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DNA methylation-independent growth restriction and altered developmental programming in a mouse model of preconception male alcohol exposure.

ABSTRACT: The preconception environment is a significant modifier of dysgenesis and the development of environmentally-induced disease. To date, fetal alcohol spectrum disorders (FASDs) have been exclusively associated with maternal exposures, yet emerging evidence suggests male-inherited alterations in the developmental program of sperm may be relevant to the growth-restriction phenotypes of this condition. Using a mouse model of voluntary consumption, we find chronic preconception male ethanol exposure associates with fetal growth restriction, decreased placental efficiency, abnormalities in cholesterol trafficking, sex-specific alterations in the genetic pathways regulating hepatic fibrosis, and disruptions in the regulation of imprinted genes. Alterations in the DNA methylation profiles of imprinted loci have been identified in clinical studies of alcoholic sperm, suggesting the legacy of paternal drinking may transmit via heritable disruptions in the regulation of imprinted genes. However, the capacity of sperm-inherited changes in DNA methylation to broadly transmit environmentally-induced phenotypes remains unconfirmed. Using bisulphite mutagenesis and second-generation deep sequencing, we find no evidence to suggest that these phenotypes or any of the associated transcriptional changes are linked to alterations in the sperm-inherited DNA methylation profile. These observations are consistent with recent studies examining the male transmission of diet-induced phenotypes and emphasize the importance of epigenetic mechanisms of paternal inheritance beyond DNA methylation. This study challenges the singular importance of maternal alcohol exposures and suggests paternal alcohol abuse is a significant, yet overlooked epidemiological factor complicit in the genesis of alcohol-induced growth defects, and may provide mechanistic insight into the failure of FASD children to thrive postnatally.

SUBMITTER: Chang RC

PROVIDER: S-EPMC5788439 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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DNA methylation-independent growth restriction and altered developmental programming in a mouse model of preconception male alcohol exposure.

Chang Richard C RC Skiles William M WM Chronister Sarah S SS Wang Haiqing H Sutton Gabrielle I GI Bedi Yudhishtar S YS Snyder Matthew M Long Charles R CR Golding Michael C MC

Epigenetics 20171207 10

The preconception environment is a significant modifier of dysgenesis and the development of environmentally-induced disease. To date, fetal alcohol spectrum disorders (FASDs) have been exclusively associated with maternal exposures, yet emerging evidence suggests male-inherited alterations in the developmental program of sperm may be relevant to the growth-restriction phenotypes of this condition. Using a mouse model of voluntary consumption, we find chronic preconception male ethanol exposure ...[more]

PMID: 28816587

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Project description:BACKGROUND:Although clinical data support an association between paternal alcohol use and deficits in child neurocognitive development, the relationship between paternal drinking and alcohol-induced growth phenotypes remains challenging to define. Using an established mouse model of chronic exposure, previous work by our group has linked preconception paternal alcohol use to sex-specific patterns of fetal growth restriction and placental dysfunction. The aim of the present study was to investigate the long-term impact of chronic preconception paternal alcohol use on offspring growth and metabolic programming. RESULTS:Preconception paternal alcohol exposure induced a prolonged period of fetal gestation and an increased incidence of intrauterine growth restriction, which affected the male offspring to a greater extent than the females. While the female offspring of ethanol-exposed males were able to match the body weights of the controls within the first 2 weeks of postnatal life, male offspring continued to display an 11% reduction in weight at 5 weeks of age and a 6% reduction at 8 weeks of age. The observed growth deficits associated with insulin hypersensitivity in the male offspring, while in contrast, females displayed a modest lag in their glucose tolerance test. These metabolic defects were associated with an up-regulation of genes within the pro-fibrotic TGF-? signaling pathway and increased levels of cellular hydroxyproline within the livers of the male offspring. We observed suppressed cytokine profiles within the liver and pancreas of both the male and female offspring, which correlated with the up-regulation of genes in the LiverX/RetinoidX/FarnesoidX receptor pathways. However, patterns of gene expression were highly variable between the offspring of alcohol-exposed sires. In the adult offspring of alcohol-exposed males, we did not observe any differences in the allelic expression of Igf2 or any other imprinted genes. CONCLUSIONS:The impact of paternal alcohol use on child development is poorly explored and represents a significant gap in our understanding of the teratogenic effects of ethanol. Our studies implicate paternal exposure history as an additional and important modifier of alcohol-induced growth phenotypes and challenge the current maternal-centric exposure paradigm.

Project description:Phthalate plasticizers are ubiquitous chemicals linked to several cardiovascular diseases in animal models and humans. Despite this, the mechanisms by which phthalate exposures cause adverse cardiac health outcomes are unclear. In particular, whether phthalate exposures during pregnancy interfere with normal developmental programming of the cardiovascular system, and the resulting implications this may have for long-term disease risk, are unknown. Recent studies suggest that the effects of phthalates on metabolic and neurobehavioral outcomes are sex-specific. However, the influence of sex on cardiac susceptibility to phthalate exposures has not been investigated. One mechanism by which developmental exposures may influence long-term health is through altered programming of DNA methylation. In this work, we utilized an established mouse model of human-relevant perinatal exposure and enhanced reduced representation bisulfite sequencing to investigate the long-term effects of diethylhexyl phthalate (DEHP) exposure on DNA methylation in the hearts of adult male and female offspring at 5 months of age (n = 5-7 mice per sex and exposure). Perinatal DEHP exposure led to hundreds of sex-specific, differentially methylated cytosines (DMCs) and differentially methylated regions (DMRs) in the heart. Pathway analysis of DMCs revealed enrichment for several pathways in females, including insulin signaling, regulation of histone methylation, and tyrosine phosphatase activity. In males, DMCs were enriched for glucose transport, energy generation, and developmental programs. Notably, many sex-specific genes differentially methylated with DEHP exposure in our mouse model were also differentially methylated in published data of heart tissues collected from human heart failure patients. Together, these data highlight the potential role for DNA methylation in DEHP-induced cardiac effects and emphasize the importance of sex as a biological variable in environmental health studies.

Project description:Background: Prenatal alcohol exposure (PAE) can alter the development of neurobiological systems, leading to lasting neuroendocrine, neuroimmune, and neurobehavioral deficits. Although the etiology of this reprogramming remains unknown, emerging evidence suggests DNA methylation as a potential mediator and biomarker for the effects of PAE due to its responsiveness to environmental cues and relative stability over time. Here, we utilized a rat model of PAE to examine the DNA methylation profiles of rat hypothalami and leukocytes at four time points during early development to assess the genome-wide impact of PAE on the epigenome and identify potential biomarkers of PAE. Our model of PAE resulted in blood alcohol levels of ~80-150 mg/dl throughout the equivalent of the first two trimesters of human pregnancy. Hypothalami were analyzed on postnatal days (P) 1, 8, 15, 22 and leukocytes at P22 to compare central and peripheral markers. Genome-wide DNA methylation analysis was performed by methylated DNA immunoprecipitation followed by next-generation sequencing. Results: PAE resulted in lasting changes to DNA methylation profiles across all four ages, with 118 differentially methylated regions (DMRs) displaying persistent alterations across the developmental period at a false-discovery rate (FDR) < 0.05. In addition, 299 DMRs showed the same direction of change in the hypothalamus and leukocytes of P22 pups at an FDR < 0.05, with some genes overlapping with the developmental profile findings. The majority of these DMRs were located in intergenic regions, which contained several computationally-predicted transcription factor binding sites. Differentially methylated genes were generally involved in immune function, epigenetic remodeling, metabolism, and hormonal signaling, as determined by gene ontology analyses. Conclusions: Persistent DNA methylation changes in the hypothalamus may be associated with the long-term physiological and neurobehavioral alterations in observed in PAE. Furthermore, correlations between epigenetic alterations in peripheral tissues and those in the brain will provide a foundation for the development of biomarkers of fetal alcohol spectrum disorder (FASD). Finally, findings from studies of PAE provide important insight into the etiology of neurodevelopmental and mental health disorders, as they share numerous phenotypes and comorbidities.

Project description:IntroductionAs providing health education, optimizing nutrition, and managing risk factors can be effective for ensuring a healthy outcome for women and her yet un-conceived baby, external influences play a significant role as well. Alcohol, smoking, caffeine use and other similar lifestyle factors, have now become an integral part of the daily life of most men and women, who use/misuse one or more of these harmful substances regularly despite knowledge of their detrimental effects. The adverse health outcomes of these voluntary and involuntary exposures are of even greater concern in women of child bearing age where the exposure has the potential of inflicting harm to two generations. This paper is examining the available literature for the possible effects of caffeine consumption, smoking, alcohol or exposure to chemicals may have on the maternal, newborn and child health (MNCH).MethodsA systematic review and meta-analysis of the evidence was conducted to ascertain the possible impact of preconception usage of caffeine, tobacco, alcohol and other illicit drugs; and exposure to environmental chemicals and radiant on MNCH outcomes. A comprehensive strategy was used to search electronic reference libraries, and both observational and clinical controlled trials were included. Cross-referencing and a separate search strategy for each preconception risk and intervention ensured wider study capture.ResultsHeavy maternal preconception caffeine intake of >300 mg/d significantly increase the risk of a subsequent fetal loss by 31% (95% CI: 8-58%). On the other hand, preconception alcohol consumption leads to non-significant 30% increase in spontaneous abortion (RR 1.30; 95% CI: 0.85-1.97). Preconception counselling can lead to a significant decrease in the consumption of alcohol during the first trimester (OR 1.79; 95% CI: 1.08-2.97). Periconception smoking, on the other hand, was found to be associated with an almost 3 times increased risk of congenital heart defects (OR 2.80; 95% CI 1.76-4.47). While the review found limited evidence of preconception environmental exposure on maternal, newborn and child health outcomes, occupational exposure in female radiation workers before conception showed an increased impact in risk of early miscarriages.ConclusionIdentification of substance abuse and environmental history during preconception period provides an opportunity to assist women in reducing major health risks and identify key determinants of healthy pregnancy. Studies have shown that the aversion and prevention of exposure feasibility can play an important role in improving the health of women and their families, however, the results should be interpreted with great caution as there were few studies in each section. Therefore, there is a need for more rigorous studies to test the hypotheses.

Project description:BACKGROUND:Fetal growth restriction (FGR) is associated with an increased susceptibility for various noncommunicable diseases in adulthood, including cardiovascular and renal disease. During FGR, reduced uteroplacental blood flow, oxygen and nutrient supply to the fetus are hypothesized to detrimentally influence cardiovascular and renal programming. This study examined whether developmental programming profiles, especially related to the cardiovascular and renal system, differ in human umbilical vein endothelial cells (HUVECs) collected from pregnancies complicated by placental insufficiency-induced FGR compared to normal growth pregnancies. Our approach, involving transcriptomic profiling by RNA-sequencing and gene set enrichment analysis focused on cardiovascular and renal gene sets and targeted DNA methylation assays, contributes to the identification of targets underlying long-term cardiovascular and renal diseases. RESULTS:Gene set enrichment analysis showed several downregulated gene sets, most of them involved in immune or inflammatory pathways or cell cycle pathways. seven of the 22 significantly upregulated gene sets related to kidney development and four gene sets involved with cardiovascular health and function were downregulated in FGR (n?=?11) versus control (n?=?8). Transcriptomic profiling by RNA-sequencing revealed downregulated expression of LGALS1, FPR3 and NRM and upregulation of lincRNA RP5-855F14.1 in FGR compared to controls. DNA methylation was similar for LGALS1 between study groups, but relative hypomethylation of FPR3 and hypermethylation of NRM were present in FGR, especially in male offspring. Absolute differences in methylation were, however, small. CONCLUSION:This study showed upregulation of gene sets related to renal development in HUVECs collected from pregnancies complicated by FGR compared to control donors. The differentially expressed gene sets related to cardiovascular function and health might be in line with the downregulated expression of NRM and upregulated expression of lincRNA RP5-855F14.1 in FGR samples; NRM is involved in cardiac remodeling, and lincRNAs are correlated with cardiovascular diseases. Future studies should elucidate whether the downregulated LGALS1 and FPR3 expressions in FGR are angiogenesis-modulating regulators leading to placental insufficiency-induced FGR or whether the expression of these genes can be used as a biomarker for increased cardiovascular risk. Altered DNA methylation might partly underlie FPR3 and NRM differential gene expression differences in a sex-dependent manner.

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DNA methylation-independent growth restriction and altered developmental programming in a mouse model of preconception male alcohol exposure.

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DNA methylation-independent growth restriction and altered developmental programming in a mouse model of preconception male alcohol exposure.

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