Obese Fathers Research Articles

N-acetyl-L-cysteine reduces testis ROS in obese fathers but fails in protecting offspring from acquisition of epigenetic traits at cyp19a1 and IGF11/H19 ICR loci.

Paternal nutrition before conception has a marked impact on offspring's risk of developing metabolic disorders during adulthood. Research on human cohorts and animal models has shown that paternal obesity alters sperm epigenetics (DNA methylation, protamine-to-histone replacement, and non-coding RNA content), leading to adverse health outcomes in the offspring. So far, the mechanistic events that translate paternal nutrition into sperm epigenetic changes remain unclear. High-fat diet (HFD)-driven paternal obesity increases gonadic Reactive Oxygen Species (ROS), which modulate enzymes involved in epigenetic modifications of DNA during spermatogenesis. Thus, the gonadic pool of ROS might be responsible for transducing paternal health status to the zygote through germ cells. The involvement of ROS in paternal intergenerational transmission was assessed by modulating the gonadic ROS content in male mice. Testicular oxidative stress induced by HFD was counterbalanced by N-acetylcysteine (NAC), an antioxidant precursor of GSH. The sires were divided into four feeding groups: i) control diet; ii) HFD; iii) control diet in the presence of NAC; and iv) HFD in the presence of NAC. After 8weeks, males were mated with females that were fed a control diet. Antioxidant treatment was then evaluated in terms of preventing the HFD-induced transmission of dysmetabolic traits from obese fathers to their offspring. The offspring were weaned onto a regular control diet until week 16 and then underwent metabolic evaluation. The methylation status of the genomic region IGFII/H19 and cyp19a1 in the offspring gDNA was also assessed using Sanger sequencing and methylation-dependent qPCR. Supplementation with NAC protected sires from HFD-induced weight gain, hyperinsulinemia, and glucose intolerance. NAC reduced oxidative stress in the gonads of obese fathers and improved sperm viability. However, NAC did not prevent the transmission of epigenetic modifications from father to offspring. Male offspring of HFD-fed fathers, regardless of NAC treatment, exhibited hyperinsulinemia, glucose intolerance, and hypoandrogenism. Additionally, they showed altered methylation at the epigenetically controlled loci IGFII/H19 and cy19a1. Although NAC supplementation improved the health status and sperm quality of HFD-fed male mice, it did not prevent the epigenetic transmission of metabolic disorders to their offspring. Different NAC dosages and antioxidants other than NAC might represent alternatives to stop the intergenerational transmission of paternal dysmetabolic traits.

Paternal obesity induces changes in sperm chromatin accessibility and has a mild effect on offspring metabolic health

The increasing global burden of metabolic disorders including obesity and diabetes necessitates a comprehensive understanding of their etiology, which not only encompasses genetic and environmental factors but also parental influence. Recent evidence has unveiled paternal obesity as a contributing factor to offspring's metabolic health via sperm epigenetic modifications. In this study, we investigated the impact of a Western diet-induced obesity in C57BL/6 male mice on sperm chromatin accessibility and the subsequent metabolic health of their progeny. Utilizing Assay for Transposase-Accessible Chromatin with sequencing, we discovered 450 regions with differential accessibility in sperm from obese fathers, implicating key developmental and metabolic pathways. Contrary to expectations, these epigenetic alterations in sperm were not predictive of long-term metabolic disorders in offspring, who exhibited only mild transient metabolic changes early in life. Both male and female F1 progeny showed no enduring predisposition to obesity or diabetes. These results underscore the biological resilience of offspring to paternal epigenetic inheritance, suggesting a complex interplay between inherited epigenetic modifications and the offspring's own developmental compensatory mechanisms. This study calls for further research into the biological processes that confer this resilience, which could inform interventional strategies to combat the heritability of metabolic diseases.

Associations between Paternal Obesity and Cardiometabolic Alterations in Offspring via Assisted Reproductive Technology.

Both assisted reproductive technology (ART) and obesity are associated with adverse cardiometabolic alterations in offspring. However, the combined effects of paternal obesity and ART on offspring cardiometabolic health are still unclear. To clarify cardiometabolic changes in offspring of obese fathers conceived using ART. Retrospective cohort study conducted between June 2014 and October 2019. Center for reproductive medicine. A total of 2890 singleton visits aged 4-10 years were followed. None. Age-and sex-specific z-score of body mass index(BMI), blood pressure, insulin resistance and lipid profile were examined. We observed a strong association between paternal BMI categories and offspring BMI, blood pressure, and insulin resistance. Compared to offspring of fathers with normal weight, multivariable-adjusted mean difference for BMI z-score were 0.53 (95%CI: 0.37-0.68) for obese fathers, 0.17 (95%CI: 0.05-0.30) for overweight fathers, and -0.55 (95%CI: -0.95--0.15) for underweight fathers; corresponding values for systolic blood pressure z-score were 0.21(95%CI: 0.07-0.35), 0.10 (95%CI: -0.01-0.21), and -0.24 (95%CI: -0.59-0.11), and corresponding values for HOMA-IR z-score were 0.31(95%CI: 0.16-0.46), 0.09(95%CI: -0.02-0.21), and -0.11 (95%CI: -0.48-0.28), respectively. The mediation analyses suggested that 57.48% to 94.75% of the associations among paternal obesity and offspring cardiometabolic alterations might be mediated by offspring BMI. Paternal obesity was associated with an unfavourable cardiometabolic profile in ART-conceived offspring. Mediation analyses indicated that offspring BMI was a possible mediator of the association between paternal obesity and the offspring impaired metabolic changes.

Adult rats sired by obese fathers present learning deficits associated with epigenetic and neurochemical alterations linked to impaired brain glutamatergic signaling.

Offspring of obese mothers are at high risk of developing metabolic syndrome and cognitive disabilities. Impaired metabolism has also been reported in the offspring of obese fathers. However, whether brain function can also be affected by paternal obesity has barely been examined. This study aimed to characterize the learning deficits resulting from paternal obesity versus those induced by maternal obesity and to identify the underlying mechanisms. Founder control and obese female and male Wistar rats were mated to constitute three first-generation (F1) experimental groups: control mother/control father, obese mother/control father, and obese father/control mother. All F1 animals were weaned onto standard chow and underwent a learning test at 4 months of age, after which several markers of glutamate-mediated synaptic plasticity together with the expression of miRNAs targeting glutamate receptors and the concentration of kynurenic and quinolinic acids were quantified in the hippocampus and frontal cortex. Maternal obesity induced a severe learning deficit by impairing memory encoding and memory consolidation. The offspring of obese fathers also showed reduced memory encoding but not impaired long-term memory formation. Memory deficits in offspring of obese fathers and obese mothers were associated with a down-regulation of genes encoding NMDA glutamate receptors subunits and several learning-related genes along with impaired expression of miR-296 and miR-146b and increased concentration of kynurenic acid. Paternal and maternal obesity impair offspring's learning abilities by affecting different processes of memory formation. These cognitive deficits are associated with epigenetic and neurochemical alterations leading to impaired glutamate-mediated synaptic plasticity.

Effects of Fish Oil Supplementation on Reducing the Effects of Paternal Obesity and Preventing Fatty Liver in Offspring.

Nonalcoholic fatty liver disease (NAFLD) is a serious public health concern, which calls for appropriate diet/nutrition intervention. Fish oil (FO) has several benefits in reducing obesity, but its intergenerational role in reducing the effects of paternal obesity has not been established. Hence, we hypothesized that FO supplementation to an obese father during the pre-conceptional period could improve the metabolic health of the offspring, specifically in the liver. Three groups of male mice were fed with a low-fat (LF), high-fat (HF), or high-fat diet supplemented with FO (HF-FO) for 10 weeks and were then allowed to mate with female mice fed a chow diet. Offspring were sacrificed at 16 weeks. The liver tissue was harvested for genomic and histological analyses. The offspring of HF and HF-FO fathers were heavier compared to that of the LF mice during 9-16 weeks. The glucose tolerance of the offspring of HF-FO fathers were significantly improved as compared to the offspring of HF fathers. Paternal FO supplementation significantly lowered inflammation and fatty acid synthesis biomarkers and increased fatty acid oxidation biomarkers in the offspring liver. In summary, FO supplementation in fathers shows the potential to reduce metabolic and cardiovascular diseases through genetic means in offspring.

Abstract 15128: Impact of Paternal and Maternal Obesity on Offspring Systolic and Diastolic Function, and Liver Steatosis Early in Life

Introduction: Obesity in women and men of reproductive age may lead to adverse cardiovascular and metabolic developmental programing in their offspring. For example, we observed signs of cardiac diastolic dysfunction in offspring from obese rats as early as 3 weeks of age. However, the contribution from paternal and maternal obesity to increased susceptibility for developing cardiac dysfunction in their offspring early in life is unknown. Hypothesis: We hypothesized that paternal and maternal obesity both play important roles in causing impaired cardiac function and metabolic disorders such as fatty liver in their offspring early in life. Methods: Livers from male newborn Sprague-Dawley rats born from obese fathers (fHFD-offs), obese mothers (mHFD-offs), or from both parents being obese (fmHFD-offs) were weighed and analyzed for fat content by oil red-O and ECHOMRI. Additionally, within 1-3 days after weaning, male offspring were submitted to cardiac catheterization for assessment of cardiac function. Age-matched offspring from lean rats (ND-Offs) were used as controls. Results: fmHFD-Offs and mHFD-offs groups were heavier compared to fHFD-offs and ND-offs groups (61±4 and 64±2 vs 57±2 and 48±2 g, respectively) at 1-3 days after weaning. Newborn rats with at least one obese parent had more liver fat infiltration compared to ND-offs controls. Compared to ND-offs, only offspring from obese mothers (mHFD-offs) exhibited reduced dP/dt max (8998±466 vs. 10560±807, 11869±1171, and 11611±436 mmHg/s for mHFD-offs vs fHFD-offs, fmHFD-offs and ND-offs, respectively); fmHFD-offs and mHFD-offs showed additional signs of impaired diastolic function as indicated by increased Tau values (5.7±0.2 and 5.6±0.3 vs. 4.7±0.2 and 5.0±0.1 ms for fmHDF-offs and mHFD-offs vs ND-offs and fHFD-offs, respectively). Conclusions: These results indicate that while increased liver steatosis develops independent of which parent is obese, the presence of maternal obesity appears to be more critical for male offspring to develop cardiac dysfunction early in life. Additional studies in adult and aged offspring are needed to test if the impact of paternal and maternal obesity on offspring cardiometabolic function gets stronger with aging.

Paternal Obesity Induced by High-Fat Diet Impairs the Metabolic and Reproductive Health of Progeny in Rats.

Due to the increased incidence of obesity, it is of great importance to identify all the possible consequences in those who suffer from it and their descendants. This study aimed to investigate how paternal obesity, resulting from an 18-week high-fat diet (HFD), affects the metabolic and reproductive health of offspring. In the fathers (F0 generation), the HFD led to significant weight gain, primarily due to increased visceral fat. It also resulted in impaired glucose control and reduced insulin sensitivity. Furthermore, F0 males from the HFD group had reduced sperm concentration and lower sperm viability but were still able to sire litters. F1 offspring were monitored during 18 weeks; F1 offspring from obese fathers displayed increased body weight during the experimental window, especially in males, without significant metabolic disturbances. Additionally, F1 males showed reduced sperm viability, indicating potential reproductive implications. On the other hand, F1 females showed normal estrous cycle patterns but had a reduced number of primordial follicles, suggesting a decrease in their follicular reserve and reproductive potential. This study highlights that metabolic and reproductive issues may be passed down to future generations through the paternal line.

Maternal and paternal obesity differentially reprogram the ovarian mitochondrial biogenesis of F1 female rats

Obesity has harmful consequences on reproductive outcomes and the rapid increase in obesity is assumed to be influenced by epigenetics and trans-generation effects. Our study aimed to explore the effect of maternal and/or paternal obesity on the ovarian tissues of the first-generation female offspring in rats. The study was conducted on 40 adult Wistar albino rats (20 males and 20 females). Obesity was induced by feeding them an obesogenic diet for 3 months. The pregnancy was induced in the females by mating with males in four combinations: healthy mother with healthy father (control parents, CP), healthy mother with obese fathers (OF), obese mothers with healthy father (OM), and obese mother with obese father (obese parents, OP). After delivery, the female offspring at two months were sacrificed, and the blood and ovarian tissues were collected to assess the studied parameters. Our result showed differential impacts of maternal and paternal obesity on the ovarian health of the female offspring. The female offspring of obese OM or OP showed early signs of obesity. These metabolic abnormalities were associated with signs of ovarian lesions, impaired folliculogenesis, and decreased oocyte quality and also showed significant alterations in mitochondrial biogenesis, redox status, inflammation, and microRNAs expression (miR-149 and miR-494). In conclusion, altered ovarian expression of microRNAs and associated impaired mitochondrial biogenesis pathways may be the root causes for the observed intergeneration transmission of the obesogenic phenotype.

The anti-inflammatory agent 5-ASA reduces the level of specific tsRNAs in sperm cells of high-fat fed C57BL/6J mouse sires and improves glucose tolerance in female offspring

IntroductionThe prevalence of obesity and associated comorbidities have increased to epidemic proportions globally. Paternal obesity is an independent risk factor for developing obesity and type 2 diabetes in the following generation, and growing evidence suggests epigenetic inheritance as a mechanism for this predisposition. How and why obesity induces epigenetic changes in sperm cells remain to be clarified in detail. Yet, recent studies show that alterations in sperm content of transfer RNA-derived small RNAs (tsRNAs) can transmit the effects of paternal obesity to offspring. Obesity is closely associated with low-grade chronic inflammation. Thus, we evaluated whether the anti-inflammatory agent 5-aminosalicylic acid (5-ASA) could intervene in the transmission of epigenetic inheritance of paternal obesity by reducing the inflammatory state in obese fathers. MethodsMale C57BL/6JBomTac mice were either fed a high-fat diet or a high-fat diet with 5-ASA for ten weeks before mating. The offspring metabolic phenotype was evaluated, and spermatozoa from sires were isolated for assessment of specific tsRNAs levels. Results5-ASA intervention reduced the levels of Glu-CTC tsRNAs in sperm cells and improved glucose tolerance in female offspring fed a chow diet. Paternal high-fat diet-induced obesity per se had only a moderate impact on the metabolic phenotype of both male and female offspring in our setting. ConclusionThe results indicate that the low-grade inflammatory response associated with obesity may be an important factor in epigenetic inheritance of paternal obesity.

P-023 Weight loss in obese fathers improves hepatic lipid metabolism in offspring

Abstract Study question Does paternal obesity affect offspring lipid metabolism and whether paternal weight loss can correct this effect? Summary answer The lipid metabolism of male offspring of obese fathers is abnormal, especially under the second hit, and paternal weight loss could rescue it. What is known already So far we have known that epigenetic modifications in spermatogenesis, are directly involved in the etiopathology of adult diseases transmitted by sperm. It was found that the offspring had more weight gain and impaired glucose tolerance and insulin resistance in adulthood, although they kept a normal diet through microinjecting ncRNA of obese mice spermatozoa into fertilized eggs from normal parents. The above evidence supported that epigenetic modifications can undertake part of the transmission from father to offspring. Study design, size, duration The 30 4-week-old C57 male mice were divided into three groups, normal diet as the control group (NCD) for 30 weeks, high-fat diet as the obese group (HFD) for 30 weeks, first high-fat diet for 10 weeks then low-fat and high-fiber diet as weight loss for 20 weeks (LFD). The male offspring of these groups were normally fed after weaning, then received a second hit (fasting for 36 hours or high-fat diet for 4 weeks). Participants/materials, setting, methods These offspring were divided NCD F1, HFD F1 and LFD F1, respectively. And in the fasting condition, the oil tolerance test and P407 test were carried out to detect the hepatic lipid metabolism function. HE staining and Oil Red O staining were performed on the liver sections of offspring to clarify the accumulation of lipid droplets in the liver. Liver autophagy was detected by western blotting and confocal microscopy. Main results and the role of chance Through oil tolerance test, it was found that TG and NEFA of HFD F1 increased at 1 hour and 3 hours after gavage, while LFD F1 significantly decreased. The P407 test further proved that under fasting conditions, the release of TG from the liver of HFD F1 was significantly weakened, and LFD F1 was restored. HE staining and Oil Red O staining of liver sections indicated that lipid droplets accumulated in the liver of HFD F1, while LFD F1 were significantly reduced. Under the second hit, the difference in liver lipid droplets among the three groups was more obvious. In addition, we found the levels of serum C-reactive protein, TNFα, and IL-6 increased in HFD F1 under the second hit, while LFD F1 could restore. It was found that the p62 of HFD F1 was higher and the ratio of LC3II to LC3I was lower than that of NCD F1, which indicated that HFD offspring liver autophagy was weakened through western blotting, and LFD offspring could restore liver autophagy. It was found that the co-localization of lipid droplets and lysosomes in the HFD offspring was reduced, which was more obvious under the second hit, while the LFD offspring could recover. Limitations, reasons for caution This study provides phenotypic evidence, however, the genetics of paternal disease remain to be explored. Wider implications of the findings The study provides new evidence that the father's lifestyle affects offspring metabolism, but this effect is not permanent and can be eliminated by changing the lifestyle. Trial registration number 82088102

Biomarkers of prostate cancer transgenerational transmission risk in the progeny of obese fathers subjected to dietary correction

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Assessment of Risk Factors for Obesity in Children Aged 6-17 Years Where Obesity Reaches Peak

Objective: Obesity is an important health problem affecting 25-30% of children and adolescents. This study, it was aimed to determine the age intervals in which obesity reaches to peak incidence and risk factors playing role in the development obesity among children and adolescents aged 6-17 years who presented to pediatrics outpatient clinic of Ankara Keçiören Training and Research Hospital. Material and Methods: This cross-sectional study included 3.000 children and adolescents aged 6-17 years and their parents who presented with any reason to pediatrics outpatient clinic of Ankara Keçiören Training and Research Hospital between October, 2019 and December, 2019. Results: Obesity was detected in 21.4% of children while 78.6% were not obese. A significant correlation was detected between birth weight and obesity (p=0.001). A significant correlation was found between obesity and time spent for TV, computer and video games per day (p<0.001). The obesity was significantly decreased by increasing duration of physical activity. In the study, the obesity incidence was 1.77-folds (1.25-2.50) higher in children with obese mother and 2.01-folds (1.42-2.85) in children with obese father. Conclusion: The obesity incidence is progressively increasing in childhood as with other age groups. To prevent such increase, measures should be taken as early as possible. An adequate and balanced nutrition and physical activity are of important in prevention and treatment of obesity. Although primary goal is to achieve lifestyle modifications, pharmacotherapy or surgery may be attempted in the presence of severe obesity-related complications.

Do Parental Comorbidities Affect the Severity of Autism Spectrum Disorder?

Background Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by defective social communication and interaction with a repetitive pattern of monotonous or stereotyped behavior.Although the exact etiology of ASD is unknown, many factors may be implicated in the development of ASD.We aimed to determine the correlation between specific parental factors and Autism Treatment Evaluation Checklist (ATEC) scores. Methods This cross-sectional study was conducted at the Prince Nasser Bin Abdulaziz Center for Autism, Autism Center for Excellence, and Academy of Special Education for Autism in Riyadh, Saudi Arabia. We enrolled children diagnosed with ASD and their parents from these centers. Data were collected through self-administered questionnaires to the patients' parents. Results All included children were <18 years old. In total, 71 (92.2%) children were male and six (7.8%) were female. Further, 77 (100%) patients were diagnosed with autistic disorder. Children of consanguineous parents, underweight mothers and obese fathers, mothers with a history of depression during pregnancy, and mothers aged ≥31 years during pregnancy tend to have a higher mean ATEC score. The health domain was the most significantly correlated with ATEC scores, with a Pearson correlation of 0.880. In linear regression analysis, only maternal depression during pregnancy was significantly correlated with ATEC scores. Conclusion Our patients had a mean ATEC score of 86.2. The health domain was the most significantly correlated with ATEC scores, with a Pearson correlation of 0.880. Linear regression analysis revealed that consanguinity, parental chronic disease, parental allergy, smoking, druguse during pregnancy, paternal and maternal body mass index (BMI), and siblingnumber were not significantly correlated with ATEC scores (P=0.701, 0.693, 0.133, 0.874, 0.982, 0.255, 0.778, and 0.502, respectively). However, maternal depression during pregnancy was significantly correlated with ATEC scores (P=0.055).

Paternal obesity induces placental hypoxia and sex-specific impairments in placental vascularization and offspring metabolism†.

Paternal obesity predisposes offspring to metabolic dysfunction, but the underlying mechanisms remain unclear. We investigated whether this metabolic dysfunction is associated with changes in placental vascular development and is fueled by endoplasmic reticulum (ER) stress-mediated changes in fetal hepatic development. We also determined whether paternal obesity indirectly affects the in utero environment by disrupting maternal metabolic adaptations to pregnancy. Male mice fed a standard chow or high fat diet (60%kcal fat) for 8–10 weeks were time-mated with female mice to generate pregnancies and offspring. Glucose tolerance was evaluated in dams at mid-gestation (embryonic day (E) 14.5) and late gestation (E18.5). Hypoxia, angiogenesis, endocrine function, macronutrient transport, and ER stress markers were evaluated in E14.5 and E18.5 placentae and/or fetal livers. Maternal glucose tolerance was assessed at E14.5 and E18.5. Metabolic parameters were assessed in offspring at ~60 days of age. Paternal obesity did not alter maternal glucose tolerance but induced placental hypoxia and altered placental angiogenic markers, with the most pronounced effects in female placentae. Paternal obesity increased ER stress-related protein levels (ATF6 and PERK) in the fetal liver and altered hepatic expression of gluconeogenic factors at E18.5. Offspring of obese fathers were glucose intolerant and had impaired whole-body energy metabolism, with more pronounced effects in female offspring. Metabolic deficits in offspring due to paternal obesity may be mediated by sex-specific changes in placental vessel structure and integrity that contribute to placental hypoxia and may lead to poor fetal oxygenation and impairments in fetal metabolic signaling pathways in the liver.

CHILDHOOD OVERWEIGHT AMONG UNDER FIVE IN PUTRAJAYA, MALAYSIA: THE CONTRIBUTING FACTORS

Being overweight and obese during childhood increases the potential of becoming obese adults later in life. Therefore, this study aims to determine the factors associated with overweight (including obesity) among children under five years of age in Putrajaya, Malaysia. A total of 211 children with overweight cases were successfully recruited in this case-control study. The same number for control group which was normal children also being recruited by matching according to sex and age group with the case group. Data collection was performed by four approaches such as face-to-face interview, anthropometric measurements, finger prick for haemoglobin level and self-administered 3-day food diary. WHO Anthro software was used to determine the nutritional status of children. Descriptive statistic and logistic regression were performed to determine risk factors that contributed to overweight. Multiple logistic regressions showed overweight or obese father was 1.88 times more likely to have overweight children compared to normal BMI father. Mothers who had gestational diabetes mellitus (GDM) were 2.93 times more likely to have overweight children compared to those with no complication during pregnancy. Pregnant women who attended antenatal visits for less than 9 times were 3.33 times more likely to have overweight children compared to pregnant women who attended 9 to 14 times of antenatal visits. Children with fewer siblings were 2.10 times more likely to be overweight compared to children with four or more siblings. These findings indicated related risks factors contributing to childhood overweight from the early stages including maternal and paternal factors. Early life intervention especially during pregnancy stages which include antenatal care and antenatal intervention on dietary and physical activity during peri-conception period is seen to be important to prevent adverse pregnancy outcomes and further improve maternal and child’s health. Hence it would be more effective to prevent childhood overweight or obesity in later age and its long-term consequences.

O-011 You are what your father ate- epigenetic implications

Abstract An unhealthy life style, obesity and excess of dietary fats or chronic consumption of processed foods create a harmful environment for sperm health. In the current presentation our most recent findings will be presented on male exposures related to an unhealthy life style and the effects measured on clinical sperm and/or embryo parameters in humans. Next, epigenetic implications will be shown from male obesity, “healthy” and “unhealthy” foods and other related determinants (such as advanced age) before conception. Our results lend support for the existence of epigenetic windows of susceptibility in life. If the acquired epigenetic signatures are passed down to the next generation(s) this may affect future health. Our data are based on human studies, including the Newborn Epigenetics Study (NEST) cohort, The Influence of the Environment on Gametic Epigenetic Reprogramming (TIEGER) study and the Epigenetic Legacy of Paternal Obesity (ELPO) cohort. In brief, we found that consumption of healthy food items, such as vegetables, fruits and nuts, is positively related to total motile sperm count (TMC), while consumption of fast foods (such as fries) is associated with lower TMC. Frequent consumption of fast foods (incl. pizza and fries) is associated with opposing effects on DNA methylation patterns at the DMRs of imprinted genes (such as IGF2 and MEG3-IG), compared to dietary patterns rich in whole grains and vegetables. These results correspond to our findings in sperm from obese versus non-obese men, and are in line with our earlier findings in children from obese fathers. While this talk will be a compilation and comparison of our research findings, it will also serve as a base for guidance and counselling in infertility. Our results fit our new concept of the Paternal Origins of Health and Disease (POHaD), where the role of the father has been suggested in disease development of his future offspring. If better understood, tailored dietary changes may positively shape the human sperm epigenetic profile and future programming of offspring health. Trial registration number Study funding Funding source

Systemic alterations play a dominant role in epigenetic predisposition to breast cancer in offspring of obese fathers and is transmitted to a second generation

We previously showed that environmentally-induced epigenetic inheritance of cancer occurs in rodent models. For instance, we reported that paternal consumption of an obesity-inducing diet (OID) increased breast cancer susceptibility in the offspring (F1). Nevertheless, it is still unclear whether programming of breast cancer in daughters is due to systemic alterations or mammary epithelium-specific factors and whether the breast cancer predisposition in F1 progeny can be transmitted to subsequent generations. In this study, we show that mammary glands from F1 control (CO) female offspring exhibit enhanced growth when transplanted into OID females compared to CO mammary glands transplanted into CO females. Similarly, carcinogen-induced mammary tumors from F1 CO female offspring transplanted into OID females has a higher proliferation/apoptosis rate. Further, we show that granddaughters (F2) from the OID grand-paternal germline have accelerated tumor growth compared to CO granddaughters. This between-generation transmission of cancer predisposition is associated with changes in sperm tRNA fragments in OID males. Our findings indicate that systemic and mammary stromal alterations are significant contributors to programming of mammary development and likely cancer predisposition in OID daughters. Our data also show that breast cancer predisposition is transmitted to subsequent generations and may explain some familial cancers, if confirmed in humans.

Paternal obesity impairs hepatic gluconeogenesis of offspring by altering Igf2/H19 DNA methylation

Over the past four decades, the global prevalence of obesity has increased rapidly in all age ranges. Emerging evidence suggests that paternal lifestyle and environmental exposure have a crucial role in the health of offspring. Therefore, the current study investigated the impact of paternal obesity on the metabolic profile of offspring in a male mouse model of obesity. Female offspring of obese fathers fed a high-fat diet (HFD) (60% kcal fat) showed hyperglycemia because of enhanced gluconeogenesis and elevated expression of phosphoenolpyruvate carboxykinase (PEPCK), which is a key enzyme involved in the regulation of gluconeogenesis. Methylation of the Igf2/H19 imprinting control region (ICR) was dysregulated in the liver of offspring, and the sperm, of HFD fathers, suggesting that epigenetic changes in germ cells contribute to this father-offspring transmission. In addition, we explored whether H19 might regulate hepatic gluconeogenesis. Our results showed that overexpression of H19 in Hepa1-6 cells enhanced the expression of PEPCK and gluconeogenesis by promoting nuclear retention of forkhead box O1 (FOXO1), which is involved in the transcriptional regulation of Pepck. Thus, the current study suggests that paternal exposure to HFD impairs the gluconeogenesis of offspring via altered Igf2/H19 DNA methylation.

Maternal swimming mitigates liver damage caused by paternal obesity

ObjectivesParents' lifestyle and nutrition can program offspring obesity in adulthood. We hypothesized that maternal swimming has beneficial effects on the adversity caused by paternal obesity on offspring. MethodsTwelve-week-old male C57 BL/6 J mice (fed a high-fat diet, obese father [ObFa], or control diet, lean father [LFa]) were mated with female mice fed only the control diet. Mothers were trained (TMo) or untrained (UMo): swimming for 6 wk before and the first 2 wk of gestation. Pups were fed only the control diet. ResultsFathers showed different body mass (BM) at copulation, but not the mothers. The ObFa had 20% higher BM than the LFa. Twelve-week-old ObFa/UMo offspring showed a higher BM gain than the LFa/UMo and ObFa/TMo. There was BM sexual dimorphism in the LFa/UMo (female mice +24% than male mice). There was hyperglycemia and hyperinsulinemia in the ObFa/UMo, but low glycemia and insulin levels were seen in the ObFa/TMo. There was augmented liver steatosis in the ObFa/UMo compared with the LFa/UMo, and the ObFa/TMo compared with the LFa/TMo, but reduced steatosis in the ObFa/TMo compared with the ObFa/UMo. In addition, lipogenic markers were more expressed and beta-oxidation markers less expressed in the ObFa/UMo compared with the LFa/UMo, but the opposite was observed in the ObFa/TMo compared with the ObFa/UMo. Proinflammatory markers were higher in the liver of the ObFa/UMo compared with the LFa/UMo and lower in the ObFa/TMo compared with the ObFa/UMo. ConclusionsObese fathers produced offspring that were overweight and had altered fasting glycemia and insulin sensitivity, leading to higher liver lipogenesis and inflammation, as well as lower beta-oxidation. The swimming mother mitigated these adverse effects in mice offspring.

Prevalence and correlates of adherence to the combined movement guidelines among Czech children and adolescents

BackgroundThere are limited studies on the prevalence of adherence to the combined guidelines for physical activity (PA), sedentary behavior, and sleep in children and adolescents. Moreover, little is known about correlates of adherence to the guidelines. Therefore, the main aim of this study is to examine the prevalence and identify the correlates of adherence to the combined movement guidelines among children and adolescents.MethodsA total of 355 children aged 8–13 years (44% boys) and 324 adolescents aged 14–18 years (43% boys) from the Czech Republic participated in this study. PA and sleep duration were estimated using multi-day 24-h raw data from wrist-worn accelerometers. Recreational screen time was parent proxy-reported in children and self-reported in adolescents. Seventeen potential correlates were grouped into three homogenous categories for biological and cognitive, behavioral, and family correlates. The multi-level multivariable logistic regression was applied to identify correlates of adherence to combined movement guidelines and to specific combinations of any of two recommendations.ResultsApproximately 6.5% of children and 2.2% of adolescents met all recommendations of the combined movement guidelines. In children, girls (OR = 0.4; 95% CI = 0.1–0.9) and participants with overweight or obese fathers (OR = 0.3; 95% CI = 0.1–0.7) had significantly lower odds of adherence to the combined movement guidelines. Additionally, children had higher odds of meeting specific combinations of two recommendations if they reported regular fruit and vegetable intake, participated in organized PA, or if their fathers had a university degree. Meanwhile, paternal overweight and obesity, and high sleep efficiency were associated with lower odds of meeting specific combinations of recommendations. In adolescents, sex, fruit and vegetable intake, organized PA, and active play were correlates of meeting specific combinations of any two recommendations.ConclusionsA low proportion of children and adolescents met the combined movement guidelines and several correlates related to family were identified. Family is a key source of influence for healthy movement behaviors during childhood and adolescence.