TY - JOUR
T1 - Cytotoxicity and aromatase (CYP19) activity modulation by organochlorines in human placental JEG-3 and JAR choriocarcinoma cells
AU - Letcher, Robert J.
AU - Van Holsteijn, Ineke
AU - Drenth, Henk Jan
AU - Norstrom, Ross J.
AU - Bergman, Åke
AU - Safe, Stephen
AU - Pieters, Raymond
AU - Van Den Berg, Martin
N1 - Funding Information:
We thank Christina Larsson (Wallenberg Laboratory, Stockholm University) for the synthesis of the MeSO2-PCBs. This study was supported from a postdoctoral fellowship from the M&T Graduate School (R.J.L.), Utrecht University and Environment Canada.
PY - 1999/10/1
Y1 - 1999/10/1
N2 - 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 μM 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-MeSO2-2,2',5,5'- tetrachlorobiphenyl 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 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- tetrachlorodibenzo-p-dioxin (up to 10 μM). 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.
AB - 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 μM 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-MeSO2-2,2',5,5'- tetrachlorobiphenyl 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 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- tetrachlorodibenzo-p-dioxin (up to 10 μM). 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.
KW - Aromatase (CYP19)
KW - Cytotoxicity
KW - JEG-3/JAR cells
KW - Metabolites
KW - Organochlorines
KW - Placenta
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U2 - 10.1006/taap.1999.8746
DO - 10.1006/taap.1999.8746
M3 - Article
C2 - 10502498
AN - SCOPUS:0033214715
SN - 0041-008X
VL - 160
SP - 10
EP - 20
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
IS - 1
ER -