Paternal exposure to the pesticide DDT induces intergenerational programming of breast cancer predisposition via sperm miRNA

Abstract

AbstractBackgroundDNA sequence accounts for the majority of disease heritability, including cancer. However, it is becoming clear that environmentally-induced epigenetic inheritance can also occur. Epidemiological studies have shown that maternal exposure to the pesticide DDT in pregnancy is associated with increased breast cancer risk in women. Yet, the effects of paternal exposure to this and other pesticides on the progeny’s breast cancer development has not been investigated.MethodsMale 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 miRNA-10b and implanted into surrogate mothers to produce miR-10b offspring. DDT daughters or miRNA-10b females were used to study breast cancer development and metabolic parameters. Paternal sperm was used for RNA-seq analysis and miRNA expression levels.ResultsPre-conception paternal DDT exposure altered the sperm small non-coding RNA load, with an increase in miRNAs and a specific surge in miRNA-10b levels. DDT offspring weighed less at birth and at weaning, but became overweight and showed metabolic dysfunction in adulthood compared to CO. DDT daughters also showed increased mammary tumorigenesis, developing more aggressive tumors that grew faster than in CO. This tumor phenotype was linked to suppression of the AMPK energy sensing pathway and mTOR activation in mammary tissues. Remarkably, embryonic injection of miRNA-10b recapitulated the mammary gland and tumor phenotypes observed in DDT daughters.ConclusionsTo our knowledge, this is the first report of an association between paternal DDT exposure and breast cancer in offspring. Paternal DDT-induced programming of breast cancer development in daughters is mechanistically linked to sperm miRNA-10b. The impact of DDT and other endocrine disrupting chemicals on sperm and programming of breast and other cancers in offspring needs to be evaluated in humans.