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Male metabolic and reproductive health are perturbed by both under- and over-nutrition in mice

ABSTRACT: The association between poor paternal diet at the time of conception and impairments in offspring health and well-being is becoming increasingly established. However, the impacts of such poor-quality diets on the father’s metabolic health and physiology have been investigated to a lesser extent. Therefore, the aim of this study was to define how both under- and over-nutrition impact male metabolic and reproductive physiology. Male C57BL/6 mice were fed either control diet (CD), low protein diet (LPD), ‘Western’ diet (WD), or the LPD or WD supplemented with methyl donors (MD-LPD and MD-WD, respectively) for at least eight weeks. Under- (LPD) or over-nutrition (WD), with or without methyl donors, had minimal impact on male growth or organ weight. However, concentrations of hepatic cholesterol and free fatty acids were significantly increased in WD and MD-WD fed males. Furthermore, levels of serum inhibin β-A chain were increased in WD males when compared to LPD and MD-LPD fed males. We also observed differential abundance of multiple bacterial species at the family and phylum level in the lower gastro-intestinal tract of males fed WD and MD-WD when compared to all other groups. Within the testis, WD and MD-WD increased the number of morphologically abnormal seminiferous tubules when compared to all other males, while the number of Plzf positive cells, taken as a marker of spermatogonial stem cells, were decreased in LPD and WD fed males when compared to CD fed males. Finally, analysis of testicular gene expression revealed minimal changes in LPD and MD-LPD fed males, while WD and MD-WD males both showed differential expression of genes related to metabolism and transcriptional regulation. These findings suggest that paternal under- and over-nutrition influence metabolic status and reproductive physiology in diet-specific manners. Interestingly, supplementation of these diets with a range of methyl-donors and carries had minimal additional impact in ameliorating the effects of over- and under-nutrition.

ORGANISM(S): Mus musculus

PROVIDER: GSE279868 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Under- and over-nutrition are directly linked to poor physiological, metabolic and reproductive health. While the association between paternal diet and offspring well-being is becoming established, the underlying mechanisms are yet to be fully defined. The aim of this study was to establish and compare the impact of over- and under-nutrition on male reproductive fitness and post-fertilisation development, with the additional exploration of the role that specific micronutrient supplementation may play in ameliorating any detrimental effects of poor paternal diet. Male C57/BL6J mice were fed either control diet (CD), isocaloric low protein diet (LPD), ‘Western’ diet (WD) or LPD or WD supplemented with methyl-donors and carriers (MD-LPD or MD-WD respectively) for 8 weeks before mating with virgin C57/BL6J females maintained on standard mouse chow. Placental tissue was collected at embryonic day (E)8.5 to assess early placental morphology and metabolism or E17.5 for sex-specific transcriptomic profiling. Post-mating male tissues were harvested for assessment of testicular morphology, gene expression and metabolic profiling and fecal microbiome was analysed. This study found significant increases in adiposity, hepatic cholesterol and FFAs in WD and MDWD fed males, alongside an increase in the abundance of Defferibacteres, Proteobacteria and reduction TM7 abundance in fecal samples compared to CD fed males. Analysis of testicular gene expression revealed 402 (267 down-regulated, 135 upregulated) genes and 285 (187 down-regulated, 98 up-regulated) genes differentically expressed in WD and MD-WD-fed males, respectively, with minimal changes observed in LPD and MD-LPD groups compared to CD-fed males. Placenta from LPD fed fathers had a significant reduction in lactate production at E8.5 and significant sex-specific influences of paternal diet on late gestation fetal and placental growth were observed in both LPD and MD-LPD groups, which had a significantly higher proportion of fetuses with weights below the 10th centile when compared to CD fetuses. We also identified a significant reduction in sexually dimorphic gene expression in response to paternal diet, with 301, 13, 0, 14 and 15 placental genes to be differentially expressed between males and females in the CD, LPD, MD-LPD, WD and MD-WD. We observed that males consuming a high fat/sugar diet (WD and MD-WD), displayed a series of physiological changes in their metabolic health, gut bacterial profiles and testicular morphology and gene expression. While both over- and under-nutritional regimens had no impact on fundamental male fertility, we observed a significant loss in sexual-dimorphism in the late gestation placenta in response to our experimental diets. Such loss of sexual- dimorphism could provide one process through which poor paternal diet programs offspring ill-health in adulthood.

Project description:The importance of parental diet in relation to eventual offspring health is increasing in prominence due to the increased frequency of reproductive age adults consuming poor diets. Whilst maternal health and offspring outcome have been studied in some detail, the paternal impacts are not as well understood. A father’s poor nutritional status has been shown to have negative consequences on fetal growth and development and ultimately impact the long-term adult health of the offspring. In this study we examined sperm and seminal plasma mediated mechanisms of preimplantation embryo development alterations in response to sub-optimal paternal diets. Male mice were fed a diet to model either under (low protein diet (LPD)) or over (high fat/sugar (Western) diet (WD)) nutrition, LPD or WD supplemented with methyl-donors or a control diet before mating with age-matched control fed females. Male metabolic health was influenced by WD and MD-WD; with significant changes in serum lipids and hepatic 1-carbon metabolites. Sperm RNA sequencing revealed significant changes to mRNA profiles in all groups when compared to CD (LPD: 32, MD-LPD: 17, WD: 53, MD-WD: 35). In vitro embryo development was revealed all sub-optimal diets with and without methyl-donors increased the rate of embryo development. As embryo development can be directed by sperm and seminal plasma mediated mechanism, we also examined the proteomic profile of the seminal plasma, revealing a significant number of changes in all groups compared to control (LPD: 13, MD-LPD: 27, WD: 24, MD-WD: 19). Male diet also altered uterine gene expression examined via qPCR, specifically alterations in Cd14 and Ptgs1 were observed in response to male WD matings. Our current study shows that paternal nutritional status has the potential to influence male metabolic and reproductive factors, which can ultimately alter embryonic development and the post-mating maternal environment. This study highlights potential direct (sperm mediated) and indirect (semen mediated) pathways in which a father's poor diet could shape the long-term health of his offspring.

Project description:BACKGROUND & AIMS: Inflammatory Bowel Diseases (IBD), including Crohn’s disease and ulcerative colitis, are chronic illnesses that are thought to develop secondary to a pathologic interaction between the immune system and the intestinal microflora that is manifested by the gut mucosa. IBD has been recognized as disorders in which developmental epigenetic changes, such as DNA methylation, may play an important pathogenic role. DNA methylation can be influenced in mammals by dietary exposures. A methyl-donor diet has been specifically found to be effective in inducing permanent changes in DNA methylation at certain genomic loci in murine models. Importantly, the methyl-donor substances utilized are routinely incorporated into prenatal micronutrient supplements for humans. In this study we addressed whether maternal exposure to a methyl-donor diet induces prolonged alterations in offspring colitis susceptibility and whether it leads to stable colonic mucosal epigenetic changes and gene expression alterations in mice. We also assessed whether the maternal methyl-donor diet induced persistent changes in the colonic microbiota in the offspring. METHODS: Colonic mucosa from offspring of mothers fed a methyl donor diet (MD) or control diet was interrogated by methylation specific amplification microarray (MSAM) at postnatal day 30 (P30) and P90 to screen for changes in DNA methylation, with bisulfite pyrosequencing validation. Transcriptomic changes in the same tissue were analyzed by microarray expression profiling and real time RT-PCR. The mucosal microbiome was studied by high throughput, detailed pyrosequencing of 16S rRNA. RESULTS: MD exposure during prenatal and early development lead to a significant increase in colitis susceptibility that persisted even after 69 days of diet reversal (P90). MD exposure also influenced DNA methylation and expression at select genomic loci. Overlap between DNA methylation and gene expression changes was confirmed at Ppara, a gene previously implicated in murine colitis. Metagenomic analyses failed to reveal consistent bacteriomic differences between the P30 and P90 age groups. CONCLUSIONS: Prenatal and early developmental exposure to MD induces increased colitis susceptibility, mucosal epigenomic, and transcriptomic changes that do not appear to associate with consistent microbiomic alterations. These findings underscore the importance of maternal nutrition on offspring colitis susceptibility in mammals and implicate the importance of the associated mucosal epigenetic modification. Our results bare potentially significant public health relevance as well.

Project description:BACKGROUND & AIMS: Inflammatory Bowel Diseases (IBD), including Crohnâ??s disease and ulcerative colitis, are chronic illnesses that are thought to develop secondary to a pathologic interaction between the immune system and the intestinal microflora that is manifested by the gut mucosa. IBD has been recognized as disorders in which developmental epigenetic changes, such as DNA methylation, may play an important pathogenic role. DNA methylation can be influenced in mammals by dietary exposures. A methyl-donor diet has been specifically found to be effective in inducing permanent changes in DNA methylation at certain genomic loci in murine models. Importantly, the methyl-donor substances utilized are routinely incorporated into prenatal micronutrient supplements for humans. In this study we addressed whether maternal exposure to a methyl-donor diet induces prolonged alterations in offspring colitis susceptibility and whether it leads to stable colonic mucosal epigenetic changes and gene expression alterations in mice. We also assessed whether the maternal methyl-donor diet induced persistent changes in the colonic microbiota in the offspring. METHODS: Colonic mucosa from offspring of mothers fed a methyl donor diet (MD) or control diet was interrogated by methylation specific amplification microarray (MSAM) at postnatal day 30 (P30) and P90 to screen for changes in DNA methylation, with bisulfite pyrosequencing validation. Transcriptomic changes in the same tissue were analyzed by microarray expression profiling and real time RT-PCR. The mucosal microbiome was studied by high throughput, detailed pyrosequencing of 16S rRNA. RESULTS: MD exposure during prenatal and early development lead to a significant increase in colitis susceptibility that persisted even after 69 days of diet reversal (P90). MD exposure also influenced DNA methylation and expression at select genomic loci. Overlap between DNA methylation and gene expression changes was confirmed at Ppara, a gene previously implicated in murine colitis. Metagenomic analyses failed to reveal consistent bacteriomic differences between the P30 and P90 age groups. CONCLUSIONS: Prenatal and early developmental exposure to MD induces increased colitis susceptibility, mucosal epigenomic, and transcriptomic changes that do not appear to associate with consistent microbiomic alterations. These findings underscore the importance of maternal nutrition on offspring colitis susceptibility in mammals and implicate the importance of the associated mucosal epigenetic modification. Our results bare potentially significant public health relevance as well. 4 independent MD versus control comparisons at P90 were performed as follows. RNA (0.4ug) samples were processed and labelled with Cy3 and Cy5 (Quick Amp labelling kit, two color, Agilent technologies) and 4 independent P90 MD to P90 control comparisons were done on Agilent technologies 4x44k whole genomic expression microarray G2519F, Amadid:014868)

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Male metabolic and reproductive health are perturbed by both under- and over-nutrition in mice

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