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Toxicity and Carcinogenicity of Dichlorodiphenyltrichloroethane (DDT)
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  • Journal title : Toxicological Research
  • Volume 32, Issue 1,  2016, pp.21-33
  • Publisher : The Korean Society of Toxicology
  • DOI : 10.5487/TR.2016.32.1.021
 Title & Authors
Toxicity and Carcinogenicity of Dichlorodiphenyltrichloroethane (DDT)
Harada, Takanori; Takeda, Makio; Kojima, Sayuri; Tomiyama, Naruto;
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 Abstract
Dichlorodiphenyltrichloroethane (DDT) is still used in certain areas of tropics and subtropics to control malaria and other insect-transmitted diseases. DDT and its metabolites have been extensively studied for their toxicity and carcinogenicity in animals and humans and shown to have an endocrine disrupting potential affecting reproductive system although the effects may vary among animal species in correlation with exposure levels. Epidemiologic studies revealed either positive or negative associations between exposure to DDT and tumor development, but there has been no clear evidence that DDT causes cancer in humans. In experimental animals, tumor induction by DDT has been shown in the liver, lung, and adrenals. The mechanisms of hepatic tumor development by DDT have been studied in rats and mice. DDT is known as a non-genotoxic hepatocarcinogen and has been shown to induce microsomal enzymes through activation of constitutive androstane receptor (CAR) and to inhibit gap junctional intercellular communication (GJIC) in the rodent liver. The results from our previously conducted 4-week and 2-year feeding studies of p,p`-DDT in F344 rats indicate that DDT may induce hepatocellular eosinophilic foci as a result of oxidative DNA damage and leads them to hepatic neoplasia in combination with its mitogenic activity and inhibitory effect on GJIC. Oxidative stress could be a key factor in hepatocarcinogenesis by DDT.
 Keywords
Enzyme induction;CAR activation;Oxidative stress;Cell proliferation;Intercellular communication;Eosinophilic foci;DDT;
 Language
English
 Cited by
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Shedding New Lights with the Breakthrough Ideas to Understand Current Trends in Modern Toxicology, Toxicological Research, 2016, 32, 1, 1  crossref(new windwow)
 References
1.
ATSDR. (2002) Toxicological profile for DDT, DDE and DDD. U.S. department of health and human services. Public health service. Agency for toxic substances and disease registry.

2.
Vos, J.G., Dybing, E., Greim, H.A., Ladefoged, O., Lambre, C., Tarazona, J.V., Brandt, I. and Vethaak, A.D. (2000) Health effects of endocrine-disrupting chemicals on wildlife, with special reference to European situation. Crit. Rev. Toxicol., 30, 71-133. crossref(new window)

3.
WHO. (2008) World malaria report 2008. Global malaria program. World health organization.

4.
International Agency for Research on Cancer (IARC). (1991) Occupational exposures in insecticide application, and some pesticides. IARC monographs on the evaluation of carcinogenic risks to humans, 53, 179-249.

5.
Harada, T., Yamaguchi, S., Ohtsuka, R., Takeda, M., Fujisawa, H., Yoshida, T., Enomoto, A., Chiba, Y., Fukumori, J., Kojima, S., Tomiyama, N., Saka, M., Ozaki, M. and Maita, K. (2003) Mechanisms of promotion and progression of preneoplastic lesions in hepatocarcinogenesis by DDT in F344 rats. Toxicol. Pathol., 31, 87-98. crossref(new window)

6.
Lee, S. and Kim, J.S. (2014) Mitophagy: Therapeutic potentials for liver disease and beyond. Toxicol. Res., 30, 243-250. crossref(new window)

7.
Auger, C., Alhasawi, A., Contravadoo, M. and Appanna, V.D. (2015) Dysfunctional bioenergetics and the pathogenesis of hepatic disorders. Front. Cell Dev. Biol., 3, 40.

8.
Jaeschke, H., Gores, G.J., Cederbaum, A.I., Hinson, J.A., Pessayre, D. and Lemasters, J.J. (2002) Mechanisms of hepatotoxicity. Toxicol. Sci., 65, 166-176. crossref(new window)

9.
Pessayre, D., Mansouri, A., Haouzi, D. and Fromenty, B. (1999) Hepatotoxicity due to mitochondrial dysfunction. Cell Biol. Toxicol., 15, 367-373. crossref(new window)

10.
Rogan, W.J. and Chen, A. (2005) Health risks and benefits of bis(4-chlorophenyl)-1,1,1-trichloroethane (DDT). Lancet, 366, 763-773. crossref(new window)

11.
Kelce, W.R., Stone, C.R., Laws, S.C., Gray, L.E., Kemppainen, J.A. and Wilson, E.M. (1995) Persistent DDT metabolite p,p'-DDE is a potent androgen receptor antagonist. Nature, 375, 581-585. crossref(new window)

12.
Hojo, H., Aoyama, H., Takahashi, K.L., Shimizu, N., Araki, M., Takizawa, Y., Sakasai, K., Kuwahara, M., Saka, M. and Teramoto, S. (2006) Two-generation reproduction toxicity study in rats with 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (p,p'-DDT). Congenital Anomalies, 46, 105-114. crossref(new window)

13.
Turusov, V., Rakitsky, V. and Tomatis, L. (2002) Dichlorodiphenyltrichloroethane (DDT): ubiquity, persistence, and risks. Environ. Health Perspect., 110, 125-128. crossref(new window)

14.
Flodstrom, S., Hemming, H., Warngard, L. and Ahlborg, U.G. (1990) 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. Carcinogenesis, 11, 1413-1417. crossref(new window)

15.
Lubet, R.A., Dragnev, K.H., Chauhan, D.P., Nims, R.W., Diwan, B.A., Ward, J.M., Jones, C.R., Rice, J.M. and Miller, M.S. (1992) A pleiotropic response to phenobarbital-type enzyme inducers in the F344/NCr rat. Biochem. Pharmacol., 43, 1067-1078. crossref(new window)

16.
Nims, R.W., Lubet, R.A., Fox, S.D., Jones, C.R., Thomas, P.E., Reddy, A.B. and Kocarek, T.A. (1998) Comparative pharmacodynamics of CYP2B induction by DDT, DDE, and DDD in male rat liver and cultured rat hepatocytes. J. Toxicol. Environ. Health Part A, 53, 455-477. crossref(new window)

17.
Sierra-Santoyo, A., Hernandez, M., Albores, A. and Cebrian, M.E. (2000) Sex-dependent regulation of hepatic cytochrome P-450 by DDT. Toxicol. Sci., 54, 81-87. crossref(new window)

18.
Jansen, L.A. and Jongen, W.M. (1996) The use of initiated cells as a test system for detection of inhibitors of gap junctional intercellular communication. Carcinogenesis, 17, 333-339. crossref(new window)

19.
Klaunig, J.E. and Ruch, R.J. (1987) Strain and species effects on the inhibition of hepatocyte intercellular communication by liver tumor promoters. Cancer Lett., 36, 161-168. crossref(new window)

20.
Krutovskikh, V.A., Mesnil, M., Mazzoleni, G. and Yamasaki, H. (1995). Inhibition of rat liver gap junction intercellular communication by tumor-promoting agents in vivo. Lab. Invest., 72, 571-577.

21.
Williams, G.M. (1990) Epigenetic mechanisms of liver tumor promotion. In: mouse liver carcinogenesis: mechanisms and species comparisons (Stevenson, D.E., McClain, R.M., Popp, J.A., Slaga, T.J., Ward, J.M. and Pitot, H.C. edition). Wiley-Liss, New York, pp. 131-145.

22.
Trosko, J.E. and Ruch, R.J. (2002) Gap junctions as targets for cancer chemoprevention and chemotherapy. Curr. Drug Targets, 3, 465-482. crossref(new window)

23.
Parke, D.V. and Ioannides, C. (1990) Role of cytochromes P-450 in mouse liver tumor production. In: mouse liver carcinogenesis: Mechanisms and species Comparisons (Stevenson, D.E., McClain, R.M., Popp, J.A., Slaga, T.J., Ward, J.M. and Pitot, H.C. edition). Wiley-Liss, New York, pp. 215-230.

24.
Hall, A.P., Elcombe, C.R., Foster, J.R., Harada, T., Kaufmann, W., Knippel, A., Kuttler, K., Malarkey, D.E., Maronpot, R.R., Nishikawa, A., Nolte, T., Schulte, A., Strauss, V. and York, M.J. (2012) Liver hypertrophy: a review of adaptive (adverse and non-adverse) changes- conclusions from the 3rd International ESTP Expert Workshop. Toxicol. Pathol., 40, 971-994. crossref(new window)

25.
Parkinson, A. (1996) An overview of current cytochrome P450 technology for assessing the safety and efficacy of new materials. Toxicol. Pathol., 24, 48-57.

26.
Simic, M.G. (1988) Mechanisms of inhibition of free-radical processes in mutagenesis and carcinogenesis. Mutat. Res., 202, 377-386. crossref(new window)

27.
Clayson, D.B., Mehta, R. and Iverson, F. (1994) Oxidative DNA damage - The effects of certain genotoxic and operationally non-genotoxic carcinogens. Mutat. Res., 317, 25-42. crossref(new window)

28.
Butterworth, B.E., Conolly, R.B. and Morgan, K.T. (1995) A strategy for establishing mode of action of chemical carcinogens as a guide for approaches to risk assessments. Cancer Lett., 93, 129-146. crossref(new window)

29.
Schulte-Hermann, R., Schuppler, J., Timmermann-Trosiener, I., Ohde, G., Bursch, W. and Berger, H. (1983) The role of growth of normal and preneoplastic cell populations for tumor promotion in rat liver. Environ. Health Perspect., 50, 185-194. crossref(new window)

30.
Schulte-Hermann, R., Bursch, W., Grasl-Kranpp, B., Huber, W., and Parzefall, W. (1994) Nongenotoxic carcinogenesis in the liver. In: nongenotoxic carcinogenesis (Cockburn, A. and Smith, L. editions). Springer-Verlag, Berlin, pp. 109-120.

31.
Busser, M.T. and Lutz, W.K. (1987) Stimulation of DNA synthesis in rat and mouse liver by various tumor promoters. Carcinogenesis, 8, 1433-1437. crossref(new window)

32.
Beer, D.G. and Neveu, M.J. (1990) Proto-oncogene and gapjunction protein expression in rodent liver neoplasms. In: mouse liver carcinogenesis: mechanisms and species comparisons (Stevenson, D.E., McClain, R.M., Popp, J.A., Slaga, T.J., Ward, J.M., Pitot, H.C. edition). Wiley-Liss, New York, pp. 293-309.

33.
Whysner, J., Ross, P.M. and Williams, G.M. (1996) Phenobarbital mechanistic data and risk assessment: enzyme induction, enhanced cell proliferation, and tumor promotion. Phamacol. Ther., 71, 153-191.

34.
Yamasaki, H. (1996) Role of disrupted gap junctional intercellular communication in detection and characterization of carcinogens. Mutat. Res., 365, 91-105. crossref(new window)

35.
Loewenstein, W.R. (1979) Junctional intercellular communication and the control of growth. Biochim. Biophys. Acta, 560, 1-65.

36.
Strobel, P., Klimek, F., Zerban, H., Kopp-Schneider, A. and Bannasch, P. (1998) Xenomorphic hepatocellular precursors and neoplastic progression of tigroid cell foci induced in rats with low doses of N-nitrosomorpholine. Carcinogenesis, 19, 2069-2080. crossref(new window)

37.
Bannasch, P., Zerban, H. and Hacker, H.J. (1985) Foci of altered hepatocytes, rat. In: monographs on pathology of laboratory animals, digestive system (Jones, T.C., Mohr, U. and Hunt, R.D. edition). Springer-Verlag, Berlin, pp. 10-30.

38.
Harada, T., Maronpot, R.R., Morris, R.W. and Boorman, G.A. (1989) Observations on altered hepatocellular foci in National Toxicology Program two-year carcinogenicity studies in rats. Toxicol. Pathol., 17, 690-706.

39.
Toh, Y.C. (1973) Physiological and biochemical reviews of sex differences and carcinogenesis with particular reference to the liver. Adv. Cancer Res., 18, 155-209. crossref(new window)

40.
Harada, T., Maronpot, R.R., Morris, R.W., Stitzel, K.A. and Boorman, G.A. (1989) Morphological and stereological characterization of hepatic foci of cellular alteration in control Fischer 344 rats. Toxicol. Pathol., 17, 579-593.

41.
Thurman, J.D., Bucci, T.J., Hart, R.W. and Turturro, A. (1994) Survival, body weight, and spontaneous neoplasms in ad libitum-fed and food-restricted Fischer-344 rats. Toxicol. Pathol., 22, 1-9. crossref(new window)