title: Cytotoxicity and aromatase (CYP19) activity modulation by organochlorines in human placental JEG-3 and JAR choriocarcinoma cells.
abstract: The human placental JEG-3 and JAR choriocarcinoma cell lines have been used as placental models for the study of aromatase (CYP19) activity and endocrine functions. In the present study, 21 organochlorines (OCs) mediated decreases in aromatase activity and protein and DNA content and increases in the percent lactate dehydrogenase (LDH) leakage in JEG-3 cells. These effects were highly variable among the types of OC and their treatment concentrations. Lowest observed effective concentrations reached 0. 001 microM for several OCs. Aromatase activity decreases and OC-mediated cytotoxicity were related. Thus, it was not possible to clearly assess the capacity of the OCs to modulate aromatase activity. Similar to 1,4-naphthoquinone, the most cytotoxic OCs contained a hydroxyl (4'-OH-2,4,6-trichlorobiphenyl and tris(4-chlorophenyl)methanol) or methylsulfonyl- (3- and 4-MeSO(2)-2, 2',5,5'-tetrachlorobiphenyl and -2,3',4',5-tetrachlorobiphenyl, and 3'- and 4'-MeSO(2)-2,2',3,4,5'-pentachlorobiphenyl and -2,2',4,5, 5'-pentachlorobiphenyl) functional group. Modulation of aromatase activity and LDH leakage were less for 3,3',4,4', 5-pentachlorobiphenyl and benzo[a]pyrene and insignificant for five alkyl-substituted trichloro-dibenzofurans and 2,3,7, 8-tetrachloro-dibenzo-p-dioxin (up to 10 microM). Cytotoxicity-related effects were influenced by the cell density and the presence of 10% fetal calf serum in the medium during compound incubation. Similar cytotoxic effects were observed for the JAR cell line. The involvement of an apoptotic mechanism of cytotoxicity in OC-treated JEG-3 cells was suggested by the binding of APO2.7 (an antibody specific to apoptotic cells), DNA fragmentation, and trypan blue staining. JEG-3 and JAR cells appear too sensitive toward OC-mediated cytotoxicity for use as in vitro bioassays to evaluate the potential modulation of aromatase activity. However, these cell lines may prove useful for examining the capacity of xenobiotics to modulate placental toxicity.
authors.affiliation: Research Institute of Toxicology (RITOX), Utrecht University, Utrecht, The Netherlands. r.letcher@ritox.vet.uu.nl
authors.forename: R J
authors.initials: RJ
authors.lastname: Letcher
authors.forename: I
authors.initials: I
authors.lastname: van Holsteijn
authors.forename: H J
authors.initials: HJ
authors.lastname: Drenth
authors.forename: R J
authors.initials: RJ
authors.lastname: Norstrom
authors.forename: A
authors.initials: A
authors.lastname: Bergman
authors.forename: S
authors.initials: S
authors.lastname: Safe
authors.forename: R
authors.initials: R
authors.lastname: Pieters
authors.forename: M
authors.initials: M
authors.lastname: van den Berg
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001141:Aromatase / Q000378:metabolism*; D001572:Benzofurans / Q000633:toxicity*; D002822:Choriocarcinoma / Q000473:pathology; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004249:DNA Damage; D000072338:Dibenzofurans, Polychlorinated; D005260:Female; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D010920:Placenta / Q000187:drug effects* / Q000201:enzymology; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011247:Pregnancy; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D001572:Benzofurans; D000072338:Dibenzofurans, Polychlorinated; D011078:Polychlorinated Biphenyls; D007770:L-Lactate Dehydrogenase; D001141:Aromatase; D019363:Cytochrome P-450 CYP1A1