p-Nonylphenol (p-NP) is a metabolite of alkylphenol ethoxylates used as surfactants in the manufacturing industry. Although it is reported to have estrogenic activity and to be transferred from the mother to the embryo, no data are available on its effects on the development of the human placenta. In the present study, we investigated estrogen receptors' (ERs) expression in the first trimester human placenta. Using an in vitro model of chorionic villous explants, we then compared the effects of p-NP and 17beta-estradiol (17beta-E2). Finally, a trophoblast-derived choriocarcinoma cell line, BeWo, was used as a model of trophoblast cell differentiation. Our results showed that the first trimester placenta expresses three ER-alpha isoforms of 67, 46, and 39 kDa and one ER-beta isoform of 55 kDa. Immunohistochemistry revealed the expression of ER-alpha in the villous cytotrophoblast, whereas ER-beta was mainly expressed by the syncytiotrophoblast. Treatment of explant cultures with p-NP (10(-9)M) and 17beta-E2 (10(-9)M) significantly increased beta-hCG secretion and cell apoptosis but did not modify ER expression. After 72 h of exposure, hormone release was significantly higher in p-NP- than 17beta-E2-treated explant cultures. By this time, cleavage of caspase-3 was evident in cultures treated with 17beta-E2 and p-NP. In BeWo cells, a caspase-3 band of 20-16 kDa was evident after 1 h of treatment with p-NP and after 24 h of treatment with 17beta-E2 or forskolin. These findings suggest that the human trophoblast may be highly responsive to p-NP and raise concern about maternal exposure in early gestation.