Mitigating the detrimental developmental impact of early fetal alcohol exposure using a maternal methyl donor‐enriched diet

Breton-Larrivée, Mélanie; Legault, Lisa-Marie; Langford-Avelar, Alexandra; MacFarlane, Amanda J.; McGraw, Serge

doi:10.1096/fj.202201564r

Cited by 6 publications

(17 citation statements)

References 151 publications

(362 reference statements)

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“…Prenatal alcohol exposure was previously shown to alter embryonic development in different contexts, by inducing fetal growth restriction or growth delay (14, 15). With our model, we found that the impact on growth and related pathways was more pronounced in male ethanol-exposed placentas, consistent with the observed male-specific changes in genes regulating growth, cytoskeletal organization, placental development, and vascularization.…”

Section: Discussionmentioning

confidence: 99%

“…Pregnant females were separated from the males and housed together ( n= 2–3) in a 12-h light/dark cycle with unrestricted access to food and water. Like in our previously published preimplantation binge-like PAE model (14, 15), pregnant females were subcutaneously injected with two doses of either 2.5 g/kg of 50% ethanol or an equivalent volume of saline at 2-h intervals on E2.5 (the 8-cell stage), then housed under similar conditions with limited handling during gestation.…”

Section: Methodsmentioning

confidence: 99%

“…Given the increasing number of women of 18-34 years old consuming alcohol, including binge drinking (10), and the substantial number of unintended pregnancies worldwide (approximately 40%) (11), it is essential to investigate the impact of alcohol during this critical phase. Despite its importance for proper embryonic development and its heightened susceptibility to adverse environmental exposures, the preimplantation period has been understudied in relation to PAE, with only a few models focusing exclusively on this early developmental timepoint (12)(13)(14)(15). DNA methylation, established by DNMT3A/DNMT3B and maintained by DNMT1, is a stable modification of the DNA consisting in the covalent addition of a methyl group to cytosine (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

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Sex-Specific DNA Methylation and Gene Expression Changes in Mouse Placentas After Early Preimplantation Alcohol Exposure

Legault,

Dupas,

Breton-Larrivée

et al. 2023

Preprint

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The placenta is vital for proper embryonic development and successful pregnancy. Preimplantation alcohol exposure can negatively impact embryonic development and lead to fetal alcohol spectrum disorder. We and others have demonstrated the adverse effects of preimplantation alcohol exposure on embryo morphology and molecular profiles at late gestation, but studies on the placenta are markedly lacking. Here, we used an established preclinical mouse model to assess the impact of preimplantation (8-cell stage) binge-like alcohol exposure on the morphology, DNA methylation, and gene expression patterns in male and female late-gestation placentas. While overall placental morphology was not affected, we uncovered numerous differentially methylated regions (DMRs;n=991 in males;n=1309 in females) and differentially expressed genes (DEGs;n=1046 in males;n=340 in females) in the placentas. Remarkably, only 21 DMRs and 54 DEGs were common to both sexes, which were enriched for genes involved in growth factor response pathways. Using LASSO regression, we were able to precisely discriminate control and ethanol-exposed placentas based on their specific DNA methylation patterns. This is the first study demonstrating that preimplantation alcohol exposure alters the DNA methylation and transcriptomic profiles of late-gestation placentas. Importantly, it reveals a placental DNA methylation signature that can detect prenatal alcohol exposure and provide appropriate support to prevent eventual impact.GRAPHICAL ABSTRACT

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sex-Specific DNA Methylation and Gene Expression Changes in Mouse Placentas After Early Preimplantation Alcohol Exposure

Legault,

Dupas,

Breton-Larrivée

et al. 2023

Preprint

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“…The hallmark features of FASD include physical anomalies, cognitive deficits, and behavioral issues [19]. Physical characteristics may include facial abnormalities, growth deficiencies, and organ malformations [20]. Cognitive impairments often encompass difficulties in learning, memory, attention, and problemsolving skills [21].…”

Section: Fetal Alcohol Spectrum Disorders (Fasd)mentioning

confidence: 99%

The Impact of Oxidative Stress on the Epigenetics of Fetal Alcohol Spectrum Disorders

Terracina,

Tarani,

Ceccanti

et al. 2024

Antioxidants

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Fetal alcohol spectrum disorders (FASD) represent a continuum of lifelong impairments resulting from prenatal exposure to alcohol, with significant global impact. The “spectrum” of disorders includes a continuum of physical, cognitive, behavioral, and developmental impairments which can have profound and lasting effects on individuals throughout their lives, impacting their health, social interactions, psychological well-being, and every aspect of their lives. This narrative paper explores the intricate relationship between oxidative stress and epigenetics in FASD pathogenesis and its therapeutic implications. Oxidative stress, induced by alcohol metabolism, disrupts cellular components, particularly in the vulnerable fetal brain, leading to aberrant development. Furthermore, oxidative stress is implicated in epigenetic changes, including alterations in DNA methylation, histone modifications, and microRNA expression, which influence gene regulation in FASD patients. Moreover, mitochondrial dysfunction and neuroinflammation contribute to epigenetic changes associated with FASD. Understanding these mechanisms holds promise for targeted therapeutic interventions. This includes antioxidant supplementation and lifestyle modifications to mitigate FASD-related impairments. While preclinical studies show promise, further clinical trials are needed to validate these interventions’ efficacy in improving clinical outcomes for individuals affected by FASD. This comprehensive understanding of the role of oxidative stress in epigenetics in FASD underscores the importance of multidisciplinary approaches for diagnosis, management, and prevention strategies. Continued research in this field is crucial for advancing our knowledge and developing effective interventions to address this significant public health concern.

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“…Preclinical studies indicated a lower risk of neural tube defects, prostatitis, and autisticlike behaviors after folate supplementation during pregnancy (Budni et al, 2013;Silva et al, 2017). These effects may extend to mitigating the negative consequences of PEE (Breton-Larrivée et al, 2023). Sogut et al (2017) reported that folic acid ameliorated PEE-induced apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Neurobehavioral alterations induced by third‐trimester gestation‐equivalent ethanol exposure are inhibited by folate administration

Marengo,

Barey,

Salguero

et al. 2023

Developmental Psychobiology

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Prenatal ethanol exposure (PEE) causes several neurobehavioral impairments in the fetus. Postnatal days (PDs) 4–9 in rodents are considered equivalent to the third trimester of gestation in humans. This period is characterized by high rates of synaptogenesis and myelination and the maturation of key structures and transmitter systems. Nutritional supplements, such as folate, have gained attention as putative treatments to mitigate detrimental effects of PEE. Folate is crucial for DNA synthesis and amino acid metabolism and heightens antioxidant defenses. The present study examined neurobehavioral effects of the concurrent administration of folate (20 mg/kg/day) and ethanol (5 g/kg/day) during PDs 4–9 in male and female Wistar rats. During PDs 16–18, the rat pups were tested for anxiety‐like and exploratory activity in the light–dark box (LDB), open field (OF), and concentric square field (CSF) tests. After weaning, they were tested for sucrose preference and ethanol intake. Neonatal ethanol exposure reduced body weight in infancy but did not enhance ethanol self‐administration or significantly affect performance in the OF or LDB. Neonatal ethanol exposure also reduced sucrose intake in the preference test and increased shelter‐seeking in the CSF, and folate significantly inhibited these effects. The present findings suggest that folate, a treatment that is devoid of serious side effects, can ameliorate some neurobehavioral effects of PEE.

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Mitigating the detrimental developmental impact of early fetal alcohol exposure using a maternal methyl donor‐enriched diet

Cited by 6 publications

References 151 publications

Sex-Specific DNA Methylation and Gene Expression Changes in Mouse Placentas After Early Preimplantation Alcohol Exposure

Sex-Specific DNA Methylation and Gene Expression Changes in Mouse Placentas After Early Preimplantation Alcohol Exposure

The Impact of Oxidative Stress on the Epigenetics of Fetal Alcohol Spectrum Disorders

Neurobehavioral alterations induced by third‐trimester gestation‐equivalent ethanol exposure are inhibited by folate administration

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