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

Kwan, Sze Ting Cecilia; Presswood, Brandon H.; Helfrich, Kaylee K.; Baulch, Joshua W.; Mooney, Sandra M.; Smith, Susan

doi:10.1186/s13293-020-00320-9

Cited by 21 publications

(27 citation statements)

References 67 publications

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“…Interestingly, in our model, female offspring appear more prone to dysregulation of these pathways and overt dysgenesis. These data are consistent with recent studies indicating female offspring are more susceptible to the teratogenic impacts of intrauterine alcohol exposures [ 63 ]. Future studies are needed to determine if this mTORC2 signature is present in other models of exposure, is sex-specific, and if pharmacological interventions that target this pathway rescue EtOH-induced patterning defects.…”

Section: Discussionsupporting

confidence: 93%

Programmed suppression of oxidative phosphorylation and mitochondrial function by gestational alcohol exposure correlate with widespread increases in H3K9me2 that do not suppress transcription

Chang

Thomas

Mehta

et al. 2021

Epigenetics & Chromatin

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Background A critical question emerging in the field of developmental toxicology is whether alterations in chromatin structure induced by toxicant exposure control patterns of gene expression or, instead, are structural changes that are part of a nuclear stress response. Previously, we used a mouse model to conduct a three-way comparison between control offspring, alcohol-exposed but phenotypically normal animals, and alcohol-exposed offspring exhibiting craniofacial and central nervous system structural defects. In the cerebral cortex of animals exhibiting alcohol-induced dysgenesis, we identified a dramatic increase in the enrichment of dimethylated histone H3, lysine 9 (H3K9me2) within the regulatory regions of key developmental factors driving histogenesis in the brain. However, whether this change in chromatin structure is causally involved in the development of structural defects remains unknown. Results Deep-sequencing analysis of the cortex transcriptome reveals that the emergence of alcohol-induced structural defects correlates with disruptions in the genetic pathways controlling oxidative phosphorylation and mitochondrial function. The majority of the affected pathways are downstream targets of the mammalian target of rapamycin complex 2 (mTORC2), indicating that this stress-responsive complex plays a role in propagating the epigenetic memory of alcohol exposure through gestation. Importantly, transcriptional disruptions of the pathways regulating oxidative homeostasis correlate with the emergence of increased H3K9me2 across genic, repetitive, and non-transcribed regions of the genome. However, although associated with gene silencing, none of the candidate genes displaying increased H3K9me2 become transcriptionally repressed, nor do they exhibit increased markers of canonical heterochromatin. Similar to studies in C. elegans, disruptions in oxidative homeostasis induce the chromatin looping factor SATB2, but in mammals, this protein does not appear to drive increased H3K9me2 or altered patterns of gene expression. Conclusions Our studies demonstrate that changes in H3K9me2 associate with alcohol-induced congenital defects, but that this epigenetic change does not correlate with transcriptional suppression. We speculate that the mobilization of SATB2 and increased enrichment of H3K9me2 may be components of a nuclear stress response that preserve chromatin integrity and interactions under prolonged oxidative stress. Further, we postulate that while this response may stabilize chromatin structure, it compromises the nuclear plasticity required for normal differentiation.

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Section: Discussionsupporting

confidence: 93%

Programmed suppression of oxidative phosphorylation and mitochondrial function by gestational alcohol exposure correlate with widespread increases in H3K9me2 that do not suppress transcription

Chang

Thomas

Mehta

et al. 2021

Epigenetics & Chromatin

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“…While choline partially ameliorated the fetal growth restriction due to PCE, there was also evidence that choline affected fetal growth independent of alcohol exposure. Fetal liver weight increased with increasing levels of choline in the diet, and there was decreased fetal brain:liver ratio, a measure of growth restriction independent of body weight (Kwan et al, 2020), particularly in cases of placental insufficiency (Man et al, 2016). This overall increase in growth associated with increased choline is consistent with previous supplementation studies in rats (Idrus et al, 2017;Thomas et al, 2009).…”

Section: Discussionsupporting

confidence: 87%

“…Fetal organs were removed and weighed. Given that changes in both fetal liver weight (Kwan et al, 2020) and heart weight (Wilcoxon et al, 2003) have been F I G U R E 1 Treatment schedule for rat dams with liquid diets and chow diets across the periconceptional period and pregnancy. Prior to starting the experimental protocol, dams received either the standard chow (Std; 1.6 g choline/kg chow) or the intermediate chow (Int; 2.6 g choline/kg chow).…”

Section: Blood and Tissue Collectionmentioning

confidence: 99%

Maternal choline supplementation in a rat model of periconceptional alcohol exposure: Impacts on the fetus and placenta

Steane

Fielding

Kent

et al. 2021

Alcoholism Clin & Exp Res

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Background: Maternal choline supplementation in rats can ameliorate specific neurological and behavioral abnormalities caused by alcohol exposure during pregnancy.We tested whether choline supplementation ameliorates fetal growth restriction and molecular changes in the placenta associated with periconceptional ethanol exposure (PCE) in the rat.Methods: Sprague Dawley dams were given either 12.5% ethanol (PCE) or 0% ethanol (Con) in a liquid diet from 4 days prior to 4 days after conception. At day 5 of pregnancy, dams were either placed on a standard chow (1.6 g choline/kg chow) or an intermediate chow (2.6 g choline/kg chow). On day 10 of pregnancy, a subset of the intermediate dams were placed on a chow further supplemented with choline (7.2 g choline/kg chow), resulting in 6 groups. Fetuses and placentas were collected on day 20 of pregnancy for analysis.Results: Choline supplementation resulted in increased fetal weight at late gestation, ameliorating the deficits due to PCE. This was most pronounced in litters on a standard chow during pregnancy. Choline also increased fetal liver weight and decreased fetal brain:liver ratio, independent of alcohol exposure. Placental weight was reduced as choline levels in the chow increased, particularly in female placentas. This resulted in a greater ratio of fetal:placental weight, suggesting increased placental efficiency.Global DNA methylation in the placenta was altered in a sex-specific manner by both PCE and choline. However, the increased glycogen deposition in female placentas, previously reported in this PCE model, was not prevented by choline supplementation. Conclusions:Our results suggest that choline has the potential to ameliorate fetal growth restriction associated with PCE and improve placental efficiency following prenatal alcohol exposure. Our study highlights the importance of maternal nutrition in moderating the severity of adverse fetal and placental outcomes that may arise from prenatal alcohol exposure around the time of conception.

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“…Furthermore, we conducted a prenatal choline intervention in this model, and examined its impacts on morphometric parameters of the alcohol-exposed fetuses. We hypothesized that this alcohol dose would elicit outcomes similar to those observed in the higher alcohol dose and that concurrent choline treatment would mitigate these alcohol-induced effects in fetal organs in a fetal sex-dependent manner, as suggested by our previous studies (Bearer et al, 2015;Kwan et al, 2020;Waddell & Mooney, 2017). (Reeves et al, 1993) from arrival through pregnancy.…”

Section: Introductionmentioning

confidence: 86%

“…PCR for sex determination was done as previously described (Kwan et al, 2020). Briefly, DNA was isolated and PCR was performed using the Platinum Taq DNA Polymerase PCR…”

Section: Genotyping For Fetal Sexmentioning

confidence: 99%

Prenatal choline supplementation during mouse pregnancy has differential effects in alcohol‐exposed fetal organs

Kwan

Ricketts

Presswood

et al. 2021

Alcoholism Clin & Exp Res

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Background: Fetal alcohol spectrum disorders (FASD) are preventable adverse outcomes consequent to prenatal alcohol exposure. Supplemental choline confers neuroprotection to the alcohol-exposed offspring, but its actions outside the brain are unclear. We previously reported that prenatal exposure of mice to 4.5 g/kg of alcohol decreased placental weight in females only, but decreased body weight and liver-tobody weight ratio and increased brain-to-body weight ratio in both sexes. Here we test the hypotheses that a lower alcohol dose will elicit similar outcomes, and that concurrent choline treatment will mitigate these outcomes.Methods: Pregnant C57BL/6J mice were gavaged with alcohol (3 g/kg; Alc) or maltodextrin (MD) from embryonic day (E) 8.5-17.5. Some also received a subcutaneous injection of 100 mg/kg choline chloride (Alc + Cho, MD + Cho). Outcomes were evaluated on E17.5.Results: Alc dams had lower gestational weight gain than MD; this was normalized by choline. In males, Alc decreased placental weight whereas choline increased placental efficiency, and Alc + Cho (vs. MD) tended to further reduce placental weight and increase efficiency. Despite no significant alcohol effects on these measures, choline increased fetal body weight but not brain weight, thus reducing brain-to-body weight ratio in both sexes. This ratio was also lower in the Alc + Cho (vs. MD) fetuses.Alc reduced liver weight and the liver-to-body weight ratio; choline did not improve these. Placental weight and efficiency correlated with litter size, whereas placental efficiency correlated with fetal morphometric measurements. Conclusions:Choline prevents an alcohol-induced reduction in gestational weight gain and fetal body weight and corrects fetal brain sparing, consistent with clinical findings of improvements in alcohol-exposed children born to mothers receiving choline supplementation. Importantly, we show that choline enhances placental efficiency in the alcohol-exposed offspring but does not normalize fetal liver growth. Our findings support choline supplementation during pregnancy to mitigate the severity of FASD and emphasize the need to examine choline's actions in different organ systems.

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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

Cited by 21 publications

References 67 publications

Programmed suppression of oxidative phosphorylation and mitochondrial function by gestational alcohol exposure correlate with widespread increases in H3K9me2 that do not suppress transcription

Programmed suppression of oxidative phosphorylation and mitochondrial function by gestational alcohol exposure correlate with widespread increases in H3K9me2 that do not suppress transcription

Maternal choline supplementation in a rat model of periconceptional alcohol exposure: Impacts on the fetus and placenta

Prenatal choline supplementation during mouse pregnancy has differential effects in alcohol‐exposed fetal organs

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