Open AccessComparative Tumorigenicity and DNA Damage Induced by Dibenzo[def,p]chrysene and Its Metabolites in the Mouse Ovary
Author(s) -
Kun Ming Chen,
Yuan Sun,
Timothy K. Cooper,
Gabrielle Benitez,
César Aliaga,
Junjia Zhu,
Raghavendra Gowda,
Shantu Amin,
Karam ElBayoumy
Publication year - 2018
Publication title -
chemical research in toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.031
H-Index - 156
eISSN - 1520-5010
pISSN - 0893-228X
DOI - 10.1021/acs.chemrestox.8b00152
Subject(s) - ovary , chrysene , carcinogen , dna damage , ovarian cancer , chinese hamster ovary cell , dimethyl sulfoxide , biology , chemistry , cancer , physiology , dna , toxicology , medicine , pharmacology , endocrinology , biochemistry , genetics , pyrene , cell culture , organic chemistry , astrobiology
Ovarian cancer ranked second in incidence among gynecologic cancers, but it causes more deaths than any other gynecologic cancer; at present there is no curative treatment beyond surgery. Animal models that employ carcinogens found in the human environment can provide a realistic platform to understand the mechanistic basis for disease development and to design rational chemopreventive/therapeutic strategies. We and others have shown that the administration of the environmental pollutant and tobacco smoke constituent dibenzo[ def,p]chrysene (DBP) to mice by several routes of exposure can induce tumors in multiple sites including the ovary. In the present study we compared, for the first time, the tumorigenicity and DNA damage induced by DBP and its metabolites DBP-dihydrodiol (DBPDHD) and DBP-dihydrodiol epoxide (DBPDE) in the mouse ovary. Compounds were dissolved in dimethyl sulfoxide (DMSO) as the vehicle and administered by topical application into the mouse oral cavity three times per week for 38 weeks. No tumors were observed in mice treated with DMSO. At equal dose (24 nmol/30 μL DMSO), the incidence of ovarian tumors induced by DBPDHD was higher (60.7%), although not significantly, than that induced by DBP (44.8%). Similarly the levels of DNA damage induced by DBPDHD in the ovary were higher than those observed with DBP. We did not observe any histological abnormality in the ovary of mice treated with DBPDE, which is consistent with lack of DNA damage. Our results suggested that both DBP and DBPDHD can be metabolized in the mouse ovary leading to the formation of DBPDE that can damage DNA, which is a prerequisite step in the initiation stage of carcinogenesis.