Transgenerational inheritance of fetal alcohol exposure adverse effects on immune gene interferon-ϒ

Abstract

Background: Alcohol exposures in utero have been shown to alter immune system functions in the offspring which persists into adulthood. However, it is not apparent why the in utero alcohol effect on the immune system persists into adulthood of fetal alcohol-exposed offspring. The objective of this study was to determine the longterm effects of fetal alcohol exposure on the production of interferon-ϒ (IFN-ϒ), a cytokine known to regulate both innate and adaptive immunity. Methods: Isogenic Fisher 344 rats were bred to produce pregnant dams, which were fed with a liquid diet containing 6.7% alcohol between gestation days 7 and 21 and pair-fed with an isocaloric liquid diet or fed ad libitum with rat chow; their male and female offspring were used for the study. F1-F3 generation rats were used when they were 2 to 3 months old. Fetal alcohol exposure effects on the Ifn-ɣ gene was determined by measuring the gene promoter methylation and mRNA and protein expression in the spleen. Additionally, transgenerational studies were conducted to evaluate the germline-transmitted effects of fetal alcohol exposure on the Ifn-ɣ gene. Results: Fetal alcohol exposure reduced the expression of Ifn-ɣ mRNA and IFN-ϒ protein while it increased the proximal promoter methylation of the Ifn-ɣ gene in both male and female offspring during the adult period. Transgenerational studies revealed that the reduced levels of Ifn-ɣ expression and increased levels of its promoter methylation persisted only in F2 and F3 generation males derived from the male germ line. Conclusion: Overall, these findings provide the evidence that fetal alcohol exposures produce an epigenetic mark on the Ifn-ɣ gene that passes through multiple generations via the male germ line. These data provide the first evidence that the male germ line transmits fetal alcohol exposure's adverse effects on the immune system.

Transgenerational inheritance of fetal alcohol effects on proopiomelanocortin gene expression and methylation, cortisol response to stress, and anxiety-like behaviors in offspring for three generations in rats: Evidence for male germline transmission

“…A study has provided evidence for the implication of sperm microRNAs in transgenerational inheritance of trauma-induced phenotypes across generations [ 36 ]. Fetal alcohol exposure elicits epigenetic marks on interferon-γ that pass through multiple generations via the male germ line, providing evidence of FAE’s adverse effect on the immune system [ 37 ]. Some human studies provided evidence for epigenetic transgenerational inheritance.…”

Sex-Determining Region Y Controls the Effects of Fetal Alcohol Exposure on Proopiomelanocortin Gene Expression

“…Since FAE similarly affects the expression of Pomc and Sry genes in the F1 offspring, and FAE effects on Pomc gene expression have been shown to transmit for multiple generations ( Govorko et al, 2012 ), we tested whether the FAE effect on Sry is also transmitted transgenerationally. We produced two different germlines, a male germline by breeding male fetal alcohol-exposed rats and their male offspring with normal females, and a female germline by breeding female fetal alcohol-exposed rats and their female offspring with normal males, as we have previously described ( Govorko et al, 2012 ; Gangisetty et al, 2020 ). We also produced male (PFM) and female germlines (PFF) of control-fed rats or ad libitum -fed rats (AD).…”

Transgenerational Effects of Prenatal Ethanol Exposure in Prepubescent Mice

“…It is critically important to investigate potential driving mechanisms that may underlie unknown circuit/brain changes and behavioral disruptions within transgenerational PrEE offspring. Recent reports within animal models of PrEE have suggested transgenerational epigenetic inheritance may play a key role in inducing adverse phenotypes in offspring ( Govroko et al, 2012 ; Abbott et al, 2018 ; Gangisetty et al, 2020 ). However, this proposed mechanism is still a topic of debate ( Horsthemke, 2018 ), largely due to the vast majority of the mammalian epigenome undergoing resetting in very early development ( Xia and Xie, 2020 ).…”

“…This model stands in accordance with our previously published report ( Abbott et al, 2018 ) and further supports the substantial impact of PrEE on the male germline. The conceptualization and formulation of this model was informed by studies examining the transgenerational impact of PrEE which found that PrEE produces penetrant phenotypes in subsequent generations at a much greater level when the male germline was used for propagation ( Govorko et al, 2012 ; Gangisetty et al, 2020 ). Interestingly, these differences may be directly related to the DNA methylation profiles of sperm in affected males ( Govorko et al, 2012 ), providing a mechanistic framework for these observations.…”

“…Substantial, recent evidence has suggested that varied environmental exposures may produce transgenerational inheritance of disease phenotypes that are epigenetically-driven ( Nilsson et al, 2018 ). Indeed, several recent reports have suggested that phenotypic variation induced by PrEE can extend several generations ( Govorko et al, 2012 ; Gangisetty et al, 2020 ), likely via epigenetic mechanisms ( Chastain and Sarkar, 2017 ). Because precise epigenetic regulation, or the control of gene expression not related to changes in DNA sequence, is also crucial for complex development of the neocortex ( Adam and Harwell, 2020 ; Lewis et al, 2021 ) as well as how PrEE induces widespread epigenetic dysregulation in the brain ( Subbana et al, 2014 ; Öztürk et al, 2017 ), the notion that underlying epigenetic mechanisms may be driving transgenerational FASD phenotypes represents an attractive hypothesis.…”