Expanding Waistlines Heighten the Risk for Reproductive Toxicity

Paternal reproductive health is highly sensitive to the physical and chemical environment. Today's population is exposed to widespread environmental contaminants and the number of males that are overweight and obese is rising at an alarming rate [1]. Recent estimates indicate that between 47% and 58% of men in Canada are overweight [2], and in the USA, 71% of adult males are considered overweight or obese [1]. Coinciding with higher exposure to environmental chemicals and expanding waistlines is the reported, albeit controversial, global decline in male fertility [3–6]. Moreover, exposure to environmental toxicants such as endocrine-disrupting compounds has been linked to an increased incidence of infertility, hypospadias, and testicular cancer [7,8]. What if the reproductive defects associated with exposure to environmental toxicants were compounded by a high body mass index? If this is the case and if the human population continues to follow the current trend of increasing body weight and further exposure to chemical contaminants, we will be facing greater risks of infertility. In a thought-provoking study in this issue of Biology of Reproduction, Ghanayem and colleagues [9] address the question as to whether obesity alters susceptibility to the environmental chemical, acrylamide, a known reproductive toxicant. This report is one of the first to probe the combined effects of physical status with toxicant exposure. Strikingly, their results indicate that the negative consequences of acrylamide exposure on male fertility parameters are enhanced by an obese physiological condition (Fig. 1). Acrylamide exposure will cause reproductive defects in exposed males, and these effects are enhanced by an increase in body mass index (BMI). Future studies will determine if other reproductive toxicants can interact with physiological status to alter reproductive outcomes. Historically, human exposure to acrylamide was thought to occur primarily through contaminated drinking water from polyacrylamide flocculants used in water treatment. However, more recent studies report that acrylamide is formed during the frying, roasting, or baking of a variety of foods including cereals, potatoes, and coffee. The mechanism underlying acrylamide formation in cooked foodstuffs is its formation as a consequence of chemical reactivity between asparagine and sugars [10]. Concerns over acrylamide in food as a potential health hazard are based on evidence that has been accumulating since the 1980s from toxicology studies documenting the potential for acrylamide to cause germ cell mutations, cancer, and neurodevelopmental defects [11–14]. Given the probability that overweight and obese individuals consume a higher proportion of carbohydrates, their intake of acrylamide is also likely to be greater than that of lean individuals. Increased acrylamide intake imposed on already compromised reproductive parameters in overweight males may put them at a greater risk for reproductive toxicity. The reproductive consequences of obesity in males are associated with altered reproductive hormone profiles, marked by reduced testosterone and increased estradiol. In extremely obese males, sperm counts and sperm motility are reduced [15]. To explore the possibility that obesity alters the reproductive toxicity response to acrylamide, Ghanayem et al. [9] developed an animal model to test these effects. Mice of a C57/BL/6J genetic background were fed either regular chow or a high-fat chow beginning at 5 weeks of age. Males at 30 weeks of age, from either the lean or obese group, were gavaged daily for 5 days with what can be considered an acute and high dose of 25 mg/kg of acrylamide, or the vehicle control. The chosen dose of acrylamide was based on previous studies where it was shown to have dominant lethal effects, i.e., where function of the sperm remains intact, yet the fertileized egg or developing embryo do not survive. The selected dose was below the level of 50 mg/kg, which has been shown to induce sterility in wild-type mice [16]. Reproductive parameters measured in lean and obese mice exposed to either acrylamide or vehicle included performance in a breeding trial, sperm counts, sperm motility, and sperm progressivity. Blood samples were taken and amounts of glucose, cholesterol, triglycerides, insulin, leptin, and testosterone were measured. Reproductive function in obese males was compromised in comparison to lean males. Fewer females were mated by obese males as evidenced by reduced frequency of plugs and pregnancies. While sperm counts were not reduced, sperm motility was. Testosterone was not altered by body condition, but obesity was associated with elevated serum leptin and insulin. Remarkably, the negative effect of obesity on reproductive function was compounded by exposure to acrylamide. The number of embryos implanted was 30% fewer in litters sired by exposed obese mice versus exposed lean mice. More than 90% of the observed fetal resorptions occurred from matings with obese acrylamide-exposed males in comparison to 63.5% in acrylamide-exposed lean males. A particular strength of this study is the robust animal numbers per treatment group and the clear increase in detrimental reproductive outcomes of an obese phenotype exposed to acrylamide. Uncertainty in extrapolation of these types of exposure studies to humans is based on the recognition that potentially different mechanisms will be at play. In this study, the exposure to acrylamide was acute and short term, but was about 25- to 25 000-fold higher than the low environmental levels to which humans are exposed [17]. In extended studies, it will be pertinent to assess levels of acrylamide that are representative of environmental exposure, and to examine the toxicokinetics of acrylamide to determine if bioavailability from food is consistent with toxicology assays where rodents are exposed to acrylamide via either gavage or drinking water. The results of this study by Ghanayem et al. [9] suggest that the consequences of diet and weight extend beyond an increased risk for certain cancers, cardiovascular disease, metabolic dysfunction, and diabetes. This study brings to light the possibility that excess weight may also heighten effects of reproductive toxicants on male fertility parameters. If, as the data suggest, the combined interactions of reproductive toxicants and obesity are additive, we can predict a future rise in the rates of infertility and an increased dependence on assisted reproductive technologies (ART). Currently, in developed countries, about 1% to 3% of all births are achieved through the use of ART [18], such as intracytoplasmic sperm injection (ICSI) and in vitro fertilization. Of concern is that data indicate that a rise in the use of these techniques in response to decreasing male fertility will correspond to more children born with birth defects and, possibly, with imprinting disorders [19]. Although there are limited data available, one possible explanation for abnormalities in children born through ART is the link to an altered embryonic epigenome [20]. The epigenome refers to the heritable biochemical information superimposed on the DNA, and the core nucleosomal proteins the histones. The epigenetic layer determines the chromatin state and how the genome is used by controlling access of the transcriptional machinery. In the processes used for ART, errors in the epigenome may be introduced by in vitro manipulation, use of suboptimal sperm, and the process of superovulation [20]. Also worth considering is that the dynamic epigenetic program in sperm development may be sensitive to diet and toxicants [21]. Indeed, exposure of rats to the toxicant 2-methoxyacetic acid has been shown to induce global alterations in the epigenetic marking of histone H3 [22]. It is possible that the increase in detrimental effects of acrylamide on embryo development observed on the obese background are a consequence of epigenetic editing on developing sperm. A groundbreaking study by Hammoud et al. [23] recently showed that histone and DNA methylation in sperm mark genes implicated in embryo development. It is likely that DNA and histone methylation in developing sperm may be sensitive to diet. For example, a diet high in fat will alter folate metabolism by increasing levels of homocysteine [24], which will in turn alter the availability of methyl groups for DNA and histone methylation [25]. Future studies on the influence of diet and toxicants on the epigenome may reveal underlying mechanisms of paternal routes to disease and causes of embryo mortality. The implications of the study by Ghanayem et al. [9] are highly relevant in light of current trends in societal body type; the study highlights an emerging area in reproductive toxicology where future investigations will probe interactions between body condition and reproductive toxicology effects.

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