The Generation R Study Group (Na-2918), Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Clin Epigenetics. 2021 Apr 29;13(1):95. doi: 10.1186/s13148-021-01065-x.
Circulating folate, vitamin B12 and homocysteine concentrations during fetal development have been associated with health outcomes in childhood. Changes in fetal DNA methylation may be an underlying mechanism. This may be reflected in altered epigenetic aging of the fetus, as compared to chronological aging. The difference between gestational age derived in clinical practice and gestational age predicted from neonatal DNA methylation data is referred to as gestational age acceleration. Differences in circulating folate, vitamin B12 and homocysteine concentrations during fetal development may be associated with gestational age acceleration.
Up to 1346 newborns participating in the Generation R Study, a population-based prospective cohort study, had both cord blood DNA methylation data available and information on plasma folate, serum total and active B12 and plasma homocysteine concentrations, measured in early pregnancy and/or in cord blood. A subgroup of 380 newborns had mothers with optimal pregnancy dating based on a regular menstrual cycle and a known date of last menstrual period. For comparison, gestational age acceleration was calculated based the method of both Bohlin and Knight. In the total study population, which was more similar to Bohlin's training population, one standard deviation score (SDS) higher maternal plasma homocysteine concentrations was nominally associated with positive gestational age acceleration [0.07 weeks, 95% confidence interval (CI) 0.02, 0.13] by Bohlin's method. In the subgroup with pregnancy dating based on last menstrual period, the method that was also used in Knight's training population, one SDS higher cord serum total and active B12 concentrations were nominally associated with negative gestational age acceleration [(- 0.16 weeks, 95% CI - 0.30, - 0.02) and (- 0.15 weeks, 95% CI - 0.29, - 0.01), respectively] by Knight's method.
We found some evidence to support associations of higher maternal plasma homocysteine concentrations with positive gestational age acceleration, suggesting faster epigenetic than clinical gestational aging. Cord serum vitamin B12 concentrations may be associated with negative gestational age acceleration, indicating slower epigenetic than clinical gestational aging. Future studies could examine whether altered fetal epigenetic aging underlies the associations of circulating homocysteine and vitamin B12 blood concentrations during fetal development with long-term health outcomes.
胎儿发育过程中循环叶酸、维生素 B12 和同型半胱氨酸浓度与儿童期健康结局有关。胎儿 DNA 甲基化的变化可能是一个潜在的机制。这可能反映在胎儿相对于实际年龄的表观遗传衰老的改变上。在临床实践中得出的胎龄与从新生儿 DNA 甲基化数据预测的胎龄之间的差异被称为胎龄加速。胎儿发育过程中循环叶酸、维生素 B12 和同型半胱氨酸浓度的差异可能与胎龄加速有关。
多达 1346 名参加了以人群为基础的前瞻性队列研究 Generation R 研究的新生儿，其脐带血 DNA 甲基化数据和血浆叶酸、血清总活性 B12 和血浆同型半胱氨酸浓度信息均可用，这些信息在妊娠早期和/或脐带血中测量。380 名新生儿的母亲根据规律的月经周期和已知的末次月经日期进行了最佳妊娠时间测定，作为亚组。为了进行比较，胎龄加速是根据 Bohlin 和 Knight 的方法计算的。在总研究人群中，Bohlin 的训练人群更相似，母体血浆同型半胱氨酸浓度的一个标准差评分 (SDS) 升高与 Bohlin 方法的阳性胎龄加速呈名义相关[0.07 周，95%置信区间 (CI) 0.02, 0.13]。在基于末次月经的妊娠时间测定的亚组中，Knight 的训练人群也使用了该方法，脐带血清总活性 B12 浓度的一个 SDS 升高与 Knight 方法的阴性胎龄加速呈名义相关[(-0.16 周，95%CI -0.30, -0.02) 和 (-0.15 周，95%CI -0.29, -0.01)]。
我们发现一些证据支持母体血浆同型半胱氨酸浓度升高与阳性胎龄加速之间的关联，表明表观遗传胎龄比临床胎龄加速更快。脐带血清维生素 B12 浓度可能与阴性胎龄加速有关，表明表观遗传胎龄比临床胎龄加速更慢。未来的研究可以检查胎儿发育过程中循环同型半胱氨酸和维生素 B12 血液浓度与长期健康结局之间的关联是否归因于胎儿表观遗传衰老的改变。
