Diet-Induced Obesity in Male Mice Is Associated with Reduced Fertility and Potentiation of Acrylamide- Induced Reproductive Toxicity 1

The prevalence of human obesity and related chronic disorders such as diabetes, cardiovascular diseases, and cancer is rapidly increasing. Human studies have shown a direct relationship between obesity and infertility. The objective of the current work was to examine the effect of diet-induced obesity on male fertility and the effect of obesity on susceptibility to chemical-induced reproductive toxicity. From 5 to 30 wk of age, genetically intact male C57Bl/6J mice were fed a normal diet or one in which 60% of the kilocalories were from lard. Obese mice exhibited significant differences in the mRNA of several genes within the testes in comparison to lean males. Pparg was increased 2.2-fold, whereas Crem, Sh2b1, Dhh, Igf1, and Lepr were decreased 6.7, 1.4, 3.2, 1.6, and 7.2-fold, respectively. The fertility of male mice was compared through mating with control females. Acrylamide (AA)-induced reproductive toxicity was assessed in obese or lean males treated with water or 25 mg AA kg 1 day 1 via gavage for 5 days and then mated to control females. Percent body fat and weight were significantly increased in mice fed a high-fat vs. a normal diet. Obesity resulted in significant reduction in plugs and pregnancies of control females partnered with obese vs. lean males. Serum leptin and insulin levels were each approximately 5-fold higher in obese vs. age-matched lean mice. Sperm from obese males exhibited decreased motility and reduced hyperactivated progression vs. lean mice. Treatment with AA exacerbated male infertility of obese and lean mice; however, this effect was more pronounced in obese mice. Further, females partnered with AAtreated obese mice exhibited a further decrease in the percentage of live fetuses, whereas the percentage of resorptions increased. This work demonstrated that diet-induced obesity in mice caused a significant reduction in male fertility and exacerbated AAinduced reproductive toxicity and germ cell mutagenicity. acrylamide, diet-induced obesity, dominant lethal mutations, hyperinsulinemia, insulin, leptin, male mice infertility INTRODUCTION It is estimated that greater than 1 billion adults around the world are overweight (body mass index (BMI) greater than 25 kg/m) and at least one-third of this population has a BMI that exceeds 30 kg/m, classifying them as obese [1]. While genetic predisposition, age, and environmental factors may contribute to a person’s tendency to gain weight, it is generally accepted that the two primary causes of obesity are increased intake of energy-rich foods and reduced physical activity. It is well established that the higher the BMI, the greater the risks for humans to develop chronic diseases, including type 2 diabetes, infertility, hypertension, stroke, cardiovascular diseases, and cancer [2–10]. Obese and overweight men exhibit a high incidence of infertility in association with metabolic disturbances and hormonal dysregulation [5, 11–14]. In order to investigate obesity and obesity-related illnesses, in vivo studies in mouse models have recreated this obesity phenotype primarily through genetic manipulation. Obesity was associated with infertility in the ob/ob mouse in association with leptin deficiency [15–17]. Subsequent studies then demonstrated that leptin replacement therapy rescued the sterility of genetically obese ob/ob male mice [17]. Experiments in obese mice possessing lethal yellow mutations (C57BL/6J-A/a) demonstrated an association between reduced fertility, leptin resistance, and hyperleptinemia [18]. In contrast, high-fat diet consumption caused obesity in DBA/2J male mice; however, these mice exhibited no impairment in fertility despite enduring insulin resistance and hyperleptinemia [19]. On the other hand, female DBA/2J mice consuming a diet rich in fat developed obesity as well as reduced fertility in association with hyperleptinemia [19]. Using the genetically intact C57BL/6J mouse model of dietinduced obesity, the current study was undertaken to assess the impact of obesity produced by the consumption of a high-fat diet on the fertility of male C57BL/6J mice. In a second facet of this study, we have investigated our hypothesis that dietinduced obesity may influence host susceptibility to environmental chemicals. A strong correlation exists between the etiology of some human diseases and exposure to environmental pollutants [20], and it is conceivable that obese humans or individuals suffering from chronic pathophysiological conditions may exhibit varied responses to environmental pollutants. With obesity at epidemic proportions, we compared the reproductive toxic effects of orally administered acrylamide (AA) in lean and high-fat diet-induced obese mice. AA was selected because of the great potential for human exposure to this chemical. Recent reports showed that AA is present in baked and fried carbohydrate-rich foods, including French fries, potato chips, bread, and cereals. The concern over the potential for human exposure to this chemical through the consumption of AA-containing foodstuffs was compounded by the fact that AA is a known animal carcinogen, germ and somatic cell mutagen, and potent neurotoxicant [21–23]. Supported by the Division of Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. Correspondence: Burhan I. Ghanayem, National Institute of Environmental Health Sciences, P.O. Box 12233 (MD B3–10), 111 Alexander Dr., Research Triangle Park, NC 27709. FAX: 919 541 7666; e-mail: ghanayem@niehs.nih. gov Received: 17 May 2009. First decision: 17 June 2009. Accepted: 4 August 2009. 2010 by the Society for the Study of Reproduction, Inc. This is an Open Access article, freely available through Biology of Reproduction’s Authors’ Choice option. eISSN: 1529-7268 http://www.biolreprod. org ISSN: 0006-3363