Abstract
Aim: Evidence suggests that bisphenol A diglycidyl ether (BADGE), bisphenol A (BPA), and BPA analogs can interfere with human male fertility. However, the effect directly on human sperm function is not known. The CatSper Ca2+ channel in human sperm controls important sperm functions and is necessary for normal male fertility. Environmental chemicals have been shown to activate CatSper and thereby affect Ca2+ signaling in human sperm. BPA has previously been investigated for effects on Ca2+ signaling human sperm, whereas the effects of other BPA analogs are currently unknown. The aim of this study is thus to characterize the effect of BADGE, BPA, and the eight analogs BPG, BPAF, BPC, BPB, BPBP, BPE, BPF, BPS on Ca2+ signaling, and CatSper in human sperm.Methods: Direct effects of the bisphenols on Ca2+ signaling in human sperm cells were evaluated using a Ca2+ fluorimetric assay measuring changes in intracellular Ca2+. Effects via CatSper were assessed using the specific CatSper inhibitor RU1968. Effects on human sperm function was assessed using an image cytometry-based acrosome reaction assay and the modified Kremer's sperm–mucus penetration assay.Results: At 10 μM the bisphenols BPG, BPAF, BPC, BADGE, BPB, and BPBP induced Ca2+ signals in human sperm cells, whereas BPE, BPF, BPS, and BPA had no effect. The efficacy of the chemicals at 10 μM is BPG > BPAF > BPC > BADGE > BPB > BPBP. Dose-response relations of BPG, BPAF, BPC, BADGE, BPB, and BPBP yielded EC50-values in the nM-μM range. The induced Ca2+ signals were almost completely abolished using the CatSper inhibitor RU1968, indicating an effect of the bisphenols on CatSper. All bisphenols, except BPBP, were found to dose-dependently inhibit progesterone-induced Ca2+ signals, with BPG and BPAF displaying inhibition even in low μM doses. BPG and BPAF were shown to affect human sperm function in a progesterone-like manner.Conclusion: Our results show that the bisphenols BPG, BPAF, BPC, BADGE, BPB, and BPBP can affect Ca2+ signaling in human sperm cells through activation of CatSper. This could potentially disrupt human sperm function by interfering with normal CatSper-signaling and thus be a contributing factor in human infertility, either alone or in mixtures with other chemicals.
Highlights
Humans are widely exposed to bisphenol A (BPA), a highproduction-volume chemical [1], and bisphenol A diglycidyl ether (BADGE), both widely used in the production of, e.g., epoxy resins and food container linings [2]
Evidence suggests that BPA and its analogs can interfere with human male fertility [4,5,6,7,8], the effects directly on human sperm function are less well-studied
We investigated the 10 bisphenols BADGE, BPA, BPG, BPAF, BPC, BPB, BPBP, BPE, BPF, and BPS for their ability to induce Ca2+ signals in human sperm cells (Table 1), using a Ca2+ fluorimetric assay [34]
Summary
Humans are widely exposed to bisphenol A (BPA), a highproduction-volume chemical [1], and bisphenol A diglycidyl ether (BADGE), both widely used in the production of, e.g., epoxy resins and food container linings [2]. Evidence suggests that BPA and its analogs can interfere with human male fertility [4,5,6,7,8], the effects directly on human sperm function are less well-studied. The activation of CatSper by progesterone controls important sperm functions [13]. Studies have shown that human CatSper can be promiscuously activated by various signaling molecules [30], steroids [31, 32], small molecules [33], and environmental chemicals [34,35,36,37,38,39]. As only BPA, and none of its structural analogs, has previously been investigated for effects on Ca2+ signaling in human sperm cells [34, 40], we set out to screen BADGE, BPA, and its eight structural analogs BPG, BPAF, BPC, BPB, BPBP, BPE, BPF, BPS for effects on Ca2+ signaling, and CatSper in human sperm, as well as on human sperm cell function
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