Academic journal article Environmental Health Perspectives

Modulatory Effects of Neonatal Exposure to TCDD, or a Mixture of PCBs, P,p'-DDT, and P-P'-DDE, on Methylnitrosourea-Induced Mammary Tumor Development in the Rat

Academic journal article Environmental Health Perspectives

Modulatory Effects of Neonatal Exposure to TCDD, or a Mixture of PCBs, P,p'-DDT, and P-P'-DDE, on Methylnitrosourea-Induced Mammary Tumor Development in the Rat

Article excerpt

The role of organochlorine (OC) exposure in the etiology of breast cancer remains controversial. Thus, our objective was to determine whether the most abundant and toxic OCs found in human milk could, when ingested during the neonatal period, modulate the development of mammary tumors in the rat. We prepared a mixture composed of p,p'-dichlorodiphenyltrichloroethane (DDT), its major metabolite, p,p'-dichlorodiphenyldichloroethene (DDE), and 19 polychlorinated biphenyls (PCB) based on their concentrations found in the milk of Canadian women. Neonate rats at 1, 5, 10, 15, and 20 days of age were gavaged with this mixture, at 10, 100, and 1,000 times the amount that a human baby would consume. An additional group received 2.5 [micro]g 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg body weight (bw) by gavage at 18 days of age, instead of the mixture. On day 21, all treatment groups, except for a control group and a 1,000-mix group, received a single intraperitoneal injection of methylnitrosourea (MNU, 30 mg/kg bw), the initiator of the carcinogenic process. The average number of rats per treatment group was 33. Rats were sacrificed when their tumors reached 1 cm in size, or at 308 days of age. We prepared mammary tumors and mammary gland whole mounts for histologic analysis. There were no significant effects when only the malignant or only the benign tumors were considered. After all benign and malignant lesions were pooled, the number of mammary tumors differed among all MNU-treated groups (p = 0.02) with more lesions developing in the MNU-1,000x (median = 4.5; p = 0.05) and MNU-TCDD (median = 5.5; p = 0.07) compared to the MNU-0 rats (median = 2). Compared to the MNU-0 group, the percentage of rats that developed palpable tumors (benign plus malignant) was slightly higher (p = 0.06) in the MNU-TCDD group, but not in the MNU-1,000x group. The percentage of palpable tumors that were malignan was higher (p = 0.02) in the MNU-100x group (15/16, 94%) than in the MNU-0 group (10/18, 56%). The highest dose of the mixture delayed (p = 0.03) the development of tumors, but this was not observed with the MNU-TCDD treatment. These results suggest that neonatal exposure to high doses of organochlorines could favor the development of MNU-induced mammary lesions, but also delays the development of palpable tumors in the rat. Key words: DDE, DDT, mammary tumor, methylnitrosourea, organochlorines, PCB, rat, TCDD. Environ Health Perspect 109:739-747 (2001). [Online 13 July 2001] http://ehpnet1.niehs.nih.gov/docs/2001/l09p739-747desaulniers/abstract .html

Breast cancer is the most prevalent form of cancer in North American women (1,2). The death rate from breast cancer is decreasing while the incidence is slightly increasing, but this increase is statistically significant only in black American women (2). The acknowledged risk factors for breast cancer are genetic predispositions (3-6) and reproductive factors (7,8). These risk factors account for only 30-50% of the cases (5,9-12); thus, environmental factors (exposure to manmade and natural chemicals, dietary habits, lifestyle) are hypothesized to account for the remaining cases.

The possibility that exposure to environmental contaminants, such as organochlorines, may be linked with breast cancer risk was raised by some (9,13), although others disagree (14-16). Organochlorines include a large number of agricultural and industrial chemicals and by-products of combustion and incineration. Polychlorinated biphenyls (PCBs), dioxins, and p,p'-dichlorodiphenyltrichloroethane (DDT) are lipophilic organochlorines, they accumulate in fat, and they are present at the [micro]g to mg/kg levels in human tissues and milk (17-27), confirming direct exposure of the mammary tissues. Some epidemiologic investigations have found no association, or even a negative one, between human tissue levels of PCB congeners, DDT, and p,p'-dichlorodiphenyl-dichloroethene (DDE) and breast cancer (28-38); but in specific subpopulations (7,22,29,33,34,39--42) or by testing specific congeners (257,33,43,44), some did detect significant associations. …

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