Low dose DDT inhibition of hepatocarcinogenesis initiated by diethylnitrosamine in male rats: Possible mechanisms

• Published in: Toxicology and applied pharmacology Vol. 208; no. 3; pp. 285 - 294
• Main Authors: Kushida, Masahiko, Sukata, Tokuo, Uwagawa, Satoshi, Ozaki, Keisuke, Kinoshita, Anna, Wanibuchi, Hideki, Morimura, Keiichirou, Okuno, Yasuyoshi, Fukushima, Shoji
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01.11.2005; Elsevier
• Subjects: Administration, Oral; Animals; Apoptosis - drug effects; Biological and medical sciences; Cell Proliferation - drug effects; Connexins - drug effects; Connexins - genetics; Connexins - metabolism; Cytochrome P-450 Enzyme System - drug effects; Cytochrome P-450 Enzyme System - metabolism; DDT; DDT - administration & dosage; DDT - pharmacology; Deoxyguanosine - antagonists & inhibitors; Diethylnitrosamine - administration & dosage; Diethylnitrosamine - antagonists & inhibitors; Diethylnitrosamine - toxicity; Disease Models, Animal; DNA Damage - drug effects; DNA Glycosylases - drug effects; DNA Glycosylases - genetics; DNA Glycosylases - metabolism; DNA, Single-Stranded - drug effects; Dose-Response Relationship, Drug; Drug Administration Schedule; Gap junction; Gap Junction beta-1 Protein; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression; Glutathione S-Transferase pi - antagonists & inhibitors; Glutathione S-Transferase pi - drug effects; Glutathione S-Transferase pi - metabolism; Glutathione Transferase - antagonists & inhibitors; Glutathione Transferase - drug effects; Glutathione Transferase - metabolism; Hepatocarcinogenesis; Hepatocyte Nuclear Factor 1-alpha - drug effects; Hepatocyte Nuclear Factor 1-alpha - genetics; Hepatocyte Nuclear Factor 1-alpha - metabolism; Immunochemistry - methods; Injections, Intraperitoneal; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - metabolism; Liver Neoplasms, Experimental - prevention & control; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Low dose; Male; Medical sciences; Oxidative stress; Pesticides, fertilizers and other agrochemicals toxicology; Proliferating Cell Nuclear Antigen - drug effects; Rats; Rats, Inbred F344; RNA, Messenger - genetics; Time Factors; Toxicology; Tumors; Up-Regulation - drug effects; Oxidative stress; PCNA; GST-P; DAB; HNF-1α; OGG1; Low dose; TCDD; DEPC; DEN; Gap junction; Cx32; Hepatocarcinogenesis; DDT; α-BHC; GJIC; ssDNA; 8-OHdG; Insecticide; Rat; Pesticides; Rodentia; Cell junction; Hepatic disease; Male; Malignant tumor; Carcinogenesis; Liver cancer; Vertebrata; Mammalia; Organochlorine compounds; Animal; Digestive diseases; Inhibitor; Inhibition; Mechanism of action; Oxidative stress; Gap junction
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2005.03.018

Previously we reported a tendency for reduction of the development of glutathione- S-transferase placental form (GST-P) positive foci, recognized as preneoplastic changes in rat liver, by a low dose of 1,1-bis( p-chlorophenyl)-2,2,2-trichloroethane (DDT), which belongs to the same group of hepatic cytochrome P-450 inducers as phenobarbital and is itself a non-genotoxic hepatocarcinogen. In order to clarify the biological significance of this phenomenon, we investigated the reproducibility and changes in other parameters using an initiation–promotion model in which male F344 rats were treated with DDT at doses of 0, 0.005, 0.5, 500 ppm in the diet for 11 or 43 weeks after initiation of hepatocarcinogenesis with N-diethylnitrosamine (DEN). When 500 ppm DDT was applied, the formation of GST-P positive foci and tumor were markedly elevated. In contrast, induction of GST-P positive foci and liver tumors tended to be inhibited at a dose of 0.005 ppm, correlating with protein levels of cytochrome P450 2B1 and 3A2 (CYP2B1 and 3A2) and generation of 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. mRNA levels for 8-oxoguanine glycosylase 1 (OGG1), an 8-OHdG repair enzyme, connexin 32 (Cx32), a major component of Gap junctions, and hepatic nuclear factor 1α (HNF-1α), a Cx32 regulator, were inversely correlated with GST-P positive foci and tumor formation. These results indicate that low dose DDT may indeed exhibit inhibitory effects on chemically initiated-rat hepatocarcinogenicity, in contrast to the promotion observed with high doses, and that this is related to changes in metabolizing enzymes, cell communication, and DNA damage and its repair.