Polymorphism of xenobiotic metabolizing gene and susceptibility of epithelial ovarian cancer with reference to organochlorine pesticides exposure.

Abstract

The transformation of ovarian surface epithelial cells, stromal cells, sex cord, or germ cells initiates ovarian malignancy. Epithelial ovarian cancer (EOC) is clinically silent with vague, non-specific symptomatology and is generally diagnosed at an advanced stage, resulting in a high mortality rate. The known main etiological factors are: age at menarche and menopause (early menarche or late menopause), use of oral contraception (estrogen and/or progesterone), family history, genetic factors, inflammation, occupational and environmental exposure. The study is intended to assess the association between blood organochlorine pesticide (OCP) levels and polymorphic status of phase I and phase II metabolizing enzymes (CYP1A1, GSTM1, and GSTT1) in the pathogenesis of epithelial ovarian cancer. The study included 200 subjects in total, of which 100 were epithelial ovarian cancer cases and 100 were controls. Estimation of blood organochlorine pesticide levels was carried out using gas chromatography and significantly high levels of beta-hexachlorocyclohexane (β-HCH), endosulfan-I, endosulfan-II, dichlorodiphenyltrichloroethane (pʹpʹ-DDT), dichlorodiphenyldichloroethylene (pʹpʹ-DDE) were observed in cases as compared to controls ( P-value = 0.029, 0.042, 0.044, 0.039 and 0.037 respectively). For studying the polymorphism of CYP1A1, GSTM1/T1, PCR-RFLP, AS-PCR and multiplexing were performed and the frequency of null deletion of GSTM1/T1 was significantly higher in epithelial ovarian cancer cases. Regression model testing was also performed to check the interactive effect of organochlorine pesticide levels and polymorphic variant of genes keeping CA-125 as the dependent variable and observed a statistically significant role of genotypic/environmental interaction in epithelial ovarian cancer cases in the North Indian population. Impact statement Among pervasive environmental toxins, OCPs are one of the largest and most hazardous classes of contaminants in use around the world. Because these compounds possess the estrogen mimicking properties, the accumulation of these compounds in the human body may be a risk for several hormone-dependent diseases. EOC is hormonally dependent cancer and the mortality rate due to this disease is increasingly prevalent, and it has become imperative to explore the role of OCPs in the disease pathogenesis. The present study highlights the significant association of high OCPs level in the disease pathogenesis. It is also observed that the polymorphism in xenobiotic metabolism enzymes alters the predisposition of OCPs. The synergistic effect of gene polymorphism (CYP1A1, GSTM1, and GSTT1) and non-occupational exposure to OCPs was also assessed considering CA125 level as dependent variable with the risk of EOC and concluded that there exist a potential role of genotypic/environmental interaction in the etiology of EOC.