An exercise-only intervention in obese fathers restores glucose and insulin regulation in conjunction with the rescue of pancreatic islet cell morphology and microRNA expression in male offspring

Published: 9 February 2017Paternal obesity programs metabolic syndrome in offspring. Low-impact exercise in obese males improves the metabolic health of female offspring, however whether this occurred in male offspring remained unknown. C57BL/6NHsd (Harlan) mice were fed a control diet (CD; 6% fat, n = 7) or a high-fat diet (HFD; 21% fat, n = 16) for 18 weeks. After 9 weeks, HFD-fed mice either remained sedentary (HH, n = 8) or undertook low-moderate exercise (HE, n = 8) for another 9 weeks. Male offspring were assessed for glucose/insulin tolerance, body composition, plasma lipids, pancreatic islet cell morphology and microRNA expression. Founder HH induced glucose intolerance, insulin insensitivity, and hyperlipidaemia in male offspring (p < 0.05). Metabolic health was fully restored in male offspring by founder exercise to control levels. Founder HH reduced pancreatic β-cell area and islet cell size in male offspring, and altered the expression of 13 pancreatic microRNAs (p < 0.05). Founder HE led to partial restoration of pancreatic islet cell morphology and the expression of two pancreatic microRNAs (let7d-5p, 194-5p) in male offspring. Founder HE reduced male offspring adiposity, increased muscle mass, reduced plasma free fatty acids (FFAs), and further altered pancreatic microRNAs (35 vs. HH; 32 vs. CD) (p < 0.05). Low-impact exercise in obese fathers prior to conception, without dietary change, may be a viable intervention strategy to reduce the illeffects of obesity-induced paternal programming in male offspring.Nicole O. McPherson, Michelle Lane, Lauren Sandeman, Julie A. Owens and Tod Fullsto

Sperm microRNA content is altered in a mouse model of male obesity, but the same suite of microRNAs are not altered in offspring's sperm

The prevalence of obesity is increasing worldwide and has tripled in men of reproductive age since the 1970s. Concerningly, obesity is not only comorbid with other chronic diseases, but there is mounting evidence that it increases the non-communicable disease load in their children (eg mortality, obesity, autism). Animal studies have demonstrated that paternal obesity increases the risk of metabolic (eg glucose metabolism defects, obesity) and reproductive disorders in offspring. Epigenetic changes within sperm are clear mechanistic candidates that are associated with both changes to the father’s environment and offspring phenotype. Specifically there is emerging evidence that a father’s sperm microRNA content both responds to paternal environmental cues and alters the gene expression profile and subsequent development of the early embryo. We used a mouse model of high fat diet (HFD) induced obesity to investigate whether male obesity could modulate sperm microRNA content. We also investigated whether this alteration to a father’s sperm microRNA content lead to a similar change in the sperm of male offspring. Our investigations were initially guided by a Taqman PCR array, which indicated the differential abundance of 28 sperm borne microRNAs in HFD mice. qPCR confirmation in a much larger cohort of founder males demonstrated that 13 of these microRNAs were differentially abundant (11 up-regulated; 2 down-regulated) due to HFD feeding. Despite metabolic and reproductive phenotypes also being observed in grand-offspring fathered via the male offspring lineage, there was no evidence that any of the 13 microRNAs were also dysregulated in male offspring sperm. This was presumably due to the variation seen within both groups of offspring and suggests other mechanisms might act between offspring and grand-offspring. Thus 13 sperm borne microRNAs are modulated by a father’s HFD and the presumed transfer of this altered microRNA payload to the embryo at fertilisation potentially acts to alter the embryonic molecular makeup post-fertilisation, altering its growth trajectory, ultimately affecting adult offspring phenotype and may contribute to paternal programming.Tod Fullston, E. Maria C. Ohlsson-Teague, Cristin G. Print, Lauren Y. Sandeman, Michelle Lan

Obese father's metabolic state, adiposity, and reproductive capacity indicate son's reproductive health

ObjectiveTo determine whether dietary and exercise regimes in obese males can provide a novel intervention window for improving the reproductive health of the next generation.DesignExperimental animal study.SettingUniversity research facilities.Animal(s)C57BL6 male and female mice.Intervention(s)Mice were fed a control diet (6% fat) or high-fat diet (21% fat) for 9 weeks. After the initial feeding, high-fat-diet males were allocated to diet and/or exercise interventions for a further 9 weeks. After intervention males were mated with females fed standard chow (4% fat) before and during pregnancy.Main outcome measure(s)F1 sperm motility, count, morphology, capacitation, mitochondrial function, and sperm binding and weight of reproductive organs.Result(s)Our primary finding was that diet intervention alone in founders improved offspring sperm motility and mitochondrial markers of sperm health (decreased reactive oxygen species and mitochondrial membrane potential), ultimately improving sperm binding. Sperm binding and capacitation was also improved in F1 males born to a combined diet and exercise intervention in founders. Founder sperm parameters and metabolic measures as a response to diet and/or exercise (i.e., lipid/glucose homeostasis, sperm count and morphology) correlated with offspring's sperm function, independent of founder treatment. This implicates paternal metabolic and reproductive status in predicting male offspring's reproductive function.Conclusion(s)This is the first study to show that improvements to both metabolic (lipids, glucose and insulin sensitivity) and reproductive function (sperm motility and morphology) in obese fathers via diet and exercise interventions can improve subsequent reproductive health in offspring.Nicole O. McPherson, Tod Fullston, Hassan W. Bakos, Brian P. Setchell and Michelle Lan

Chemotactic synthetic vesicles: Design and applications in blood-brain barrier crossing

In recent years, scientists have created artificial microscopic and nanoscopic self-propelling particles, often referred to as nano- or microswimmers, capable of mimicking biological locomotion and taxis. This active diffusion enables the engineering of complex operations that so far have not been possible at the micro- and nanoscale. One of the most promising tasks is the ability to engineer nanocarriers that can autonomously navigate within tissues and organs, accessing nearly every site of the human body guided by endogenous chemical gradients. We report a fully synthetic, organic, nanoscopic system that exhibits attractive chemotaxis driven by enzymatic conversion of glucose. We achieve this by encapsulating glucose oxidase alone or in combination with catalase into nanoscopic and biocompatible asymmetric polymer vesicles (known as polymersomes). We show that these vesicles self-propel in response to an external gradient of glucose by inducing a slip velocity on their surface, which makes them move in an extremely sensitive way toward higher-concentration regions. We finally demonstrate that the chemotactic behavior of these nanoswimmers, in combination with LRP-1 (low-density lipoprotein receptor–related protein 1) targeting, enables a fourfold increase in penetration to the brain compared to nonchemotactic systems

Oxidative stress in mouse sperm impairs embryo development, fetal growth and alters adiposity and glucose regulation in female offspring

Paternal health cues are able to program the health of the next generation however the mechanism for this transmission is unknown. Reactive oxygen species (ROS) are increased in many paternal pathologies, some of which program offspring health, and are known to induce DNA damage and alter the methylation pattern of chromatin. We therefore investigated whether a chemically induced increase of ROS in sperm impairs embryo, pregnancy and offspring health. Mouse sperm was exposed to 1500 µM of hydrogen peroxide (H2O2), which induced oxidative damage, however did not affect sperm motility or the ability to bind and fertilize an oocyte. Sperm treated with H2O2 delayed on-time development of subsequent embryos, decreased the ratio of inner cell mass cells (ICM) in the resulting blastocyst and reduced implantation rates. Crown-rump length at day 18 of gestation was also reduced in offspring produced by H2O2 treated sperm. Female offspring from H2O2 treated sperm were smaller, became glucose intolerant and accumulated increased levels of adipose tissue compared to control female offspring. Interestingly male offspring phenotype was less severe with increases in fat depots only seen at 4 weeks of age, which was restored to that of control offspring later in life, demonstrating sex-specific impacts on offspring. This study implicates elevated sperm ROS concentrations, which are common to many paternal health pathologies, as a mediator of programming offspring for metabolic syndrome and obesity.Michelle Lane, Nicole O. McPherson, Tod Fullston, Marni Spillane, Lauren Sandeman, Wan Xian Kang, Deirdre L. Zander-Fo

Paternal obesity induces metabolic and sperm disturbances in male offspring that are exacerbated by their exposure to an "obesogenic" diet

 Un membre de la Garde civile espagnole sur la frontière entre l'Espagne et le Maroc à Melilla, le 17 octobre 2013. (Photo Pierre-Philippe Marcou. AFP) Un Africain est mort mardi en escaladant le triple grillage qui entoure l'enclave espagnole au Maroc. Une centaine de ses compagnons a réussi à passer en Europe. " Ultracontroversée depuis déjà une bonne dizaine d’années, le triple grillage qui sert de frontière entre le Maroc et Melilla, petite enclave espagnole du nord de l’Afrique, suscite..

Paternal obesity induces metabolic and sperm disturbances in male offspring that are exacerbated by their exposure to an "obesogenic" diet

Obesity and related comorbidities are becoming increasingly prevalent globally. In mice preconception paternal exposure to a high fat diet (HFD) impairs the metabolic and reproductive health of male offspring, despite their control diet (CD) consumption. However, offspring share lifestyle, including diet, with parents. We assessed if male offspring from HFD fathers have a heightened susceptibility to HFD-induced metabolic and reproductive derangements. This 2 × 2 design saw founder males (F0) and their offspring (F1) fed either a HFD or a nutritionally matched CD. Regardless of paternal diet, HFD fed male offspring had greater total body weight and adiposity. Offspring sired by a HFD male and fed a HFD were the heaviest, had the greatest adiposity and had the greatest concentration of serum cholesterol, triglyceride, HDL, and NEFA compared with CD sired/fed littermates. A synergistic increase in serum insulin was unmasked by both father/son HFD consumption, concomitant with increased sera glucose. Either a paternal or offspring HFD was associated with similar reductions to offspring sperm motility. Whereas sperm ROS concentrations and sperm-oocyte binding saw detrimental effects of both F0 HFD and F1 HFD with an interaction evident between both, culminating in the most impaired sperm parameters in this group. This indicates that metabolic and fertility disturbances in male offspring sired by HFD fathers are exacerbated by a "second-hit" of exposure to the same obesogenic environment postnatally. If translatable to human health, this suggests that adverse reproductive and metabolic outcomes may be amplified across generations through a shared calorie dense diet, relevant to the current worldwide obesity epidemic.Tod Fullston, Nicole O. McPherson, Julie A. Owens, Wan Xian Kang, Lauren Y. Sandeman & Michlle Lan

Paternal under-nutrition programs metabolic syndrome in offspring which can be reversed by antioxidant/vitamin food fortification in fathers

There is an ever increasing body of evidence that demonstrates that paternal over-nutrition prior to conception programs impaired metabolic health in offspring. Here we examined whether paternal under-nutrition can also program impaired health in offspring and if any detrimental health outcomes in offspring could be prevented by micronutrient supplementation (vitamins and antioxidants). We discovered that restricting the food intake of male rodents reduced their body weight, fertility, increased sperm oxidative DNA lesions and reduced global sperm methylation. Under-nourished males then sired offspring with reduced postnatal weight and growth but somewhat paradoxically increased adiposity and dyslipidaemia, despite being fed standard chow. Paternal vitamin/antioxidant food fortification during under-nutrition not only normalised founder oxidative sperm DNA lesions but also prevented early growth restriction, fat accumulation and dyslipidaemia in offspring. This demonstrates that paternal under-nutrition reduces postnatal growth but increases the risk of obesity and metabolic disease in the next generation and that micronutrient supplementation during this period of under-nutrition is capable of restoring offspring metabolic health

X-Linked lissencephaly with absent corpus callosum and abnormal genitalia: an evolving multisystem syndrome with severe congenital intestinal diarrhea disease

X-linked lissencephaly with abnormal genitalia is a rare and devastating syndrome. The authors present an infant with a multisystem phenotype where the intestinal manifestations were as life limiting as the central nervous system features. Severe chronic diarrhea resulted in failure to thrive, dehydration, electrolyte derangements, long-term hospitalization, and prompted transition to palliative care. Other multisystem manifestations included megacolon, colitis, pancreatic insufficiency hypothalamic dysfunction, hypothyroidism, and hypophosphatasia. A novel aristaless-related homeobox gene mutation, c.1136G>T/p.R379L, was identified. This case contributes to the clinical, histological, and molecular understanding of the multisystem nature of this disorder, especially the role of ARX in the development of the enteroendocrine system.David Coman, Tom Fullston, Cheryl Shoubridge, Richard Leventer, Flora Wong, Simon Nazaretian, Ian Simpson, Josef Gecz, and George McGillivra

It takes a community to conceive: an analysis of the scope, nature and accuracy of online sources of health information for couples trying to conceive

This study examined the nature and accuracy of information available across online platforms for couples trying to conceive. A consumer simulation-based investigation of English websites and social media (Facebook, Twitter, Instagram) was undertaken using common search terms identified in a pilot study. Claims about fertility and pregnancy health were then extracted from the results and analysed thematically. The accuracy of each claim was assessed independently by six fertility and conception experts, rated on a scale of 1 (not factual) to 4 (highly factual), with scores collated to produce a median rating. Claims with a medianscoreb3 were classified as inaccurate. The use of the terms 'trying to conceive' and '#TTC' were common identifiers on online platforms. Claims were extracted predominantly from websites (n= 89) rather than social media, with Twitter and Instagram comprising commercial elements and Facebook focused on community-based support. Thematic analysis revealed three major themes among the claims across all platforms: conception behaviour and monitoring, lifestyle and exposures, and medical. Fact-checking by the experts revealed that 40% of the information assessed was inaccurate, and that inaccuracies were more likely to be present in the conception behaviour and monitoring advice, the topics most amenable to modification. Since online information is a readily accessible and commonly utilized resource, there is opportunity for improved dissemination of evidence-based material to reach interested couples. Further cross-disciplinary and consumer-based research, such as a user survey, is required to understand how best to provide the 'trying to conceive' community with accurate information.Sophie G.E. Kedzior, Tina Bianco-Miotto, James Breen, Kerrilyn R. Diener, Martin Donnelley, Kylie R. Dunning Megan A.S. Penno, John E. Schjenken, David J. Sharkey, Nicolette A. Hodyl, Tod Fullston, Maria Gardiner, Hannah M. Brown, Alice R. Rumbol