Cytotoxicity and aromatase (CYP19) activity modulation by organochlorines in human placental JEG-3 and JAR choriocarcinoma cells

The human placental JEG3 and JAR choriocarcinoma cell. lines have been used as placental models for the study of aromatase (CYP19) activity and endocr ine functions. In the present study, 21 organochlorines (OCs) mediated decr eases in aromatase activity and protein and DNA content and increases in th e percent lactate dehydrogenase (LDH) leakage in JEG-3 cells, These effects were highly variable among the types of OC and their treatment concentrati ons. Lowest observed effective concentrations reached 0.001 mu M for severa l OCs, Aromatase activity decreases and OC-mediated cytotoxicity: were rela ted. Thus, it was not possible to clearly assess the capacity of the OCs to modulate aromatase activity, Similar to 1,4-naphthaquinone, the most cytot oxic OCs contained a hydroxyl (4'-OH-2,4,6-trichlorobiphenyl and tris(4- ch lorophenyl)methanol) or methylsulfonyl- (3- and 4-MeSO2-2,2',5,5'-tetrachlo robiphenyl and -2,3',4',5-tetrachlorobiphenyl, and 3'- and 4'-MeSO2-2,2',3, 4,5'-pentachlorobiphenyl and -2,2',4,5,5'-pentachlorobiphenyl) functional g roup. Modulation of aromatase activity and LDH leakage were less for 3,3',4 ,4',5-pentachlorobiphenyl and benzo[a]pyrene and insignificant for five alk yl-substituted trichloro-dibenzofurans and 2,3,7,8-tetrachlorodibenzo-p-dio xin (up to 10 mu M). Cytotoxicity-related effects were influenced by the ce ll density and the presence of 10% fetal calf serum in the medium during co mpound incubation, Similar cytotoxic effects were observed for the JAR cell line. The involvement of an apoptotic mechanism of cytotoxicity in OC-trea ted JEG3 cells was suggested by the binding of APO2.7 (an antibody specific to apoptotic cells), DNA fragmentation, and trypan blue staining. JEG-3 an d JAR cells appear too sensitive toward OC-mediated cytotoxicity for use as in vitro bioassays to evaluate the potential modulation of aromatase activ ity. However, these cell hues may prove useful for examining the capacity o f xenobiotics to modulate placental toxicity. (C) 1999 Academic Press.