Sex differences in the associations of placental epigenetic aging with fetal growth

Tekola‐Ayele, Fasil; Workalemahu, Tsegaselassie; Gorfu, Gezahegn; Shrestha, Deepika; Tycko, Benjamin; Wapner, Ronald J.; Zhang, Cuilin; Louis, Germaine M. Buck

doi:10.18632/aging.102124

Cited by 47 publications

(39 citation statements)

References 69 publications

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“…Indeed, maternal chronological age is prognostic of birth outcomes [17][18][19][20][21], while less clear is the role of aging biology. Accelerated placenta epigenetic aging, as indexed by the Horvath clock, has been associated with lower birthweight [28]. In parallel, the placenta also can experience telomere length shortening that induces cellular senescence and the release of secretory factors (senescenceassociated secretory phenotype) that promote parturition through increased inflammatory signaling cascades.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic age and pregnancy outcomes: GrimAge acceleration is associated with shorter gestational length and lower birthweight

et al. 2020

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Background: Advanced biological aging, as measured by epigenetic aging indices, is associated with early mortality and morbidity. Associations between maternal epigenetic aging indices in pregnancy and pregnancy outcomes, namely gestational length and birthweight, have not been assessed. The purpose of this study was to examine whether epigenetic age during pregnancy was associated with gestational length and birthweight. Results: The sample consisted of 77 women from the Los Angeles, CA, area enrolled in the Healthy Babies Before Birth study. Whole blood samples for DNA methylation assay were obtained during the second trimester (15.6 ± 2.15 weeks gestation). Epigenetic age indices GrimAge acceleration (GrimAgeAccel), DNAm PAI-1, DNAm ADM, and DNAm cystatin C were calculated. Gestational length and birthweight were obtained from medical chart review. Covariates were maternal sociodemographic variables, gestational age at blood sample collection, and prepregnancy body mass index. In separate covariate-adjusted linear regression models, higher early second trimester GrimAgeAccel, b(SE) = − .171 (.056), p = .004; DNAm PAI-1, b(SE) = − 1.95 × 10 −4 (8.5 × 10 −5), p = .004; DNAm ADM, b(SE) = − .033 (.011), p = .003; and DNAm cystatin C, b(SE) = 2.10 × 10 −5 (8.0 × 10 −5), p = .012, were each associated with shorter gestational length. Higher GrimAgeAccel, b(SE) = − 75.2 (19.7), p < .001; DNAm PAI-1, b(SE) = − .079(.031), p = .013; DNAm ADM, b(SE) = − 13.8 (3.87), p = .001; and DNAm cystatin C, b(SE) = − .010 (.003), p = .001, were also associated with lower birthweight, independent of gestational length. Discussion: Higher maternal prenatal GrimAgeAccel, DNAm PAI-1, DNAm ADM, and DNAm cystatin C were associated with shorter gestational length and lower birthweight. These findings suggest that biological age, as measured by these epigenetic indices, could indicate risk for adverse pregnancy outcomes.

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Section: Discussionmentioning

confidence: 99%

Epigenetic age and pregnancy outcomes: GrimAge acceleration is associated with shorter gestational length and lower birthweight

et al. 2020

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“…Briefly, several underpinning mechanisms may modulate sex differences in placental responses. Differences in DNA methylation or other epigenetic changes can cause such differences (Gabory et al, 2012; Gabory, Roseboom, Moore, Moore, & Junien, 2013; Gallou‐Kabani et al, 2010; Rosenfeld, 2012; Tarrade, Panchenko, Junien, & Gabory, 2015; Tekola‐Ayele et al, 2019). Changes in the expression of miR represent another type of epigenetic change, as detailed above.…”

Section: Introductionmentioning

confidence: 99%

The placenta‐brain‐axis

Rosenfeld

2020

J of Neuroscience Research

135

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All mammalian species depend on the placenta, a transient organ, for exchange of gases, nutrients, and waste between the mother and conceptus. Besides serving as a conduit for such exchanges, the placenta produces hormones and other factors that influence maternal physiology and fetal development. To meet all of these adaptations, the placenta has evolved to become the most structurally diverse organ within all mammalian taxa. However, commonalities exist as to how placental responses promote survival against in utero threats and can alter the trajectory of fetal development, in particular the brain. Increasing evidence suggests that reactions of the placenta to various in utero stressors may lead to long‐standing health outcomes, otherwise considered developmental origin of health and disease effects. Besides transferring nutrients and gases, the placenta produces neurotransmitters, including serotonin, dopamine, norepinephrine/epinephrine, that may circulate and influence brain development. Neurobehavioral disorders, such as autism spectrum disorders, likely trace their origins back to placental disturbances. This intimate relationship between the placenta and brain has led to coinage of the term, the placenta‐brain‐axis. This axis will be the focus herein, including how conceptus sex might influence it, and technologies employed to parse out the effects of placental‐specific transcript expression changes on later neurobehavioral disorders. Ultimately, the placenta might provide a historical record of in utero threats the fetus confronted and a roadmap to understand how placenta responses to such encounters impacts the placental‐brain‐axis. Improved early diagnostic and preventative approaches may thereby be designed to mitigate such placental disruptions.

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“…Placental epigenetic age acceleration was determined using a published aging "clock" estimation method [35]. We have previously shown that the methylation age of the placenta is significantly correlated with gestational age of the placenta [36]. Given the sex-biased effects of placental epigenetic age acceleration on fetal growth [36], we tested the correlation between ITPR1 gene expression and placental epigenetic age acceleration separately in male and female fetuses.…”

Section: Plos Geneticsmentioning

confidence: 99%

“…We have previously shown that the methylation age of the placenta is significantly correlated with gestational age of the placenta [36]. Given the sex-biased effects of placental epigenetic age acceleration on fetal growth [36], we tested the correlation between ITPR1 gene expression and placental epigenetic age acceleration separately in male and female fetuses. We found a significant inverse correlation between ITPR1 gene expression and placental epigenetic age acceleration among male fetuses (r = -0.4, P = 0.01) but not among female fetuses (r = 0.05, P = 0.79) (Fig 4).…”

Section: Plos Geneticsmentioning

confidence: 99%

“…that found decreased expression of ITPR1 in skeletal muscle of aged mice [44], and association of placental epigenetic age acceleration with fetal growth [36]. A more direct way to assess the mechanism is first to identify the intrauterine factor influenced by rs746039, and then examine the relationship between the putative intrauterine factor and ITPR1 expression.…”

Section: Plos Geneticsmentioning

confidence: 99%

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Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy

Tekola‐Ayele

Zhang

et al. 2020

PLoS Genet

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Abnormal fetal growth is a risk factor for infant morbidity and mortality and is associated with cardiometabolic diseases in adults. Genetic influences on fetal growth can vary at different gestation times, but genome-wide association studies have been limited to birthweight. We performed trans-ethnic genome-wide meta-analyses and fine mapping to identify maternal genetic loci associated with fetal weight estimates obtained from ultrasound measures taken during pregnancy. Data included 1,849 pregnant women from four race/ethnic groups recruited through the NICHD Fetal Growth Studies. We identified a novel genome-wide significant association of rs746039 [G] (ITPR1) with reduced fetal weight from 24 to 33 weeks gestation (P<5x10-8 ; log 10 BF>6). Additional tests revealed that the SNP was associated with head circumference (P = 4.85x10-8), but not with abdominal circumference or humerus/ femur lengths. Conditional analysis in an independent sample of mother-offspring pairs replicated the findings and showed that the effect was more likely maternal but not fetal. Transethnic approaches successfully narrowed down the haplotype block that contained the 99% credible set of SNPs associated with head circumference. We further demonstrated that decreased placental expression of ITPR1 was correlated with increased placental epigenetic age acceleration, a risk factor for reduced fetal growth, among male fetuses (r =-0.4, P = 0.01). Finally, genetic risk score composed of known maternal SNPs implicated in birthweight among Europeans was associated with fetal weight from mid-gestation onwards among Whites only. The present study sheds new light on the role of common maternal genetic variants in the inositol receptor signaling pathway on fetal growth from late second trimester to early third trimester.

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Sex differences in the associations of placental epigenetic aging with fetal growth

Cited by 47 publications

References 69 publications

Epigenetic age and pregnancy outcomes: GrimAge acceleration is associated with shorter gestational length and lower birthweight

Epigenetic age and pregnancy outcomes: GrimAge acceleration is associated with shorter gestational length and lower birthweight

The placenta‐brain‐axis

Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy

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