Childhood obesity and diabetes are closely related to these conditions in either parent, but how the father contributes is unclear. A study in rats shows that normal females mated with obese, glucose-intolerant fathers on a high-fat diet produce female offspring who develop glucose intolerance due to impaired insulin secretion and pancreatic function. This is the first report in any species that a father's diet can initiate progression to diabetes in his offspring. The work highlights a novel role for environmentally induced paternal factors in influencing metabolic disease in offspring and in the growing epidemics of obesity and diabetes. Here it is shown that the consumption of a high-fat diet by male rats has an intergenerational effect: it leads to the dysfunction of pancreatic β-cells in female offspring. Relative to controls, these offspring showed an early onset of impaired insulin secretion and glucose tolerance, which worsened with time. The results add to our understanding of the complex genetic and environmental factors that are leading to the global epidemic of obesity and type 2 diabetes. The global prevalence of obesity is increasing across most ages in both sexes. This is contributing to the early emergence of type 2 diabetes and its related epidemic1,2. Having either parent obese is an independent risk factor for childhood obesity3. Although the detrimental impacts of diet-induced maternal obesity on adiposity and metabolism in offspring are well established4, the extent of any contribution of obese fathers is unclear, particularly the role of non-genetic factors in the causal pathway. Here we show that paternal high-fat-diet (HFD) exposure programs β-cell ‘dysfunction’ in rat F1 female offspring. Chronic HFD consumption in Sprague–Dawley fathers induced increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had an early onset of impaired insulin secretion and glucose tolerance that worsened with time, and normal adiposity. Paternal HFD altered the expression of 642 pancreatic islet genes in adult female offspring (P < 0.01); genes belonged to 13 functional clusters, including cation and ATP binding, cytoskeleton and intracellular transport. Broader pathway analysis of 2,492 genes differentially expressed (P < 0.05) demonstrated involvement of calcium-, MAPK- and Wnt-signalling pathways, apoptosis and the cell cycle. Hypomethylation of the Il13ra2 gene, which showed the highest fold difference in expression (1.76-fold increase), was demonstrated. This is the first report in mammals of non-genetic, intergenerational transmission of metabolic sequelae of a HFD from father to offspring.

Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring

Ancestral environmental exposures to a variety of environmental factors and toxicants have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. The present work examined the potential transgenerational actions of the insecticide dichlorodiphenyltrichloroethane (DDT) on obesity and associated disease. Outbred gestating female rats were transiently exposed to a vehicle control or DDT and the F1 generation offspring bred to generate the F2 generation and F2 generation bred to generate the F3 generation. The F1 and F3 generation control and DDT lineage rats were aged and various pathologies investigated. The F3 generation male sperm were collected to investigate methylation between the control and DDT lineage male sperm. The F1 generation offspring (directly exposed as a fetus) derived from the F0 generation exposed gestating female rats were not found to develop obesity. The F1 generation DDT lineage animals did develop kidney disease, prostate disease, ovary disease and tumor development as adults. Interestingly, the F3 generation (great grand-offspring) had over 50% of males and females develop obesity. Several transgenerational diseases previously shown to be associated with metabolic syndrome and obesity were observed in the testis, ovary and kidney. The transgenerational transmission of disease was through both female (egg) and male (sperm) germlines. F3 generation sperm epimutations, differential DNA methylation regions (DMR), induced by DDT were identified. A number of the genes associated with the DMR have previously been shown to be associated with obesity. Observations indicate ancestral exposure to DDT can promote obesity and associated disease transgenerationally. The etiology of disease such as obesity may be in part due to environmentally induced epigenetic transgenerational inheritance.

https://link.springer.com/content/pdf/10.1186%2F1741-7015-11-228.pdf

Ancestral dichlorodiphenyltrichloroethane (DDT) exposure promotes epigenetic transgenerational inheritance of obesity

The results of several studies point to an increased likelihood of abnormal semen parameters among overweight men, and an elevated risk for subfertility among couples in which the male partner is obese. Obesity is, therefore, associated with a higher incidence of male factor infertility. Several mechanisms might account for the effect of obesity on male infertility, both directly and indirectly, by inducing sleep apnea, alterations in hormonal profiles (reduced inhibin B and androgen levels accompanied by elevated estrogen levels) and increased scrotal temperatures, ultimately manifesting as impaired semen parameters (decreased total sperm count, concentration and motility; increased DNA fragmentation index). Neither the reversibility of obesity-associated male infertility with weight loss nor effective therapeutic interventions have been studied in-depth. The increasing prevalence of obesity calls for greater clinical awareness of its effects on fertility, better understanding of underlying mechanisms, and exploration into avenues of treatment.

https://www.clevelandclinic.org/reproductiveresearchcenter/docs/scipubs2009_01.pdf

The effect of obesity on sperm disorders and male infertility.

Male obesity in reproductive-age men has nearly tripled in the past 30 y and coincides with an increase in male infertility worldwide. There is now emerging evidence that male obesity impacts negatively on male reproductive potential not only reducing sperm quality, but in particular altering the physical and molecular structure of germ cells in the testes and ultimately mature sperm. Recent data has shown that male obesity also impairs offspring metabolic and reproductive health suggesting that paternal health cues are transmitted to the next generation with the mediator mostly likely occurring via the sperm. Interestingly the molecular profile of germ cells in the testes and sperm from obese males is altered with changes to epigenetic modifiers. The increasing prevalence of male obesity calls for better public health awareness at the time of conception, with a better understanding of the molecular mechanism involved during spermatogenesis required along with the potential of interventions in reversing these deleterious effects. This review will focus on how male obesity affects fertility and sperm quality with a focus on proposed mechanisms and the potential reversibility of these adverse effects.

https://www.tandfonline.com/doi/pdf/10.4161/spmg.21362

Impact of obesity on male fertility, sperm function and molecular composition.

http://www.klinikum.uni-muenchen.de/Urologische-Klinik-und-Poliklinik/download/de/eurur/stief_2008a.pdf

A Randomised, Placebo-Controlled Study to Assess the Efficacy of Twice-Daily Vardenafil in the Treatment of Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia

Metabolic syndrome (MetS) is highly prevalent, affecting more than 47 million US residents. This condition is also multifaceted, potentially leading to significant disturbance of numerous physiologic processes. This review article evaluates the literature regarding metabolic syndrome and male reproductive health. Links between obesity, dyslipidemia, hypertension, and insulin resistance are each examined with regard to their associated detrimental effects on male fertility. At the end of this manuscript, we propose a new MetS/male infertility paradigm. Additional studies specifically addressing the components of MetS and their impact on male reproduction will enhance our understanding of the underlying pathophysiology. These studies may also help clarify the role for therapeutic intervention.

https://onlinelibrary.wiley.com/doi/pdf/10.2164/jandrol.107.003731

The Metabolic Syndrome and Male Infertility

Increasing evidence recently has pointed toward a relationship between lower urinary tract symptoms (LUTS) and the presence of metabolic syndrome. This relationship has been supported by recent epidemiologic findings. Possible pathophysiologic links also have been proposed to explain the relationship between these two syndromes. The increasing prevalence of obesity in the United States makes this an increasingly relevant problem. Animal studies support a link between autonomic nervous system (ANS) overactivity and the development of urinary symptoms, low bladder compliance, compensatory prostatic hyperplasia, and blockage of the same using α-blockade. There appears to be a significant link between ANS overactivity as part of the metabolic syndrome and LUTS secondary to benign prostatic hyperplasia (BPH). However, it is unlikely that ANS overactivity could be responsible for the development of LUTS. Rather, ANS overactivity plays a key role in increasing the severity of LUTS above an intrinsic basal intensity that is determined by the genitourinary anatomic/pathophysiologic characteristics of each BPH patient. This paper defines metabolic syndrome as a collection of abnormalities, including being overweight (visceral abdominal fat distribution), dyslipidemia, hypertension, impaired glucose metabolism, elevated C-reactive protein (chronic inflammation), and autonomic-sympathetic overactivity, with insulin resistance as the hypothesized underlying pathogenic mechanisms.

Metabolic syndrome and lower urinary tract symptoms secondary to benign prostatic hyperplasia.

Infertility is due to a significant male factor alone, whereas combined male and female factors are present in an additional 20%. Thus, a male factor is involved in approximately 50% of infertile relationships. The primary goals of the evaluation of the male presenting with infertility are to identify: etiologic conditions, irreversible conditions, irreversible conditions not amenable to assisted reproductive techniques, medically significant pathologies, and genetic etiologies. Bilateral cryptorchidism results in a significant decrease in spermatogenesis, while the effect of unilateral cryptorchidism appears to be much milder. Approximately 50% of testicular cancer patients have subnormal sperm densities prior to chemotherapy. Of note, of those with oligo- or azoospermia, 75% normalized during surveillance. Diethylstilbestrol (DES) was given to pregnant women in the 1950s, and reports of epididymal cysts and cryptorchidism in males with prenatal DES exposure have raised concerns about effects on fertility. Exogenous androgens are well known to induce hypogonadotropic hypogonadism.

Sanjay S. Kasturi

Papers

The Metabolic Syndrome and Male Infertility

Metabolic syndrome and lower urinary tract symptoms secondary to benign prostatic hyperplasia.

Infertility in the Male: The effect of genital tract infection and inflammation on male infertility