Endrin inhibits adipocyte differentiation by selectively altering expression pattern of CCAAT/enhancer binding protein-alpha in 3T3-L1 cells.
The effects of selected chlorinated cyclodiene pesticides on the adipocyte differentiation process were examined using the 3T3-L1 adipocyte model in vitro. Endrin was found to cause a dose-dependent inhibition of adipocyte differentiation in 3T3-L1 cells. Aldrin and dieldrin were less potent than endrin in interfering with the adipogenic process. Endrin's inhibitory effect was effective only when the pesticide was present in the medium during the first 48 h after exposure of 3T3-L1 cells to adipogenic inducers. Immunoblots analysis revealed that endrin caused a dose-dependent, selective inhibition of the intracellular levels of CCAAT enhancer binding protein (C/EBP)alpha without altering the expression patterns of C/EBPbeta or C/EBPdelta along the differentiation. Supershift analysis showed that DNA-binding capacity of C/EBPalpha was affected most by endrin treatment. Endrin also caused a decrease in the elevation of the adipogenic factor peroxisome proliferator-activated receptor (PPAR)gamma elicited by the adipogenic inducers. However, the cotreatment with troglitazone, a thiazolidinedione known to activate PPARgamma, did not suppress the antiadipogenic action of endrin, indicating that its direct action site is not PPARgamma receptor. Endrin also altered the pattern of activation of nuclear factor-kappaB, a factor activated by 12-O-tetradecanoylphorbol-13-acetate and tumor necrosis factor-alpha, which are known to interfere with adipocyte differentiation. Thus, endrin inhibited the normal decrease in nuclear factor-kappaB-DNA binding observed as cells are acquiring the adipocyte phenotype at a late stage of differentiation. Our results suggest that endrin inhibits adipocyte differentiation through the specific suppression of C/EBPalpha.
Moreno-Aliaga
M J
MJ
Department of Environmental Toxicology and the Center for Environmental Health Sciences, University of California, Davis, California, USA.
Matsumura
F
F
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D022762:CCAAT-Enhancer-Binding Proteins; D002454:Cell Differentiation / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism; D004026:Dieldrin / Q000494:pharmacology; D004347:Drug Interactions; D004732:Endrin / Q000494:pharmacology*; D007306:Insecticides / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D000077288:Troglitazone
D000975:Antioxidants; D022762:CCAAT-Enhancer-Binding Proteins; D002839:Chromans; D004268:DNA-Binding Proteins; D007306:Insecticides; D016328:NF-kappa B; D009687:Nuclear Proteins; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D004026:Dieldrin; D000077288:Troglitazone; D004732:Endrin