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.
Highlights
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
Perceived as a childhood disorder, the growth phenotypes associated with fetal alcohol spectrum disorders (FASDs) are lifelong, with longterm growth restriction, as well as immune dysfunction, hyperinsulinemia, and other endocrine disruptions persisting into adulthood [5,6,7,8,9,10]
Chronic paternal ethanol exposure associates with delayed parturition and intrauterine growth restriction of the offspring In clinical studies, FASDs are characterized by reductions in height, weight and body mass index that manifest at birth and persist through young adulthood [3, 5]
Summary
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. 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. As a consequence of these persistent abnormalities, the life expectancy of patients with fetal alcohol syndrome is 34 years, which is 58% lower than the general population [11]. This dramatic reduction is very likely linked to the capacity of alcohol to significantly alter developmental programming, which promotes the early onset of adult disease [12, 13]. While much research has focused on the neurological phenotypes of FASDs, the relationship between ethanol exposures and the long-term effects on growth and metabolic programming has received comparatively little attention
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