Impact of Intrauterine Tobacco Smoke Exposure on Umbilical Cord Blood Stem Cells

宫内烟草烟雾暴露对脐带血干细胞的影响

• 批准号: 7673259
• 负责人: Jennifer Lynn Kornosky
• 金额: $ 2.73万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7673259
• 关键词: Impact; Intrauterine; Tobacco; Smoke; Exposure

DESCRIPTION (provided by the investigator): Experimental and epidemiological evidence suggests that the relationship between prenatal smoking and intrauterine growth restriction (IUGR) is causal, yet the mechanism by which prenatal tobacco smoke exposure causes IUGR remains poorly defined. A plausible but, as yet, unstudied mechanism is intrauterine exposure to tobacco smoke components may prevent normal fetal programming through the hypomethylation of DNA leading to sub-optimal growth and development, which subsequently manifests as IUGR. A better understanding of the biological mechanism by which smoking causes IUGR could improve our ability to formulate more effective, targeted, and smart intervention measures. Study Objectives: The present study aims to evaluate the hypothesis that cigarette smoke exposure during pregnancy results in aberrant DNA methylation in hematopoietic stem cells in the feto-placental circulation. This epigenetic response to suboptimal uterine conditions is manifested in offspring as IUGR. We further hypothesize that cigarette smoke exposure will decrease stem cell numbers (normalized to feto-placental blood volume) as they may be more sensitive to adverse uterine conditions. Methods: The hypotheses will be tested using a case-control design involving small (SGA) and appropriate (AGA) for gestational age infants born at Tampa General Hospital. Only non-malformed singleton infants from otherwise normal pregnancies are eligible for the study. Umbilical cord blood collected as part of a larger study at Tampa General Hospital will be analyzed for concentration of red blood cell folate, cotinine, and stem cells as well as for the amount of global genomic DNA methylation. Regression models that control for potential confounders such as serum folate, maternal age, parity, race/ethnicity, body mass index status, previous IUGR/fetal death, and fetal gender will be developed to address the aims and objectives of the study. Implications of research: This study's interdisciplinary approach has the potential to provide evidence that could change our current thinking of tobacco smoke patho-physiology as epigenetic modifications have not been considered as a possible mechanism by which IUGR or other adverse pregnancy outcomes related to tobacco smoke exposure manifest. Finally, it may lead to the development of new interventions to reduce the impact of prenatal smoke exposure on the developing fetus and a more efficient detection of hematopoietic stem cells unsuitable for transplant, thus improving outcomes and preventing storage of sub-optimal umbilical cord blood samples.

描述（由研究者提供）：实验和流行病学证据表明，产前吸烟与宫内生长受限 (IUGR) 之间存在因果关系，但产前烟草烟雾暴露导致 IUGR 的机制仍不清楚。一个看似合理但尚未研究的机制是，子宫内接触烟草烟雾成分可能会通过 DNA 低甲基化来阻止正常的胎儿编程，导致生长和发育不理想，随后表现为 IUGR。更好地了解吸烟导致IUGR的生物学机制，可以提高我们制定更有效、更有针对性、更智能的干预措施的能力。研究目的：本研究旨在评估妊娠期间接触香烟烟雾导致胎儿胎盘循环中造血干细胞异常 DNA 甲基化的假设。这种对次优子宫条件的表观遗传反应在后代中表现为 IUGR。我们进一步假设，接触香烟烟雾会减少干细胞数量（标准化为胎儿胎盘血容量），因为它们可能对不利的子宫状况更敏感。方法：将使用病例对照设计对假设进行检验，该设计涉及坦帕总医院出生的小（SGA）和适当（AGA）胎龄婴儿。只有正常妊娠的非畸形单胎婴儿才有资格参加该研究。作为坦帕总医院一项更大型研究的一部分，收集的脐带血将被分析红细胞叶酸、可替宁和干细胞的浓度以及整体基因组 DNA 甲基化的量。将开发控制潜在混杂因素（如血清叶酸、母亲年龄、胎次、种族/民族、体重指数状态、既往 IUGR/胎儿死亡和胎儿性别）的回归模型，以解决研究的目的和目标。研究意义：这项研究的跨学科方法有可能提供证据，改变我们目前对烟草烟雾病理生理学的看法，因为表观遗传修饰尚未被认为是导致 IUGR 或与烟草烟雾暴露相关的其他不良妊娠结局的可能机制。最后，它可能导致开发新的干预措施，以减少产前烟雾暴露对发育中胎儿的影响，并更有效地检测不适合移植的造血干细胞，从而改善结果并防止储存次优脐带血样本。