Synergistic activation of CatSper Ca2+ channels in human sperm by oviductal ligands and endocrine disrupting chemicals

Brenker, Christoph; Rehfeld, Anders; Schiffer, Christian; Kierzek, Michelina; Kaupp, U. Benjamin; Skakkebæk, Niels E.; Strünker, Timo

doi:10.1093/humrep/dey275

Cited by 44 publications

(26 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our findings add BADGE and the five bisphenol analogs BPG, BPAF, BPC, BPB, and BPBP to the growing list of environmental chemicals that can induce Ca 2+ signals in human sperm cells through CatSper (34)(35)(36)(37)(38)(39). Studies have shown that chemicals acting on CatSper can cooperate in low dose mixtures to activate CatSper both additively (34,35) and synergistically (55). As humans in the industrialized part of the world are suggested to be exposed to thousands of environmental chemicals (58), such a low dose mixture exposure scenario is quite realistic.…”

Section: Discussionmentioning

confidence: 60%

“…Interestingly, progesterone has been suggested to activate CatSper through an activation of the enzyme ABHD2, whereas the molecular target of prostaglandins leading to CatSper activation remains unknown (54). The direct action of the bisphenols on the ligand-dependent pathway leading to activation of CatSper in human sperm cells, is similar to what has been shown for multiple other environmental chemicals previously (34,35,55).…”

Section: Discussionmentioning

confidence: 69%

See 1 more Smart Citation

Bisphenol A Diglycidyl Ether (BADGE) and Bisphenol Analogs, but Not Bisphenol A (BPA), Activate the CatSper Ca2+ Channel in Human Sperm

2020

View full text Add to dashboard Cite

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 Ca 2+ 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 Ca 2+ signaling in human sperm. BPA has previously been investigated for effects on Ca 2+ 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 Ca 2+ signaling, and CatSper in human sperm. Methods: Direct effects of the bisphenols on Ca 2+ signaling in human sperm cells were evaluated using a Ca 2+ fluorimetric assay measuring changes in intracellular Ca 2+. 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ 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. Rehfeld et al. Bisphenols Activate Human CatSper Conclusion: Our results show that the bisphenols BPG, BPAF, BPC, BADGE, BPB, and BPBP can affect Ca 2+ signaling in human sperm cells through activation of CatSper. This could potentially disrupt human sperm function by interfering with normal CatSpersignaling and thus be a contributing factor in human infertility, either alone or in mixtures with other chemicals.

show abstract

Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 69%

Bisphenol A Diglycidyl Ether (BADGE) and Bisphenol Analogs, but Not Bisphenol A (BPA), Activate the CatSper Ca2+ Channel in Human Sperm

2020

View full text Add to dashboard Cite

show abstract

“…Changes in [Ca 2+ ] i were measured in sperm (in HTF + ) loaded with the fluorescent Ca 2+ indicator Fluo‐4‐AM at 30°C in 384 multi‐well plates in a fluorescence plate reader (Fluostar Omega, BMG Labtech, Ortenberg, Germany) at 30°C as described before (Schiffer et al , ; Brenker et al , ). Briefly, sperm were loaded with Fluo‐4‐AM (5 μM, 20 min) at 37°C in the presence of Pluronic F‐127 (0.05% w/v).…”

Section: Methodsmentioning

confidence: 99%

Rotational motion and rheotaxis of human sperm do not require functional CatSper channels and transmembrane Ca ²⁺ signaling

et al. 2020

View full text Add to dashboard Cite

Navigation of sperm in fluid flow, called rheotaxis, provides long‐range guidance in the mammalian oviduct. The rotation of sperm around their longitudinal axis (rolling) promotes rheotaxis. Whether sperm rolling and rheotaxis require calcium (Ca2+) influx via the sperm‐specific Ca2+ channel CatSper, or rather represent passive biomechanical and hydrodynamic processes, has remained controversial. Here, we study the swimming behavior of sperm from healthy donors and from infertile patients that lack functional CatSper channels, using dark‐field microscopy, optical tweezers, and microfluidics. We demonstrate that rolling and rheotaxis persist in CatSper‐deficient human sperm. Furthermore, human sperm undergo rolling and rheotaxis even when Ca2+ influx is prevented. Finally, we show that rolling and rheotaxis also persist in mouse sperm deficient in both CatSper and flagellar Ca2+‐signaling domains. Our results strongly support the concept that passive biomechanical and hydrodynamic processes enable sperm rolling and rheotaxis, rather than calcium signaling mediated by CatSper or other mechanisms controlling transmembrane Ca2+ flux.

show abstract

“…Several steroids identified in follicular fluid evoke Ca 2+ and motility responses in human sperm that are similar to those evoked by progesterone ( Blackmore et al, 1990 , 1996 ; Alexander et al, 1996 ; Luconi et al, 2004 ; Brenker et al, 2018b ). Only for some of these steroids, e.g., 17-OH-progesterone and estradiol, it has been shown that they also act via CatSper ( Lishko et al, 2011 ; Strünker et al, 2011 ; Brenker et al, 2018a , b ; Rehfeld, 2020 ). Similarly, it has been shown that CatSper is also activated by prostaglandins other than PGEs, such as PGFs, which are also found in seminal fluid ( Lishko et al, 2011 ; Brenker et al, 2018a ).…”

Section: Introductionmentioning

confidence: 99%

The Action of Reproductive Fluids and Contained Steroids, Prostaglandins, and Zn2+ on CatSper Ca2+ Channels in Human Sperm

Jeschke

Biagioni

Schierling

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The sperm-specific Ca2+ channel CatSper registers chemical cues that assist human sperm to fertilize the egg. Prime examples are progesterone and prostaglandin E1 that activate CatSper without involving classical nuclear and G protein-coupled receptors, respectively. Here, we study the action of seminal and follicular fluid as well of the contained individual prostaglandins and steroids on the intracellular Ca2+ concentration of sperm from donors and CATSPER2-deficient patients that lack functional CatSper channels. We show that any of the reproductive steroids and prostaglandins evokes a rapid Ca2+ increase that invariably rests on Ca2+ influx via CatSper. The hormones compete for the same steroid- and prostaglandin-binding site to activate the channel, respectively. Analysis of the hormones’ structure–activity relationship highlights their unique pharmacology in sperm and the chemical features determining their effective properties. Finally, we show that Zn2+ suppresses the action of steroids and prostaglandins on CatSper, which might prevent premature prostaglandin activation of CatSper in the ejaculate, aiding sperm to escape from the ejaculate into the female genital tract. Altogether, our findings reinforce that human CatSper serves as a promiscuous chemosensor that enables sperm to probe the varying hormonal microenvironment prevailing at different stages during their journey across the female genital tract.

show abstract

Synergistic activation of CatSper Ca2+ channels in human sperm by oviductal ligands and endocrine disrupting chemicals

Cited by 44 publications

References 44 publications

Bisphenol A Diglycidyl Ether (BADGE) and Bisphenol Analogs, but Not Bisphenol A (BPA), Activate the CatSper Ca2+ Channel in Human Sperm

Bisphenol A Diglycidyl Ether (BADGE) and Bisphenol Analogs, but Not Bisphenol A (BPA), Activate the CatSper Ca2+ Channel in Human Sperm

Rotational motion and rheotaxis of human sperm do not require functional CatSper channels and transmembrane Ca ²⁺ signaling

The Action of Reproductive Fluids and Contained Steroids, Prostaglandins, and Zn2+ on CatSper Ca2+ Channels in Human Sperm

Contact Info

Product

Resources

About

Synergistic activation of CatSper Ca2+ channels in human sperm by oviductal ligands and endocrine disrupting chemicals

Cited by 44 publications

References 44 publications

Bisphenol A Diglycidyl Ether (BADGE) and Bisphenol Analogs, but Not Bisphenol A (BPA), Activate the CatSper Ca2+ Channel in Human Sperm

Bisphenol A Diglycidyl Ether (BADGE) and Bisphenol Analogs, but Not Bisphenol A (BPA), Activate the CatSper Ca2+ Channel in Human Sperm

Rotational motion and rheotaxis of human sperm do not require functional CatSper channels and transmembrane Ca 2+ signaling

The Action of Reproductive Fluids and Contained Steroids, Prostaglandins, and Zn2+ on CatSper Ca2+ Channels in Human Sperm

Contact Info

Product

Resources

About

Rotational motion and rheotaxis of human sperm do not require functional CatSper channels and transmembrane Ca ²⁺ signaling