The consequences of paternal acrylamide exposure and potential for amelioration

Male germ cells are vulnerable to a wide variety of substances, including hormones, drugs, environmental toxicants, heat and radiation. Acrylamide is a reproductive toxicant that is ubiquitous in human lives, with its formation occurring during the cooking of many foods such as breads, potatoes, cereals and coffee. This toxicant has well established neurotoxic effects in humans, and is recognised as a probable human carcinogen. Acute exposure in male rodents results in DNA damage, infertility, heritable translocations and embryo resorptions. Hence, prolonged acrylamide exposure in males has the potential to not only affect the individual, but may also have consequences for offspring. Studies have demonstrated one unique enzyme responsible for the phase I metabolism of acrylamide; the cytochrome P450 2E1 (CYP2E1). Via this enzyme, acrylamide is converted to the highly reactive epoxide glycidamide. Importantly, glycidamide adducts with DNA, and is responsible for the toxicities associated with acrylamide exposure. The aims of this thesis were to assess the DNA damage induced in germ cells following chronic low dose acrylamide exposure, relevant to human exposure estimates. Importantly, we sought to determine if this damage could be ameliorated by utilising an inhibitor of CYP2E1. We aimed to determine if this DNA damage harboured in the male gamete had consequences for the offspring. The fourth aim was to assess CYP2E1 localisation within the male reproductive tract and to relate this to the consequences to offspring of acute high dose paternal acrylamide exposure. Our results demonstrated that there are two major sites of CYP2E1 expression within the male reproductive tract; the testis and the epididymis. Importantly, the expression in the mouse was equivalent to that in the human, further validating the use of the mouse model. We determined that the CYP2E1 of the epididymis plays a vital role in induction of dominant lethality following acute acrylamide exposure. However, of most critical importance to humans may be the expression within the spermatocytes of the testis, which respond to chronic low level acrylamide exposure by induction of this enzyme and resultant DNA damage within the germ cells. This induction was inherited in the untreated progeny and may render these mice more susceptible to direct acrylamide exposure.