早期成长逆境致青春期发育提前和生物学老化加速效应研究

Early life adversity is closely related with multiple health problems across the lifespan. Researches from our team suggested consistent association between various forms of early adversity with early pubertal development, including childhood abuse, household socioeconomic disadvantage. These results were consistent with other studies under different culture and genetic background. Based on literature review and recent progress suggesting correlation between left-behind experiences with telomere shortening, we propose the accelerating effects of early life adversity on pubertal development and biological aging as a possible hypothesis. Prospective and multi-dimensional (maternal separation, threaten and chronic deprivation) assessment of early growing environment will be collected among participants from established kindergarten cohort and left-behind child cohort. All the participants will be followed up with pubertal maturatiom and biological aging process. Age-matched peers with different adversity background will be compared with pubertal development and biological age which is assessed through telomere length and epigenetic age computed from genomic DNA methylation. This project is expected to shed lights on different effects of three dimensions of early life adversity on pubertal tempo and biological aging pace. Results will provide new perspectives on environmental effects on growth and development and underlying embedding mechanisms, as well as theoretical framework for future intervention aiming at preventing or reducing long-term adverse health effects of early life adversity.

早期成长逆境与多种健康问题的终身风险密切相关。课题组前期研究提示：童年期虐待、家庭社会经济地位不良等多种形式的逆境与青春期发育提前存在关联，与国外不同文化与遗传背景人群研究结论较为一致。结合文献复习和课题组近期发现的持续留守经历青少年端粒长度明显缩短的线索，本课题提出“早期成长逆境致青春期发育提前和生物学老化加速假说”，基于已建立的幼儿队列和农村留守儿童队列，前瞻性、多维度（亲子分离、威胁性和慢性剥夺性）评估早期成长环境，随访男女童第二性征发育，借助两种生物学老化指标（端粒长度、基于DNA甲基化模式的表观遗传学年龄），比较不同逆境经历的同龄个体青春期发育和生物学老化指标的差异，探讨早期成长逆境类型对青春期发育进程、生物学老化速度的预测效应。课题结果将为儿童少年发育与健康的环境病因及其生物学嵌入机制研究开拓新视角，也为早期干预成长逆境终身健康危害效应提供理论框架。

本课题在建构早期成长逆境本土框架的基础上，提出适用于我国儿童青少年早期成长逆境暴露组的研究范式，基于儿童青少年发育队列，跳出单一候选因素，多时点、多维度收集早期成长逆境信息，形成早期成长逆境全景式分析。. 对已建立并随访4年的儿童青春期发育队列，分析两种核心维度的早期成长逆境与青春期发育提前（女童乳房、男童睾丸容积）的前瞻性关联。首次验证国外GWAS研究中发现的与青春期发动提前相关27个SNPs，关注生物学老化核心轴组成成分——线粒体DNA（功能性老化）和端粒长度（复制性老化）指标。. 研究结果表明，威胁性和剥夺性成长逆境均与男女童乳房和睾丸容积发育提前有关，但仅在青春期发育提前多基因遗传风险较低的群体中。威胁性早期逆境经历与儿童端粒长度衰减过快密切关联，但仅在多基因遗传风险中等和较低群体中。无亲子分离、仅童年期亲子分离、持续亲子分离青少年颊细胞端粒长度持续衰减，持续亲子分离亲少年端粒衰减速度最快（比基线缩短44%）。在细胞老化的功能方面，持续亲子分离亲少年颊细胞线粒体DNA拷贝数（mtDNAcn）最高，持续随访2年后发现，持续亲子分离青少年mtDNAcn显著下降了73%。 .本课题基于“中国健康与养老追踪调查”（China Health and Retirement Longitudinal Study，CHARLS）9674名中老年女性的数据，发现威胁性早期成长逆境，与我国女性生殖策略加速有关，表现为月经初潮年龄提前3.7个月、自然绝经年龄提前8.6个月、初次生育年龄提前1年以上和生育孩子总数增加。剥夺性逆境经历与自然绝经年龄延迟以及流产次数增加相关。. 本课题共发表16篇SCI论文（一区6篇，二区9篇），7篇中文核心论文和综述。培养硕士生6人、博士在读2人，选派硕博研究生参加国内学术交流6人次。. 研究成果已纳入申请人作为副主编的专著《青春期发育与青少年行为健康》，已送出版社校稿。课题成果多次在全国会议（2020年学校卫生年会、2021年全国儿童青少年健康发展高层论坛）、国际会议【第十七届亚洲儿科研究学会学术大会ASPR2022（The 17th Congress of Asian Society for Pediatric Research, ASPR2022）】中做大会报告。