Abstract 646: Pre conception paternal DDT exposure and programming of metabolic dysfunction and breast cancer risk in offspring

Abstract

Abstract Background: Breast cancer is the most common cancer in American women, being the second leading cause of cancer-related death in this group. Exposure to environmental chemicals, such as the pesticide DDT (dichlorodiphenyltrichloroethane), has been long suspected to be a contributing factor in the development of metabolic disease and breast cancer. For instance, early life (in utero and early childhood) exposure to DDT has been associated with increased breast cancer risk in women, and these findings are supported by animal studies. While maternal DDT exposure in pregnancy has been linked to metabolic syndrome and breast cancer risk in offspring, the effects of paternal DDT exposure in male germ-line reprogramming and phenotypes in their progeny has not been investigated. Here, we evaluated the effects of pre-conception paternal exposure to DDT on offspring’s metabolism and susceptibility of breast cancer, using a mouse model. Methods: Male mice were exposed to DDT (1.7mg/kg body weight) by oral gavage for two weeks. At the end of this period, DDT and control-vehicle (CO) were housed with female mice, with free access to a standard chow diet, for three days. Pregnancy onset was assessed by the presence of a vaginal plug. The weight and number of pups per litter were determined two days after birth. Pups were weaned from mothers at 21 days of age, fed a standard chow diet for the extent of the study and weighed weekly. Mammary tumors were induced by subcutaneous administration of 15mg of medroxyprogesterone to six-week-old female offspring, followed by oral administration of 1mg 7,12-dimethylbenz[a]anthracene once-a-week for 3 weeks. Results: Paternal DDT exposure reprogramed the sperm small non-coding RNA content. In line with that, DDT offspring had decreased birthweight (p=0.04) and weaning weight (p=0.01) compared to CO. Further, ancestral DDT exposure caused metabolic dysfunction in offspring (p<0.05) at 7 and 22 weeks of age. Further, female offspring of DDT exposed fathers showed alterations in mammary gland development with a non-significant increase in numbers of terminal end buds and lower rates of apoptosis. In line with that, our preliminary data suggest that ancestral paternal exposures to DDT increases breast cancer risk in offspring: Compared to CO, the DDT offspring presented a non-significant increase in mammary tumor incidence and shorter latency to first-tumor onset. In addition, tumor growth (volume) was significantly increased in DDT offspring compared to CO (p<0.01). In conclusion, our findings support a role for DDT exposure from the paternal lineage in metabolic dysfunction and increased breast cancer risk in their offspring. Citation Format: Raquel Santana Da Cruz, Hong Cao, Camille Castilho Fontelles, Apsra Nasir, M Idalia Cruz, Sonia de Assis. Pre conception paternal DDT exposure and programming of metabolic dysfunction and breast cancer risk in offspring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 646.