Mirzakhani Hooman, De Vivo Immaculata, Leeder J Steven, Gaedigk Roger, Vyhlidal Carrie A, Weiss Scott T, Tantisira Kelan
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Epidemiology, T.H. Chan School of Public Health, Boston, MA, USA.
Eur J Obstet Gynecol Reprod Biol. 2017 Nov;218:27-32. doi: 10.1016/j.ejogrb.2017.09.013. Epub 2017 Sep 14.
Reduced telomere length, or its accelerated attrition, has been implicated in aging, mortality, and several human diseases, including respiratory diseases. Age dependent manifestation of telomere-mediated disease during life span indicates the role of developmental stage in these diseases and highlights the importance of fetal developmental process in utero and at earlier life stages. Environmental determinants during developmental and later stages of life could affect telomere length. Smoke exposure as one of these significant determinants have been investigated in association with telomere length in neonates at time of delivery, children and adults.
We sought to investigate whether intrauterine fetal exposure to tobacco smoking characterized by placenta cotinine levels during early weeks of pregnancy might be associated with shorter relative telomere length (T/S ratio) as compared to fetuses without exposure to tobacco smoking.
207 Human placenta and epithelial lung samples were used for both fetal lung telomere length assessment and measurement of placental cotinine levels. Tissues were obtained from two NICHD-supported tissue retrieval programs with registries for elective abortions, the University of Washington Center for Birth Defects Research (Seattle, WA) and the University of Maryland Brain and Tissue Bank for Developmental Disorders (Baltimore, MD). Cotinine levels (ng/g total placental tissue) were determined in whole cell extracts prepared from human placenta samples to characterize and confirm the cotinine exposure status associated with maternal smoking. Relative telomere length (T/S ratio) in genomic DNA extracted from fetal lung tissue was measured by use of quantitative real-time polymerase chain reaction. Multivariable linear regression was used to investigate the relationship between fetal Telomere-to-Single Copy (T/S) ratio and tobacco exposure.
The estimated post-conception ages for included samples in the study ranged from 54 to 137days (7-19 weeks of gestation); 47.37% of fetal samples had female sex. Of the samples included in the analysis 96 and 111 fetal samples with and without intrauterine tobacco smoking exposure were distinguished. While T/S ratio was not different between those with and without smoking exposure (1.24±0.41 and 1.27±0.48, respectively; P=0.70), a significant effect modification of post-conception age on the relationship of intrauterine smoke exposure on fetal T/S ratio was observed (adjusted coefficient=-0.008, 95% CI: -0.016, -0.0004). The smoke exposure status was associated with T/S ratio after 93-day post conception (adjusted coefficient=-0.29, 95% CI: -0.53, -0.052).
Our results demonstrate a significant association of smoke exposure in utero at early pregnancy with shortened fetal relative telomere length in the developing lung and suggest that the detrimental effect of smoking exposure on future disease sequelae may start at the early stages of pregnancy.
端粒长度缩短或其加速损耗与衰老、死亡率以及包括呼吸系统疾病在内的多种人类疾病有关。端粒介导的疾病在生命过程中的年龄依赖性表现表明发育阶段在这些疾病中的作用，并突出了子宫内及生命早期胎儿发育过程的重要性。生命发育和后期阶段的环境决定因素可能影响端粒长度。作为这些重要决定因素之一的烟雾暴露，已在新生儿分娩时、儿童及成人中与端粒长度相关联进行了研究。
我们试图研究妊娠早期以胎盘可替宁水平为特征的子宫内胎儿暴露于吸烟情况，与未暴露于吸烟的胎儿相比，是否可能与较短的相对端粒长度（T/S 比值）相关。
207 份人胎盘和肺上皮样本用于胎儿肺端粒长度评估和胎盘可替宁水平测量。组织取自两个由美国国立儿童健康与人类发展研究所支持的组织回收项目，这些项目有选择性流产登记，分别是华盛顿大学出生缺陷研究中心（华盛顿州西雅图）和马里兰大学发育障碍脑与组织库（马里兰州巴尔的摩）。测定人胎盘样本制备的全细胞提取物中的可替宁水平（纳克/克胎盘组织总量），以表征和确认与母亲吸烟相关的可替宁暴露状态。通过定量实时聚合酶链反应测量从胎儿肺组织提取的基因组 DNA 中的相对端粒长度（T/S 比值）。使用多变量线性回归研究胎儿端粒与单拷贝（T/S）比值与烟草暴露之间的关系。
研究中纳入样本的估计受孕后年龄范围为 54 至 137 天（妊娠 7 - 19 周）；47.37%的胎儿样本为女性。在分析纳入的样本中，区分出 96 份有子宫内吸烟暴露和 111 份无子宫内吸烟暴露的胎儿样本。虽然有吸烟暴露和无吸烟暴露的样本之间 T/S 比值无差异（分别为 1.24±0.41 和 1.27±0.48；P = 0.70），但观察到受孕后年龄对子宫内烟雾暴露与胎儿 T/S 比值关系有显著的效应修饰（调整系数 = -0.008，95%置信区间：-0.016，-0.0004）。受孕后 93 天之后，烟雾暴露状态与 T/S 比值相关（调整系数 = -0.29，95%置信区间：-0.53，-0.052）。
我们的结果表明，妊娠早期子宫内烟雾暴露与发育中的肺中胎儿相对端粒长度缩短显著相关，并表明吸烟暴露对未来疾病后遗症的有害影响可能始于妊娠早期。
