Prenatal Adversity Alters the Epigenetic Profile of the Prefrontal Cortex: Sexually Dimorphic Effects of Prenatal Alcohol Exposure and Food-Related Stress

Abstract

Prenatal adversity or stress can have long-term consequences on developmental trajectories and health outcomes. Although the biological mechanisms underlying these effects are poorly understood, epigenetic modifications, such as DNA methylation, have the potential to link early-life environments to alterations in physiological systems, with long-term functional implications. We investigated the consequences of two prenatal insults, prenatal alcohol exposure (PAE) and food-related stress, on DNA methylation profiles of the rat brain during early development. As these insults can have sex-specific effects on biological outcomes, we analyzed epigenome-wide DNA methylation patterns in prefrontal cortex, a key brain region involved in cognition, executive function, and behavior, of both males and females. We found sex-dependent and sex-concordant influences of these insults on epigenetic patterns. These alterations occurred in genes and pathways related to brain development and immune function, suggesting that PAE and food-related stress may reprogram neurobiological/physiological systems partly through central epigenetic changes, and may do so in a sex-dependent manner. Such epigenetic changes may reflect the sex-specific effects of prenatal insults on long-term functional and health outcomes and have important implications for understanding possible mechanisms underlying fetal alcohol spectrum disorder and other neurodevelopmental disorders.

Sex‐related differences among individuals assessed for fetal alcohol spectrum disorder in Canada

“…Individuals with FASD experience significant neurocognitive and behavioral difficulties (Cook et al, 2016) and many also navigate complex physical and mental health challenges and environmental adversity across the lifespan (Flannigan et al, 2021; McLachlan et al, 2020). Most data on sex‐based differences in PAE/FASD come from the animal literature (Otero & Kelly, 2012), where researchers have identified differential impacts on fetal growth (Kwan et al, 2020), metabolic and immune function (Bake et al, 2021; Ieraci & Herrera, 2020), neurotransmitter systems (Converse et al, 2014), DNA methylation (Lussier et al, 2021), brain volume, memory (Zimmerberg et al, 1991), behavior, and social interaction (Bake et al, 2021). Across these studies, male animals tended to be more susceptible than females to the damaging impacts of PAE.…”

Immediate perturbations of DNA methylation and transcriptome upon acute prenatal alcohol exposure in the mouse developing brain cortex

“…Mid1, associated to the Opitz BBB/G syndrome reviewed in (Winter et al, 2016) and Shank2 and Auts2 both linked to autism spectrum disorders (ASD; reviewed in Bourgeron, 2015 andPang et al, 2021), with which FASD share overlapping traits (Lussier et al, 2021;Popova et al, 2016). We showed that these genes which were associated with immediate DMRs exhibited concomitant disturbances of their expression in the prenatal cortex (Figure 6).…”

“…Using RT-qPCR, we examined the expression of four imprinted genes ( Inpp5f_v2, Nap1l5, Peg13, and Zrsr1 ), three genes of protocadherin clusters ( Pcdhα3, Pcdhα9, and Pcdhγa2 ). We also included three genes in our analysis, whose mutations in human lead to neurodevelopment disorders and which were also associated with DMRs with similar percentages of methylation differences ( Supplementary Figure 7A ): Mid1 , associated to the Opitz BBB/G syndrome reviewed in (Winter et al, 2016) and Shank2 and Auts2 both linked to autism spectrum disorders (ASD; reviewed in Bourgeron, 2015 and Pang et al, 2021), with which FASD share overlapping traits (Lussier et al, 2021; Popova et al, 2016). We showed that these genes which were associated with immediate DMRs exhibited concomitant disturbances of their expression in the prenatal cortex ( Figure 6 ).…”

Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis

“…This foundational centrality of epigenotoxicity to the understanding of cannabinoid toxicity is highly reminiscent of the central understanding which the fundamentally epigenomic nature of fetal alcohol syndrome has been shown to display [ 309 , 310 , 311 , 312 , 313 , 314 , 315 , 316 , 317 , 318 , 319 , 320 ]. Indeed, fetal alcohol syndrome has been shown to be primarily mediated epigenomically via cannabinoid type 1 receptors (CB1Rs) [ 321 , 322 , 323 , 324 , 325 , 326 , 327 , 328 , 329 , 330 , 331 ].…”