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 AA-treated 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 AA-induced reproductive toxicity and germ cell mutagenicity.

The prevalence and increasing incidences of obesity and obesity-related illnesses are not limited to westernized countries, but exist as a global epidemic impacting the health of adults and children. According to the WHO, over 1 billion adults are overweight (BMI > 25 kg/m2) and approximately one-third of this population has been diagnosed as clinically obese (BMI > 30 kg/m2). Causality between obesity and metabolic disorders (such as type 2 diabetes), cancer, cardiovascular diseases and liver diseases have been investigated using a variety of in vitro and in vivo models, including genetically engineered mice. The overall purpose of the current study was to fully characterize a genetically intact mouse of obesity for evidence of type II diabetes using clinical and anatomical pathology examination. Male C57Bl/6J mice were fed either a control diet or one in which 60% kcal were due to lard as early as 5 weeks of age and maintained on either diet through age 30 weeks. During the study, body weight and body fat measurements were obtained and complete necropsy was performed on mice at 15, 20, 30, and 40 weeks of age. Mice physiology was assessed and characterized through the analysis of serum chemistry (glucose, cholesterol, triglycerides, insulin, and leptin), histopathologic evaluation of tissues, and determination of hepatic and renal function. Significant increases in both body weight and body fat percentages were determined in male mice fed the high-fat diet vs. age-matched littermates consuming the control diet at 15, 20, 30, and 40 weeks. In concert with increased body weight and body fat %, serum cholesterol concentrations were significantly elevated throughout the study in obese vs. mice fed the control-diet. Serum insulin levels were ≥ 4-fold higher in obese vs. controldiet fed mice by ages 30 and 40 weeks. 100% of male mice on the high fat diet developed hepatic lipidosis (steatosis) by age 30 weeks with subsequent inflammation (steatohepatitis) by age 40 weeks. Obese male mice also exhibited mesangial cell and matrix proliferation (minimal to moderate) by 30 and 40 weeks of age. Notably, similar hepatic and renal lesions have been identified in humans with obesity-related illnesses, non-alcoholic fatty liver disease (NAFLD) and/or type II diabetes. The current genetically intact animal model may prove valuable in achieving the obesity phenotype in a manner appropriate to the onset of obesity and obesity-related diseases in humans.

Human skin is continuously exposed to environmental DNA damage leading to the accumulation of somatic mutations over the lifetime of an individual. Mutagenesis in human skin cells can be also caused by endogenous DNA damage and by DNA replication errors. The contributions of these processes to the somatic mutation load in the skin of healthy humans has so far not been accurately assessed because the low numbers of mutations from current sequencing methodologies preclude the distinction between sequencing errors and true somatic genome changes. In this work, we sequenced genomes of single cell-derived clonal lineages obtained from primary skin cells of a large cohort of healthy individuals across a wide range of ages. We report here the range of mutation load and a comprehensive view of the various somatic genome changes that accumulate in skin cells. We demonstrate that UV-induced base substitutions, insertions and deletions are prominent even in sun-shielded skin. In addition, we detect accumulation of mutations due to spontaneous deamination of methylated cytosines as well as insertions and deletions characteristic of DNA replication errors in these cells. The endogenously induced somatic mutations and indels also demonstrate a linear increase with age, while UV-induced mutation load is age-independent. Finally, we show that DNA replication stalling at common fragile sites are potent sources of gross chromosomal rearrangements in human cells. Thus, somatic mutations in skin of healthy individuals reflect the interplay of environmental and endogenous factors in facilitating genome instability and carcinogenesis.