母亲童年时期的逆境与孕期及男性新生儿的表观遗传加速衰老有关。

Dye Christian K, Wu Haotian, Monk Catherine, Belsky Daniel W, Alschuler Daniel, Lee Seonjoo, O'Donnell Kieran, Scorza Pamela

Department of Environmental Health Sciences, Columbia University, New York, New York, USA.

Department of Psychiatry, Columbia University, Columbia University, New York, New York, USA.

bioRxiv. 2023 Mar 6:2023.03.02.530806. doi: 10.1101/2023.03.02.530806.

BACKGROUND

Adverse childhood experiences (ACEs) are correlated with accelerated epigenetic aging, but it is not clear whether altered epigenetic aging from childhood adversities persists into adulthood and can be transmitted to the next generation. Thus, we tested whether mothers' childhood adversity is associated with accelerated epigenetic aging during pregnancy and in their newborn offspring.

METHODS

Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC) sub-study, Accessible Resource for Integrated Epigenomic Studies (ARIES). Women provided retrospective self-reports during pregnancy of ACE exposure. DNA methylation was measured in mothers during pregnancy and cord blood at birth. Estimates of epigenetic age acceleration were calculated using Principal Components of Horvath, Hannum skin & blood, GrimAge, PhenoAge, and DunedinPACE epigenetic clocks for mothers; and the Knight and Bohlin cord blood clocks for newborns. Associations between a cumulative maternal ACE score and epigenetic age acceleration were estimated using linear regression models, adjusting for maternal age at pregnancy, smoking during pregnancy, education, and pre-pregnancy BMI. Models for offspring were stratified by sex and additionally adjusted for gestation age.

RESULTS

Mothers' total ACE score was positively associated with accelerated maternal PhenoAge and GrimAge. In newborn offspring, mothers' total ACE score was positively associated with accelerated epigenetic aging in males using the Bohlin clock, but not in females using either epigenetic clock. We found male offsprings' epigenetic age was accelerated in those born to mothers exposed to neglect using the Knight clock; and parental substance abuse using the Bohlin clock.

CONCLUSION

Our results show that mothers' ACE exposure is associated with DNAm age acceleration in male offspring, supporting the notion that DNAm age could be a marker of intergenerational biological embedding of mothers' childhood adversity. This is consistent with findings on vulnerability of male fetuses to environmental insults.

背景

童年不良经历（ACEs）与表观遗传衰老加速相关，但尚不清楚童年逆境导致的表观遗传衰老改变是否会持续到成年并传递给下一代。因此，我们测试了母亲的童年逆境是否与孕期及新生儿的表观遗传衰老加速有关。

方法

数据来自雅芳亲子纵向研究（ALSPAC）的子研究——综合表观基因组研究可获取资源（ARIES）。女性在孕期提供关于ACE暴露的回顾性自我报告。在孕期测量母亲的DNA甲基化，并在出生时测量脐带血的DNA甲基化。使用霍瓦斯主成分、汉纳姆皮肤与血液、格里姆年龄、表型年龄和达尼丁PACE表观遗传时钟计算母亲的表观遗传年龄加速估计值；使用奈特和博林脐带血时钟计算新生儿的表观遗传年龄加速估计值。使用线性回归模型估计母亲ACE累积评分与表观遗传年龄加速之间的关联，并对母亲的孕期年龄、孕期吸烟、教育程度和孕前体重指数进行调整。子代模型按性别分层，并进一步调整胎龄。

结果

母亲的ACE总分与母亲表型年龄和格里姆年龄加速呈正相关。在新生子代中，母亲的ACE总分与使用博林时钟的男性子代的表观遗传衰老加速呈正相关，但与使用任一表观遗传时钟的女性子代无关。我们发现，使用奈特时钟，在遭受忽视的母亲所生的男性子代中，其表观遗传年龄加速；使用博林时钟，在父母有药物滥用情况的母亲所生的男性子代中，其表观遗传年龄加速。