Preconception paternal alcohol exposure exerts sex-specific effects on offspring growth and long-term metabolic programming

Abstract

BackgroundAlthough 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.ResultsPreconception 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-β 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (10.1186/s13072-019-0254-0) contains supplementary material, which is available to authorized users.

Intergenerational implications of alcohol intake: metabolic disorders in alcohol-naïve rat offspring

“…In rodents, chronic paternal alcohol use affected insulin signaling and lipid homeostasis in the offspring through paternally inherited alterations in liver × receptor activity ( Chang et al, 2019a ). Similar findings were reported by Chang et al (2019b) , assessing long-term impacts of chronic preconception paternal alcohol use in mice. Evidence of metabolic programming in offspring included suppressed cytokine profiles within the liver and pancreas, consistent with findings from this study.…”

“…Also, due to ethical concerns, we were only able to include a limited number of rats per group, thus, only male offspring were examined. However, there are sex-specific effects on offspring growth and long-term metabolic programming ( Chang et al, 2019b ), thus, comparable studies on female offspring are warranted.…”

“…In another study examining parental binge alcohol abuse, differences in the expression of genes involved in neurogenesis, reproductive function, and regulation of obesity were observed in offspring ( Przybycien-Szymanska et al, 2014 ). Also, the studies of Chang et al (2019a) and Chang et al (2019b) using a mouse model of paternal alcohol exposure have identified the markers of hepatic fibrosis and abnormalities in both lipid production and insulin signaling in the offspring of alcohol-exposed sires. The aforementioned studies raise the possibility that alcohol affects naïve offspring even in the absence of direct foetal alcohol exposure, and epigenetic inheritance may be the mechanism responsible for this phenomenon.…”

Intergenerational Effects of Alcohol: A Review of Paternal Preconception Ethanol Exposure Studies and Epigenetic Mechanisms in the Male Germline

“…To date, there have been over 40 published paternal preconception alcohol exposure studies in rodents (for review, see Finegersh et al., ), most varying in species, route of administration, and duration. Despite these differences, some intergenerational (F1) effects have been consistent such as low fetal and birthweight (Bielawski et al., ; Chang et al., , ; Ledig et al., ), altered organ weights (Abel, ; Chang et al., ; Ledig et al., ; Lee et al., ), and increased number of runts (Bielawski and Abel, ; Bielawski et al., ). Additional phenotypes reported include increased cortical thickness (Jamerson et al., ), reduced testosterone (Abel and Lee, ), and altered neurotransmitter levels (Nelson et al., ).…”

Effects of Paternal Preconception Vapor Alcohol Exposure Paradigms on Behavioral Responses in Offspring

“…Remarkably, rodent studies have demonstrated that paternal preconception ethanol (PPE) exposure leads to molecular, cellular, physiological, and behavioral abnormalities in offspring (for reviews, see: [ 11 , 12 ]). For example, PPE-sired offspring exhibited insulin hypersensitivity and upregulated transforming growth factor beta signaling [ 13 ], altered enzymes and proteins involved in metabolism and weight gain [ 14 ], and altered levels of neurotrophins like brain-derived neurotrophic factor and nerve growth factor [ 15 , 16 ]. Paternal alcohol consumption impaired spatial learning performance in the eight-arm radial maze in male offspring while there was no change observed in an object exploration/recognition task compared to controls [ 17 ].…”