title: Dichlorodiphenyltrichloroethane technical mixture regulates cell cycle and apoptosis genes through the activation of CAR and ERα in mouse livers.
abstract: Dichlorodiphenyltrichloroethane (DDT) is a widely used organochlorine pesticide and a xenoestrogen that promotes rodent hepatomegaly and tumours. A recent study has shown significant correlation between DDT serum concentration and liver cancer incidence in humans, but the underlying mechanisms remain elusive. We hypothesised that a mixture of DDT isomers could exert effects on the liver through pathways instead of classical ERs. The acute effects of a DDT mixture containing the two major isomers p,p'-DDT (85%) and o,p'-DDT (15%) on CAR and ERα receptors and their cell cycle and apoptosis target genes were studied in mouse livers. ChIP results demonstrated increased CAR and ERα recruitment to their specific target gene binding sites in response to the DDT mixture. The results of real-time RT-PCR were consistent with the ChIP data and demonstrated that the DDT was able to activate both CAR and ERα in mouse livers, leading to target gene transcriptional increases including Cyp2b10, Gadd45β, cMyc, Mdm2, Ccnd1, cFos and E2f1. Western blot analysis demonstrated increases in cell cycle progression proteins cMyc, Cyclin D1, CDK4 and E2f1 and anti-apoptosis proteins Mdm2 and Gadd45β. In addition, DDT exposure led to Rb phosphorylation. Increases in cell cycle progression and anti-apoptosis proteins were accompanied by a decrease in p53 content and its transcriptional activity. However, the DDT was unable to stimulate the β-catenin signalling pathway, which can play an important role in hepatocyte proliferation. Thus, our results indicate that DDT treatment may result in cell cycle progression and apoptosis inhibition through CAR- and ERα-mediated gene activation in mouse livers. These findings suggest that the proliferative and anti-apoptotic conditions induced by CAR and ERα activation may be important contributors to the early stages of hepatocarcinogenesis as produced by DDT in rodent livers.
authors.affiliation: Institute of Molecular Biology and Biophysics SB RAMS, Novosibirsk, Timakova str., 2, 630117, Russia.
authors.forename: Yuliya A
authors.initials: YA
authors.lastname: Kazantseva
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Yarushkin
authors.forename: Vladimir O
authors.initials: VO
authors.lastname: Pustylnyak
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics*; D048429:Cell Size / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D045424:Complex Mixtures; D000090702:Constitutive Androstane Receptor; D003634:DDT / Q000633:toxicity*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000187:drug effects*; D016158:Genes, p53 / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects; D006529:Hepatomegaly / Q000139:chemically induced / Q000473:pathology; D007306:Insecticides / Q000633:toxicity*; D007536:Isomerism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D045424:Complex Mixtures; D000090702:Constitutive Androstane Receptor; D018076:DNA, Complementary; D047628:Estrogen Receptor alpha; D007306:Insecticides; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D051176:beta Catenin; D004958:Estradiol; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D003634:DDT
keywords: Apoptosis; CAR; Cell cycle; DDT; ERα