Chronic acrylamide exposure in male mice results in elevated DNA damage in the germline and heritable induction of CYP2E1 in the testes

摘要

Acute acrylamide exposure in male rodents results in reduced reproductive performance and dominant lethality. However, the reproductive effects of low-dose chronic exposure, which better reflects the nature of human exposure, remain far less certain. Human dietary consumption of acrylamide has been estimated at an average of 1–4 μg/kg bodyweight/day. In order to simulate this exposure, male mice were provided with acrylamide (1 μg/ml) via their drinking water continuously for 6 mo, which was equivalent to a human dose of 10.5 μg/kg bodyweight/day. This exposure regime increased DNA damage in the spermatozoa without affecting a concomitant reduction in overall fertility. The offspring of acrylamide-treated mice did not have an increased incidence of skin papilloma formation following the two-stage tumor-induction protocol. However, the male offspring of acrylamide-treated fathers had significantly increased levels of DNA damage in their spermatozoa, despite having had no direct toxicant exposure. It was also found that the acrylamide-treated mice and, most crucially, their progeny had increased levels of CYP2E1 protein in their spermatocytes. This is significant because CYP2E1 is the sole enzyme responsible for conversion of acrylamide to its harmful metabolite glycidamide. This altered expression may be due to epigenetic alterations. Additionally, the F0 and F1 mice had increased oxidative adducts in the DNA of their germ cells, which was hypothesized to arise as a byproduct of increased CYP2E1 levels. Therefore, chronic paternal acrylamide exposure in mice has consequences for their offspring and raises concerns for the effects of acrylamide exposure in the human population and the accumulated effects with multiple generations of exposure.