Abstract A03: Preconception paternal DDT exposure and programming of metabolic dysfunction and breast cancer in offspring

The pesticide dichlorodiphenyltrichloroethane or DDT was widely used in agriculture or to combat insect-borne diseases until the 1970s in the United States and the 1980s in Europe. It continues to be used in developing countries to combat malaria or illegally to protect crops. Because of its prolonged half-life, DDT is a persistent environmental pollutant that still can detected in the American population, particularly in minorities and recent immigrants. Epidemiologic studies have shown that early-life (in utero and early childhood) exposure to DDT is associated with a four-fold increase in breast cancer risk in women, and these findings are supported by animal studies. While maternal DDT exposure in pregnancy has been linked to breast cancer in offspring, the effects of paternal DDT exposure on their progeny’s breast cancer development have not been investigated. Environmental exposures can induce epigenetic changes in paternal sperm and affect the risk of disease in their offspring. Here, we evaluated the effects of preconception exposure to DDT on the male sperm epigenome and programming of offspring’s susceptibility to breast cancer, using a mouse model. Male mice were exposed to DDT (1.7mg/kg body weight) by oral gavage in the preconception window. DDT and control-vehicle (CO) males were then used for sperm collection or 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 at 21 days of age and fed a standard chow diet for the extent of the study. Offspring were weighed weekly and used to study metabolic parameters. Mammary tumors were induced by 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. RNA extracted from sperm CO and DDT males was used for small RNA-seq analysis. Preconception exposure to DDT altered small noncoding RNAs (e.g., miRNAs and tRNAs) in paternal sperm. In line with that, offspring of DDT-exposed fathers had a significant decrease in birth and weaning weights compared to controls. Further, DDT offspring showed metabolic dysfunction. Compared to CO, female offspring of DDT fathers had significantly accelerated breast tumor growth and a nonsignificant increase in mammary tumor incidence and shorter tumor latency. These tumor phenotypes were linked to mammary tissue inhibition of AMPK, a central metabolic sensor, and increased mTOR activity. In conclusion, our findings support a role for DDT exposure from the paternal lineage in metabolic dysfunction and increased breast cancer development in the offspring. Defining the mechanism by which paternal exposures to EDC such as DDT can promote breast cancer development in offspring is critical to identifying early detection/preventive approaches or treatments for this malignancy in a subset of women. Citation Format: Raquel Santana da Cruz, Hong Cao, Camile Fontelles, Apsra Nasir, Volkan Tekam, M. Idalia Cruz, Lu Jin, Sonia de Assis. Preconception paternal DDT exposure and programming of metabolic dysfunction and breast cancer in offspring [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A03.