Estrogenic alkylphenols induce cell death by inhibiting testis endoplasmic reticulum Ca2+ pumps

Industrial alkylphenols in the environment may act as xenoestrogens to disrupt testicular development and decrease male fertility. Amongst possible targets for these compounds are testicular Sertoli cells, which nurture the developing sperm cells. We demonstrate that SERCA 2 and 3 Ca2+ pumps are relatively abundant in rat testis microsomal membranes, and also in Sertoli, myoid, and TM4 cells (a Sertoli cell line). A number of estrogenic alkylphenols such as nonylphenol, octylphenol, bisphenol A, and butylated hydroxytoluene all inhibit testicular Ca2+ ATPase in the low micromolar concentration range. These agents also mobilize intracellular Ca2+ in intact TM4 cells in a manner consistent with the inhibition of ER Ca2+ pumps. Alkylphenols dramatically decrease the viability of TM4 cells, an effect that is reversed by either a caspase inhibitor or by BAPTA, and is therefore consistent with Ca2+-dependent cell death via apoptosis. We postulate that alkylphenols disrupt testicular development by inhibiting ER Ca2+ pumps, thus disturbing testicular Ca2+ homeostasis. (C) 2000 Academic Press.