identification by nano-liquid chromatography/mass spectrometry (MS) and sperm collected for immunodetection of acetylated lysine and phosphorylated tyrosine followed by protein characterisation using matrix-assisted laser desorption ionisation time-of-flight MS (MALDI-TOF MS).ResultsThe results indicate that compared to vehicle, 100 μg/kg/day exposure (BPS3) leads to 1) significant histopathology in testicular tissue; and, 2) higher levels of the histone protein γH2AX, a reliable marker of DNA damage. There were fewer mature spermatozoa in the germ layer in the experimental group treated with 1 μg/kg bw (BPS2). Finally, western blot and MALDI-TOF MS studies showed significant alterations in the sperm acetylome and phosphorylome in mice treated with the lowest exposure (0.001 μg/kg/day; BPS1), although the dose is several times lower than what has been published so far.ConclusionsIn summary, this range of qualitative and quantitative findings in young male mice raise the possibility that very low doses of BPS may impair mammalian reproduction through epigenetic modifications of sperm proteins.
Highlights
Bisphenol A (BPA) is well-documented as an endocrine disruptor with detrimental effects on reproduction [1]; as a result of increasing scrutiny of BPA, there is a broad interest in substitution of alternative bisphenols for human consumption
Bisphenol S (BPS) is classified as an endocrine disruptor and its dose-response is more likely to be nonmonotonic, very-low doses may be more effective than high doses
There were no differences between the experimental groups and the vehicle control (Table 1)
Summary
Bisphenol A (BPA) is well-documented as an endocrine disruptor with detrimental effects on reproduction [1]; as a result of increasing scrutiny of BPA, there is a broad interest in substitution of alternative bisphenols for human consumption. Recent studies have reported BPS induces epigenetic changes, including alterations in the histone code in oocytes, increased DNA methylation in mouse spermatocytes and changes to transcriptome and proteome of cells in testicular tissue and many other cells types [7,8,9,10] These findings suggest BPS may disrupt male reproductive functions through post-translational modifications (PTMs) of nucleic acids and proteins [1, 11, 12] and regulation of transcriptionally silenced spermatozoa [13]. Lysine acetylation and tyrosine phosphorylation of sperm proteins regulate spermatogenesis and sperm capacitation [14,15,16] Based on these studies, it is possible that low doses of BPS could modulate male reproduction through PTMs of protein and nucleic acid structure. In this study we assessed the potential harmfulness of low-dose BPS on reproduction in male mice
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