Promotion of altered hepatic foci development in rat liver, cytochrome P450 enzyme induction and inhibition of cell-cell communication by DDT and some structurally related organohalogen pesticides

Abstract

The organochlorine pesticide 1,1'-(2,2,2-trichloroethylidene) bis(4-chlorobenzene) (DDT) and four structural analogues (bromopropylate, chlorobenzilate, dicofol and fenarimol) were investigated for their ability to inhibit gap junctional intercellular communication both in the Chinese hamster V79 metabolic co-operation assay and in the scrape-loading/dye-transfer assay in WB-F344 rat liver epithelial cells. The pesticides were also studied for their ability to enhance the development of gamma-glutamyltranspeptidase-positive altered hepatic foci and induce cytochrome P450 monooxygenase isoenzymes in nitrosamine-initiated male Sprague-Dawley rats. The in vitro studies showed all organohalogens except fenarimol to be potent inhibitors of cell-cell communication in both test systems used. Concomitant results were recorded in the in vivo study. Thus, all potent inhibitors of intercellular communication were found to enhance significantly foci development and fenarimol was again without any significant effect. All pesticides studied were shown to be potent inducers of the phenobarbital-inducible cytochrome P450b isoenzyme and to cause hepatomegaly. Thus, no strict correlation between cytochrome P450b induction/liver growth and tumour promotion-related effects in vivo and in vitro was apparent for these organohalogen pesticides in the present study.

Health Effects of Chronic Pesticide Exposure: Cancer and Neurotoxicity

“…For example, metabolism of OPs is influenced by a number of genes including paraoxonase (PON1) and the cytochrome P450s (69,72,75,113,161,278). Recently, polymorphisms in PON1 were associated with increased prostate cancer risk among Finnish men (199).…”

Prostate cancer and exposure to pesticides in agricultural settings

“…[12][13][14][15][16][17][18][19][20][21][22][23] With reference to the excesses reported here, the available experimental and epidemiological data suggest that DDT may act as a multiple cancerogen 24 through different epigenetic mechanisms of action. [25][26][27] Limited evidence is available on the ability of dicofol to induce liver cancer in mouse. 28 As reported for DDT, this chemical is also able to inhibit gap-junctional intercellular communications in rodents and human cell systems.…”

“…28 As reported for DDT, this chemical is also able to inhibit gap-junctional intercellular communications in rodents and human cell systems. 25 The available toxicological information on tetradifon only indicate that this compound is weakly positive in sister chromatid exchange assay with human lymphocyte cultures. 29 Specific observations about carcinogenic effects of organochlorine compounds on the prostate gland are very limited.…”

Detailed low‐dose study of 1,1‐b™IS(p‐chlorophenyl)‐2,2,2‐ trichloroethane carcinogenesis suggests the possibility of a hormetic effect

“…7,8 According to many previous reports regarding DDT hepatocarcinogenicity and its mechanisms, the number and area of GST-P-positive foci are increased in an in vivo medium-term bioassay of liver carcinogenesis in rats 9 and gap junctional intercellular communication in liver is inhibited in several in vivo and in vitro bioassays. 10 -15 Furthermore, it is suggested that oxidative DNA damage induced by DDT is one of the important factors in hepatocarcinogenesis, since DDT elicits an increase in lipid peroxidation 16 and its inhibition of gap junctional intercellular communication is partially prevented by the antioxidant vitamin E. 17 The hepatic cytochrome P-450 multistage family of microsomal enzymes can be induced by numerous compounds as a phase I metabolizing enzyme, but the oxidative metabolism partially contributes to elicit the carcinogenic potential of some xenobiotics by augmenting oxidative stress.…”