Alterations in sperm-inherited noncoding RNAs associate with late-term fetal growth restriction induced by preconception paternal alcohol use

Bedi, Yudhishtar S.; Chang, Richard; Gibbs, Rachel L; Clement, Tracy M.; Golding, Michael C.

doi:10.1016/j.reprotox.2019.04.006

Cited by 43 publications

(63 citation statements)

References 73 publications

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“…Using a mouse model of preconception paternal alcohol exposure, Bedi and colleagues [ 66 ] demonstrated that both male and female fetuses from the alcohol-exposed sires exhibit growth reduction similar in magnitude to those detected in the fetuses from our alcohol-exposed dams. Consistent with data from our mouse model of maternal gestational alcohol exposure, the fetal body reduction in their model was associated with the lower placental efficiency.…”

Section: Discussionmentioning

confidence: 89%

An interaction between fetal sex and placental weight and efficiency predicts intrauterine growth in response to maternal protein insufficiency and gestational exposure window in a mouse model of FASD

et al. 2020

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Background: Individuals exposed to gestational stressors such as alcohol exhibit a spectrum of growth patterns, suggesting individualized responses to the stressors. We hypothesized that intrauterine growth responses to gestational alcohol are modified not only by the stressor's severity but by fetal sex and the placenta's adaptive capacity. Methods: Pregnant C57BL/6J mice were assigned to one of three groups. Group 1 consumed a normal protein diet (18% protein by weight) and received 4.5 g alcohol/kg body weight (NP-Alc-8) or isocaloric maltodextrin (NP-MD-8) daily from embryonic day (E) 8.5-E17.5. Group 2 consumed the same diet but received alcohol (NP-Alc-13) or maltodextrin (NP-MD-13) daily from E13.5-E17.5. Group 3 consumed the same diet but containing a lower protein content (12% protein by weight) from E0.5 and also received alcohol (LP-Alc-8) or maltodextrin (LP-MD-8) daily from E8.5-E17.5. Maternal, placental, and fetal outcomes were assessed on E17.5 using 2-way ANOVA or mixed linear model.

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Section: Discussionmentioning

confidence: 89%

An interaction between fetal sex and placental weight and efficiency predicts intrauterine growth in response to maternal protein insufficiency and gestational exposure window in a mouse model of FASD

et al. 2020

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“…Several studies have reported that alcohol can act as an epimutagen and has the ability to induce alterations in DNA methylation, chromatin modifications, and noncoding RNAs in sperm (for review, see: [ 11 ]). Previous studies from our laboratory [ 35 ] and others [ 65 ] found that chronic ethanol exposure altered several small noncoding RNAs including tRNA derived fragments, PIWI-interacting RNAs, and miRNAs in sperm. Studies demonstrating a causal role of these alcohol-induced sperm RNA changes are desperately needed.…”

Section: Discussionmentioning

confidence: 98%

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

et al. 2020

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We and others previously reported that paternal preconception chronic ethanol exposure leads to molecular, physiological, and behavioral changes in offspring including reduced ethanol consumption and preference relative to controls. The goal of the present study was to further explore the impact of paternal ethanol exposure on a wide variety of basal and drug-induced behavioral responses in first generation offspring. Adult male mice were exposed to chronic intermittent vapor ethanol or control conditions for 5–6 weeks before being mated with ethanol-naïve females to produce ethanol (E)- and control (C)-sired offspring. E-sired male offspring showed stress hyporesponsivity in a stress-induced hyperthermia assay and E-sired female offspring had reduced binge-like ethanol consumption in a drinking in the dark assay compared to C-sired offspring. E-sired offspring also showed altered sensitivity to a sedative/hypnotic dose of the GABAergic drug midazolam, but not ketamine or ethanol, in a loss of the righting response assay. E-sired offspring did not differ from controls in marble burying, novel object location, novel object recognition, social interaction, bottle-brush, novelty suppressed feeding, prepulse inhibition, every-other-day ethanol drinking, or home cage activity assays. This study adds to a growing body of literature suggesting that like in utero alcohol exposure, paternal preconception alcohol exposure can also have effects that persist and impact behavior of offspring.

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“…We maintained individually caged postnatal day 90 adult males on a standard diet (catalog no. 2019, Teklad Diets, Madison, WI, USA) and exposed them to either a control or alcohol preconception treatment using a previously described limited access model of voluntary exposure [[5], [6], [7]]. In this model, males are provided limited access to the preconception treatments during a four-hour window, beginning one hour after the initiation of the dark cycle.…”

Section: Methodsmentioning

confidence: 99%

“…Similar to rodent models examining a wide range of other environmental and metabolic stressors, paternal exposures to alcohol and drugs correlate with alterations to the sperm epigenome, as well as changes in offspring behavior, metabolism and the propensity to develop disease [3,4]. Using a mouse model of voluntary consumption, our lab recently identified an association between chronic paternal alcohol use and long-term effects on the growth and metabolic health of the offspring [[5], [6], [7]]. Specifically, the offspring of males continuously exposed to alcohol before conception displayed placental dysfunction and late-term fetal growth restriction [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…Using a mouse model of voluntary consumption, our lab recently identified an association between chronic paternal alcohol use and long-term effects on the growth and metabolic health of the offspring [[5], [6], [7]]. Specifically, the offspring of males continuously exposed to alcohol before conception displayed placental dysfunction and late-term fetal growth restriction [5,6]. Interestingly, the male offspring of alcohol-exposed fathers continued to exhibit growth deficits in postnatal life, which persisted into adolescence [7].…”

Section: Introductionmentioning

confidence: 99%

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Programmed increases in LXRα induced by paternal alcohol use enhance offspring metabolic adaptation to high-fat diet induced obesity

Chang

Thomas

Bedi

et al. 2019

Molecular Metabolism

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ObjectivesPaternally inherited alterations in epigenetic programming are emerging as relevant factors in numerous disease states, including the growth and metabolic defects observed in fetal alcohol spectrum disorders. In rodents, chronic paternal alcohol use induces fetal growth restriction, as well as sex-specific alterations in insulin signaling and lipid homeostasis in the offspring. Based on previous studies, we hypothesized that the observed metabolic irregularities are the consequence of paternally inherited alterations liver x receptor (LXR) activity.MethodsMale offspring of alcohol-exposed sires were challenged with a high-fat diet and the molecular pathways controlling glucose and lipid homeostasis assayed for LXR-induced alterations.ResultsSimilar to findings in studies employing LXR agonists we found that the male offspring of alcohol-exposed sires display resistance to diet-induced obesity and improved glucose homeostasis when challenged with a high-fat diet. This improved metabolic adaptation is mediated by LXRα trans-repression of inflammatory cytokines, releasing IKKβ inhibition of the insulin signaling pathway. Interestingly, paternally programmed increases in LXRα expression are liver-specific and do not manifest in the pancreas or visceral fat.ConclusionsThese studies identify LXRα as a key mediator of the long-term metabolic alterations induced by preconception paternal alcohol use.

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Alterations in sperm-inherited noncoding RNAs associate with late-term fetal growth restriction induced by preconception paternal alcohol use

Cited by 43 publications

References 73 publications

An interaction between fetal sex and placental weight and efficiency predicts intrauterine growth in response to maternal protein insufficiency and gestational exposure window in a mouse model of FASD

An interaction between fetal sex and placental weight and efficiency predicts intrauterine growth in response to maternal protein insufficiency and gestational exposure window in a mouse model of FASD

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

Programmed increases in LXRα induced by paternal alcohol use enhance offspring metabolic adaptation to high-fat diet induced obesity

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