Synthetic endocrine disrupting chemicals (EDCs), omnipresent in food, household, and personal care products, have been implicated in adverse trends in human reproduction, including infertility and increasing demand for assisted reproduction. Here, we study the action of 96 ubiquitous EDCs on human sperm. We show that structurally diverse EDCs activate the sperm-specific CatSper channel and, thereby, evoke an intracellular Ca 2+ increase, a motility response, and acrosomal exocytosis. Moreover, EDCs desensitize sperm for physiological CatSper ligands and cooperate in low-dose mixtures to elevate Ca 2+ levels in sperm. We conclude that EDCs interfere with various sperm functions and, thereby, might impair human fertilization.

Progesterone released by cumulus cells surrounding the egg induces a Ca influx into human sperm cells via the cationic channel of sperm (CatSper) Ca channel and controls multiple Ca-dependent responses essential for fertilization. We hypothesized that chemical UV filters may mimic the physiological action of progesterone on CatSper, thus affecting Ca signaling in human sperm cells. We examined 29 UV filters allowed in sunscreens in the United States and/or the European Union for their ability to induce Ca signals in human sperm by applying measurements of the intracellular free Ca concentration. We found that 13 UV filters induced a significant Ca signal at 10 μM. Nine UV filters induced Ca signals primarily by activating the CatSper channel. The UV filters 3-benzylidene camphor (3-BC) and benzylidene camphor sulfonic acid competitively inhibited progesterone-induced Ca signals. Dose-response relations for the UV filters showed that the Ca signal-inducing effects began in the nanomolar-micromolar range. Single-cell Ca measurements showed a Ca signal-inducing effect of the most potent UV filter, 3-BC, at 10 nM. Finally, we demonstrated that the 13 UV filters acted additively in low-dose mixtures to induce Ca signals. In conclusion, 13 of 29 examined UV filters (44%) induced Ca signals in human sperm. Nine UV filters primarily activated CatSper and thereby mimicked the effect of progesterone. The UV filters 3-BC and benzylidene camphor sulfonic acid competitively inhibited progesterone-induced Ca signals. In vivo exposure studies are needed to investigate whether UV filter exposure affects human fertility.

The sperm-specific Ca2+ channel CatSper (cation channel of sperm) is vital for male fertility. Contradictory findings have been published on the regulation of human CatSper by the endogenous steroids estradiol, testosterone and hydrocortisone, as well as the plant triterpenoids lupeol and pristimerin. This aim of this study was to elucidate this controversy by investigating the action of these steroids and plant triterpenoids on human CatSper using population based Ca2+-fluorimetric measurements, the specific CatSper inhibitor RU1968, and a functional test assessing the CatSper-dependent penetration of human sperm cells into methylcellulose. Estradiol, testosterone and hydrocortisone were found to induce Ca2+-signals in human sperm cells with EC50 values in the lower μM range. By employing the specific CatSper inhibitor RU1968, all three steroids were shown to induce Ca2+-signals through an action on CatSper, similar to progesterone. The steroids were found to dose-dependently inhibit subsequent progesterone-induced Ca2+-signals with IC50 values in the lower μM range. Additionally, the three steroids were found to significantly increase the penetration of human sperm cells into methylcellulose, similar to the effect of progesterone. The two plant triterpenoids, lupeol and pristimerin, were unable to inhibit progesterone-induced Ca2+-signals, whereas the CatSper inhibitor RU1968 strongly inhibited progesterone-induced Ca2+-signals. In conclusion, this study supports the claim that the steroids estradiol, testosterone and hydrocortisone act agonistically on CatSper in human sperm cells, thereby mimicking the effect of progesterone, and that lupeol and pristimerin do not act as inhibitors of human CatSper.