Paternal alcohol exposures program intergenerational hormetic effects on offspring fetoplacental growth

Abstract

Hormesis refers to graded adaptive responses to harmful environmental stimuli where low-level toxicant exposures stimulate tissue growth and responsiveness while, in contrast, higher-level exposures induce toxicity. Although the intergenerational inheritance of programmed hormetic growth responses is described in plants and insects, researchers have yet to observe this phenomenon in mammals. Using a physiologically relevant mouse model, we demonstrate that chronic preconception paternal alcohol exposures program nonlinear, dose-dependent changes in offspring fetoplacental growth. Our studies identify an inverse j-shaped curve with a threshold of 2.4 g/Kg per day; below this threshold, paternal ethanol exposures induce programmed increases in placental growth, while doses exceeding this point yield comparative decreases in placental growth. In male offspring, higher paternal exposures induce dose-dependent increases in the placental labyrinth layer but do not impact fetal growth. In contrast, the placental hypertrophy induced by low-level paternal ethanol exposures associate with increased offspring crown-rump length, particularly in male offspring. Finally, alterations in placental physiology correlate with disruptions in both mitochondrial-encoded and imprinted gene expression. Understanding the influence of ethanol on the paternally-inherited epigenetic program and downstream hormetic responses in offspring growth may help explain the enormous variation observed in fetal alcohol spectrum disorder (FASD) phenotypes and incidence.

Teratogenesis and the epigenetic programming of congenital defects: Why paternal exposures matter

“…Alcohol is a potent teratogen and the most common cause of birth defects, with an estimated 6-17 children per 1000 live births diagnosed with some degree of fetal alcohol spectrum disorder (May et al, 2017;Popova et al, 2017). Although well established that maternal alcohol use during pregnancy causes birth defects, our group recently reported teratogenic outcomes resulting from chronic preconception paternal alcohol exposures, including defects in craniofacial growth consistent with alcohol-related birth defects observed in maternal models of exposure (Thomas et al, 2022(Thomas et al, , 2023. Our studies demonstrate that male drinking is a plausible yet completely unexamined factor in the development of alcohol-related craniofacial abnormalities.…”

“…This challenge largely stems from our inability to measure dimensions of sperm quality beyond morphology, motility, and DNA strand breaks. For example, our research has identified significant impacts of preconception paternal alcohol exposure on offspring craniofacial development, fetoplacental growth, and longer‐term impacts on the metabolic health of the adult offspring, all of which occur without any overt changes in sperm counts, morphology, or fertility (Y. Bedi et al, 2019; R. C. Chang et al, 2017; R. C. Chang, Thomas, et al, 2019; R. C. Chang, Wang, et al, 2019; Thomas et al, 2022, 2023). Similarly, males maintained on a diet deficient in folic acid have normal testes morphology and sperm counts yet were able to transmit adverse outcomes to their offspring via epigenetic mechanisms (Lambrot et al, 2013; Lismer et al, 2021).…”

“…C. Chang, Thomas, et al, 2019;R. C. Chang, Wang, et al, 2019;Thomas et al, 2022Thomas et al, , 2023. Similarly, males maintained on a diet deficient in folic acid have normal testes morphology and sperm counts yet were able to transmit adverse outcomes to their offspring via epigenetic mechanisms (Lambrot et al, 2013;Lismer et al, 2021).…”

Prenatal paternal anxiety symptoms predict child DHEA levels and internalizing symptoms during adrenarche

“…The field of genomic imprinting has revealed that sperm predominantly controls the growth and differentiation of extraembryonic tissues such as the placenta and yolk sac ( Bhadsavle and Golding, 2022 ). Studies have consistently shown that preconception paternal exposures such as age ( Denomme et al, 2020 ), obesity ( Mitchell et al, 2017 ; Jazwiec et al, 2022 ), toxicants ( Ding et al, 2018 ), cannabis ( Innocenzi et al, 2019 ) and alcohol ( De Cock et al, 2017 ; Thomas et al, 2022 ) result in sex-specific alterations of placental imprinted gene expression, as well as reduced placental weights and disruptions in placental histology. Importantly, the placenta is essential for regulating transport of nutrients and by-products, including maternal hormones between the fetal and maternal circulation, for protecting the fetus from the maternal immune system, and for producing hormones to support fetal development ( Rossant and Cross, 2001 ; Adamson et al, 2002 ).…”

Transgenerational Hangovers: A Rat Model for Behavioural and Epigenetic Changes Across Generations due to Paternal Preconceptual Alcohol Consumption

“…However, we cannot rule out the possibility of ethanol induced epigenetic changes in the sperm affecting placental function and leading to alterations in the offspring development. While research on the effects of PPAC on the placental function is scarce, studies show paternal drinking is associated with altered transcription of placental mitochondrial genes and placental histology (Thomas et al, 2021;Thomas et al, 2022). There are also reported changes in placental expression of imprinted genes Ascl2, Igf2, H19, Peg3 and Slc22a18 (Thomas et al, 2022).…”