Abstract 1429: DDT induces intergenerational epigenetic inheritance of cancer predisposition in a mouse model

DNA sequence accounts for the majority of disease heritability, including cancer. Yet, not all familial cancer cases can be explained by genetic factors. There is mounting evidence that environmentally-induced epigenetic inheritance occurs and that the progeny’s traits can be shaped by parental environmental experiences. In humans, epidemiologic studies have implicated endocrine disruptors and environmental toxicants such as the pesticide DDT in intergenerational cancer development, including breast and childhood tumors. Using a mouse model, we investigated whether paternal DDT exposure may result in an intergenerational increase in breast cancer development. We also investigated the effects of DDT on the paternal germline and the mechanisms underlying intergenerational transmission. Male mice (c57bl/6) were exposed to DDT or to a control-vehicle (CO) solution and used for sperm collection or mating with unexposed females to produce the DDT or CO daughters. In another experiment, normal mouse embryos (zygote stage) were injected with RNA purified from sperm of DDT or CO males or miRNA mimic. Resulting zygotes were implanted into surrogate mothers to produce offspring. DDT daughters or RNA injected females were used to study breast cancer development (carcinogen-induced or orthotopic models). We found that the female progeny of males exposed to DDT in the pre-conception period have higher susceptibility of developing aggressive tumors in two different mouse models of breast cancer. Sperm of DDT-exposed males exhibited distinct patterns of small non-coding RNAs, with an increase in miRNAs and a specific surge in miRNA-10b levels. Remarkably, embryonic injection of the entire sperm RNA load of DDT-exposed males or synthetic miRNA-10b recapitulated the tumor phenotypes observed in DDT daughters. We also found that E3.5 embryos injected with miR-10b have altered transcriptional profile compared to controls. Our findings reveal a causal role for sperm RNAs in the inheritance of cancer predisposition and could explain some of the “missing heritability” of breast and other malignancies, if confirmed in humans. Citation Format: Raquel Santana Da Cruz, Odalys Dominguez, Apsra Nasir, Alexandra K. Gonsiewski, Maria Idalia Cruz, Lu Jin, Matthew McCoy, Sonia de Assis. DDT induces intergenerational epigenetic inheritance of cancer predisposition in a mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1429.