Effect of nonylphenol and other endocrine-disrupting chemicals on apoptosis and hormone secretion in human granulosa-luteal cells. Exposure to environmental estrogens, nonylphenol, a breakdown product of nonylphenol polyethoxylates, and 4-t-octylphenol, a nonylphenol analogue, has been associated with reduced fertility. The aim of this study was to investigate the mechanism by which 4-t-octylphenol inhibits estrogen and progesterone secretion by granulosa-luteal cells (GLC). Human GLC were treated with 4-t-octylphenol, nonylphenol, 17alpha-ethynylestradiol, tamoxifen, or progesterone and were analyzed for effects on cell number, viability, cell cycle status, and apoptosis. GLCs were cultured for 24 or 48 hours in the presence of vehicle or at concentrations ranging from 0.1 to 10 microM nonylphenol, nonylphenol ethoxylate (NP2), or 4-t-octylphenol. These compounds were also tested at concentrations ranging from 0.1 to 10 microM after exposure to 10(-8) M estradiol or progesterone for 48 hours. After 24 hours, all the test chemicals significantly increased the number of apoptotic cells. There was a dose-related effect on apoptosis with NP2 (0.1 microM-10 microM) and 4-t-octylphenol (10 microM). These results suggest that nonylphenol and other endocrine-disrupting chemicals cause apoptosis in human GLC. Because estradiol and progesterone inhibited estradiol and progesterone secretion in the GLC, estrogen and progesterone-induced apoptosis may be an important mechanism of hormone disruption in the ovary. These findings have implications for human reproduction.