AbstractMaternal smoking during pregnancy (MSDP), driven by nicotine crossing the placenta, causes lifelong decreases in offspring pulmonary function and vitamin C supplementation during pregnancy prevents some of those changes. We have also shown in animal models of prenatal nicotine exposure that vitamin C supplementation during pregnancy improves placental function.

摘要孕妇在怀孕期间吸烟（MSDP），由尼古丁穿过胎盘驱动，导致后代肺功能终身下降，怀孕期间补充维生素C可防止其中一些变化。我们还在产前尼古丁暴露的动物模型中表明，怀孕期间补充维生素C可改善胎盘功能。

In this study we examined whether vitamin C supplementation mitigates the effects of MSDP on placental structure, function, and gene expression in pregnant human smokers. Doppler ultrasound was performed in a subset of 55 pregnant smokers participating in the “Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function” (VCSIP) randomized clinical trial (NCT01723696) and in 33 pregnant nonsmokers.

在这项研究中，我们检查了补充维生素C是否减轻了MSDP对孕妇吸烟者胎盘结构，功能和基因表达的影响。。

Doppler ultrasound measurements showed decreased umbilical vein Doppler velocity (Vmax) in placebo-treated smokers that was significantly improved in smokers randomized to vitamin C, restoring to levels comparable to nonsmokers. RNA-sequencing demonstrated that vitamin C supplementation to pregnant smokers was associated with changes in mRNA expression in genes highly relevant to vascular and cardiac development, suggesting a potential mechanism for vitamin C supplementation in pregnant smokers to improve some aspects of offspring health..

多普勒超声测量显示，安慰剂治疗吸烟者的脐静脉多普勒速度（Vmax）降低，随机服用维生素C的吸烟者的脐静脉多普勒速度（Vmax）显着改善，恢复到与不吸烟者相当的水平。RNA测序表明，向孕妇吸烟者补充维生素C与与血管和心脏发育高度相关的基因中mRNA表达的变化有关，这表明孕妇吸烟者补充维生素C以改善后代健康某些方面的潜在机制。。

IntroductionDespite strong smoking cessation efforts, over 50% of smokers who become pregnant will continue to smoke during pregnancy1,2. Maternal smoking during pregnancy (MSDP) affects the development of the placenta and multiple fetal organ systems including lung, brain, kidney and vasculature3,4,5,6.

引言尽管戒烟力度很大，但超过50%的怀孕吸烟者将在怀孕期间继续吸烟1,2。孕妇在怀孕期间吸烟（MSDP）会影响胎盘和多个胎儿器官系统的发育，包括肺，脑，肾和血管3,4,5,6。

Offspring of women who smoked during pregnancy have decreased lung function caused by narrowing and increased branching of airways7,8. The vasculature of offspring of smokers is affected by increased intimal and medial thickness and they show modest increases in blood pressure and decreased renal glomerular filtration rates9,10,11,12.Not surprisingly, MSDP also effects placental structure and function.

怀孕期间吸烟的女性后代由于气道狭窄和分支增加而导致肺功能下降7,8。吸烟者后代的脉管系统受到内膜和中层厚度增加的影响，血压适度升高，肾小球滤过率降低[9,10,11,12]。毫不奇怪，MSDP也会影响胎盘的结构和功能。

Both animal studies and histologic analysis of placentas from pregnant human smokers show that nicotine accumulates in amniotic fluid and freely crosses the placental barrier13 where it can bind to nicotinic acetylcholine receptors expressed in multiple placental cell types14 to potentially alter placental development.

对孕妇吸烟者胎盘的动物研究和组织学分析均表明，尼古丁在羊水中积累并自由穿过胎盘屏障13，在那里它可以与多种胎盘细胞类型14中表达的烟碱乙酰胆碱受体结合，从而可能改变胎盘发育。

MSDP is associated with increased connective tissue in the placenta and thickening of the trophoblastic basement membrane15. Doppler ultrasound (US) measurements in pregnant smokers show increased umbilical artery pulsatility index, suggesting increased placental vascular resistance, and decreased umbilical venous volume blood flow, consistent with reduced blood supply to the fetus3,16,17.

MSDP与胎盘结缔组织增加和滋养层基底膜增厚有关15。孕妇吸烟者的多普勒超声（US）测量显示脐动脉搏动指数增加，表明胎盘血管阻力增加，脐静脉血流量减少，与胎儿血液供应减少一致3,16,17。

Along with the decrease in placental function there is an increase in relative weight of placentas after correction for the intrauterine growth restriction (IUGR) associated with MSDP, such that the ratio of fetal weight to placental weight (F/P ratio) is decreased in offspring of smokers; suggesting a potential compensatory mechanism for a less robust placental unit that.

随着胎盘功能的下降，校正与MSDP相关的宫内生长受限（IUGR）后，胎盘的相对重量增加，因此胎儿体重与胎盘重量的比例（F/P比）在后代中降低吸烟者；提出了一种潜在的补偿机制，用于不太强大的胎盘单位。

Data availability

数据可用性

The raw and processed RNAseq data is publicly accessible through the NCBI Gene Expression Omnibus (GEO) via accession series GSE253158.

原始和处理的RNAseq数据可通过NCBI Gene Expression Omnibus（GEO）通过登录系列GSE253158公开访问。

ReferencesTong, V. T. et al. Trends in smoking before, during, and after pregnancy—pregnancy risk Assessment Monitoring System, United States, 40 sites, 2000–2010. MMWR Surveill Summ. 62, 1–19 (2013).PubMed

ReferencesTong，V.T.等人，《怀孕前、怀孕期间和怀孕后吸烟趋势妊娠风险评估监测系统》，美国，40个地点，2000-2010年。MMWR监督总结。62，1-19（2013）。PubMed出版社

Google Scholar

谷歌学者

Lange, S., Probst, C., Rehm, J. & Popova, S. National, regional, and global prevalence of smoking during pregnancy in the general population: a systematic review and meta-analysis. Lancet Glob Health. 6, e769–e776 (2018).Article

Lange，S.，Probst，C.，Rehm，J。＆Popova，S。国家，地区和全球普通人群怀孕期间吸烟率：系统评价和荟萃分析。柳叶刀全球健康。6，e769–e776（2018）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Rizzo, G., Capponi, A., Pietrolucci, M. E. & Arduini, D. Effects of maternal cigarette smoking on placental volume and vascularization measured by 3-dimensional power Doppler ultrasonography at 11 + 0 to 13 + 6 weeks of gestation. Am. J. Obstet. Gynecol. 200, 415e1–415e5 (2008).Article .

Rizzo，G.，Capponi，A.，Pietrolucci，M.E。和Arduini，D。在妊娠11 + 0至13 + 6周时，母亲吸烟对胎盘体积和血管形成的影响。美国J.Obstet。妇科。200415E1-415e5（2008）。。

Google Scholar

谷歌学者

Block, D. B., Mesquita, F. F., de Lima, I. P., Boer, P. A. & Gontijo, J. A. Fetal kidney programming by maternal smoking exposure: effects on kidney structure, blood pressure and urinary sodium excretion in adult offspring. Nephron. 129, 283–292 (2015).Article

Block，D.B.，Mesquita，F.F.，de Lima，I.P.，Boer，P.A。＆Gontijo，J.A。母亲吸烟暴露对胎儿肾脏编程：对成年后代肾脏结构，血压和尿钠排泄的影响。肾单位。129283-292（2015）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Roza, S. J. et al. Effects of maternal smoking in pregnancy on prenatal brain development. The Generation R Study. Eur. J. Neurosci. 25, 611–617 (2007).Article

Roza，S.J.等人。孕期母亲吸烟对产前大脑发育的影响。R代研究。Eur.J.Neurosci。25611-617（2007）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Zdravkovic, T., Genbacev, O., McMaster, M. T. & Fisher, S. J. The adverse effects of maternal smoking on the human placenta: a review. Placenta. 26 (Suppl), S81–S86 (2005).Article

Zdravkovic，T.，Genbacev，O.，McMaster，M.T。＆Fisher，S.J。母亲吸烟对人类胎盘的不利影响：综述。胎盘。26（增刊），S81–S86（2005）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Elliot, J., Vullermin, P. & Robinson, P. Maternal cigarette smoking is Associated with increased inner Airway Wall Thickness in Children who die from Sudden Infant Death Syndrome. Am. J. Respir Crit. Care Med. 158, 802–806 (1998).Article

Elliot，J.，Vullermin，P。＆Robinson，P。母亲吸烟与死于婴儿猝死综合征的儿童的内气道壁厚度增加有关。Am.J.Respir Crit.Care Med.158802–806（1998）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Gilliland, F. D. et al. Maternal smoking during pregnancy, environmental tobacco smoke exposure and childhood lung function. Thorax. 55, 271–276 (2000).Article

Gilliland，F.D.等人，《孕期母亲吸烟、环境烟草烟雾暴露和儿童肺功能》。胸部。55271-276（2000）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Hogberg, L. et al. Effects of maternal smoking during pregnancy on offspring blood pressure in late adolescence. J. Hypertens. 30, 693–699 (2012).Article

Hogberg，L.等人。怀孕期间母亲吸烟对青春期后期后代血压的影响。J、 高血压。30693-699（2012）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Oken, E., Huh, S. Y., Taveras, E. M., Rich-Edwards, J. W. & Gillman, M. W. Associations of maternal prenatal smoking with child adiposity and blood pressure. Obes. Res. 13, 2021–2028 (2005).Article

Oken，E.，Huh，S.Y.，Taveras，E.M.，Rich Edwards，J.W。＆Gillman，M.W。母亲产前吸烟与儿童肥胖和血压的关系。Obes。第13号决议，2021–2028（2005）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

McEvoy, C. T. & Spindel, E. R. Pulmonary effects of maternal smoking on the Fetus and Child: effects on Lung Development, respiratory morbidities, and Life Long Lung Health. Paediatr. Respir Rev. 21, 27–33 (2017).PubMed

McEvoy，C.T。＆Spindel，E.R。母亲吸烟对胎儿和儿童的肺部影响：对肺部发育，呼吸系统疾病和终身肺部健康的影响。儿科。Respir Rev.21，27–33（2017）。PubMed出版社

Google Scholar

谷歌学者

Kooijman, M. N. et al. Fetal smoke exposure and kidney outcomes in school-aged children. Am. J. Kidney Dis. 66, 412–420 (2015).Article

Kooijman，M.N.等人，《学龄儿童的胎儿烟雾暴露和肾脏结局》。美国肾脏病杂志。66412-420（2015）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Pastrakuljic, A. et al. Transplacental transfer and biotransformation studies of nicotine in the human placental cotyledon perfused in vitro. Life Sci. 63, 2333–2342 (1998).Article

。生命科学。632333-2342（1998）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Lips, K. S. et al. Nicotinic acetylcholine receptors in rat and human placenta. Placenta. 26, 735–746 (2005).Article

Lips，K.S.等人。大鼠和人胎盘中的烟碱乙酰胆碱受体。胎盘。26735-746（2005）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Jauniaux, E. & Burton, G. J. Morphological and biological effects of maternal exposure to tobacco smoke on the feto-placental unit. Early Hum. Dev. 83, 699–706 (2007).Article

Jauniaux，E。＆Burton，G.J。母亲暴露于烟草烟雾对胎儿-胎盘单位的形态学和生物学影响。早期嗡嗡声。发展83699-706（2007）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Newnham, J. P., Patterson, L., James, I. & Reid, S. E. Effects of maternal cigarette smoking on ultrasonic measurements of fetal growth and on doppler flow velocity waveforms. Early Hum. Dev. 24, 23–36 (1990).Article

。《早期嗡嗡声》，第24、23–36页（1990年）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Pintican, D., Poienar, A. A., Strilciuc, S. & Mihu, D. Effects of maternal smoking on human placental vascularization: a systematic review. Taiwan. J. Obstet. Gynecol. 58, 454–459 (2019).Article

Pintican，D.，Poinear，A.A.，Strilciuc，S。＆Mihu，D。母亲吸烟对人胎盘血管形成的影响：系统评价。台湾。J、 障碍。妇科。。文章

PubMed

PubMed

Google Scholar

谷歌学者

Jaitner, A. et al. Smoking during pregnancy and its effect on placental weight: a mendelian randomization study. medRxiv (2023).Mitsuda, N. et al. Association between maternal active smoking during pregnancy and placental weight: the Japan environment and children’s study. Placenta. 94, 48–53 (2020).Article .

Jaitner，A.等人，《怀孕期间吸烟及其对胎盘重量的影响：孟德尔随机研究》。medRxiv（2023）。Mitsuda，N.等人，《孕期母亲主动吸烟与胎盘重量之间的关系：日本环境与儿童研究》。胎盘。94,48-53（2020）。。

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Sekhon, H. S. et al. Prenatal nicotine increases pulmonary alpha7 nicotinic receptor expression and alters fetal lung development in monkeys. J. Clin. Investig. 103, 637–647 (1999).Article

Sekhon，H.S.等人。产前尼古丁会增加肺部α7烟碱受体的表达，并改变猴子的胎儿肺发育。J、 临床。调查。103637-647（1999）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Sekhon, H. S., Keller, J. A., Benowitz, N. L. & Spindel, E. R. Prenatal nicotine exposure alters pulmonary function in newborn rhesus monkeys. Am. J. Respir Crit. Care Med. 164, 989–994 (2001).Article

Sekhon，H.S.，Keller，J.A.，Benowitz，N.L。和Spindel，E.R。产前尼古丁暴露会改变新生恒河猴的肺功能。Am.J.Respir Crit.Care Med.164989–994（2001）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Wongtrakool, C., Wang, N., Hyde, D. M., Roman, J. & Spindel, E. R. Prenatal nicotine exposure alters lung function and airway geometry through alpha7 nicotinic receptors. Am. J. Respir Cell. Mol. Biol. 46, 695–702 (2012).Article

Wongtrakool，C.，Wang，N.，Hyde，D.M.，Roman，J。＆Spindel，E.R。产前尼古丁暴露通过α7烟碱受体改变肺功能和气道几何形状。Am.J.呼吸细胞。分子生物学。46695-702（2012）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Rehan, V. K., Asotra, K. & Torday, J. S. The effects of smoking on the developing lung: insights from a biologic model for lung development, homeostasis, and repair. Lung. 187, 281–289 (2009).Article

Rehan，V.K.，Asotra，K。＆Torday，J.S。吸烟对发育中的肺的影响：来自肺发育，体内平衡和修复生物学模型的见解。肺。187281-289（2009）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Proskocil, B. J. et al. Vitamin C prevents the effects of prenatal nicotine on pulmonary function in Newborn monkeys. Am. J. Respir Crit. Care Med. 171, 1032–1039 (2005).Article

Proskocil，B.J.等人。维生素C可防止产前尼古丁对新生猴肺功能的影响。Am.J.Respir Crit.Care Med.1711032-1039（2005）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Lo, J. O. et al. Vitamin C supplementation ameliorates the adverse effects of nicotine on placental hemodynamics and histology in nonhuman primates. Am. J. Obstet. Gynecol. 212, 370–378 (2015).Article

补充维生素C可以改善尼古丁对非人灵长类动物胎盘血流动力学和组织学的不利影响。美国J.Obstet。妇科。212370-378（2015）。文章

PubMed Central

公共医学中心

Google Scholar

谷歌学者

McEvoy, C. T. et al. Vitamin C supplementation for pregnant smoking women and pulmonary function in their newborn infants: a randomized clinical trial. JAMA. 311, 2074–2082 (2014).Article

McEvoy，C.T.等人，《孕妇吸烟补充维生素C及其新生儿肺功能：一项随机临床试验》。杰玛。3112074-2082（2014）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

McEvoy, C. T. et al. Effect of vitamin C supplementation for pregnant smokers on offspring airway function and wheeze at age 5 years: follow-up of a randomized clinical trial. JAMA Pediatr. 177, 16–24 (2023).Article

McEvoy，C.T.等人。孕妇吸烟者补充维生素C对5岁时后代气道功能和喘息的影响：一项随机临床试验的随访。JAMA儿科。177，16-24（2023）。文章

PubMed

PubMed

Google Scholar

谷歌学者

McEvoy, C. T. et al. Oral vitamin C (500 mg/d) to pregnant smokers improves infant airway function at 3 months (VCSIP). A randomized trial. Am. J. Respir Crit. Care Med. 199, 1139–1147 (2019).Article

McEvoy，C.T.等人，向孕妇吸烟者口服维生素C（500 mg/d）可改善3个月时的婴儿气道功能（VCSIP）。。Am.J.Respir Crit.Care Med.1991139-1147（2019）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Khong, T. Y. et al. Sampling and definitions of placental lesions: Amsterdam placental workshop group consensus statement. Arch. Pathol. Lab. Med. 140, 698–713 (2016).Article

Khong，T.Y.等。胎盘病变的取样和定义：阿姆斯特丹胎盘研讨会小组共识声明。拱门。病理学。实验室医学140698-713（2016）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Geelhoed, J. J. et al. Maternal smoking during pregnancy, fetal arterial resistance adaptations and cardiovascular function in childhood. BJOG. 118, 755–762 (2011).Article

Geelhoed，J.J.等人。孕妇在怀孕期间吸烟，胎儿动脉阻力适应和儿童心血管功能。北京奥组委。118755-762（2011）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Wongtrakool, C., Roser-Page, S., Rivera, H. N. & Roman, J. Nicotine alters lung branching morphogenesis through the alpha7 nicotinic acetylcholine receptor. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L611–L618 (2007).Article

Wongtrakool，C.，Roser-Page，S.，Rivera，H.N。＆Roman，J。尼古丁通过α7烟碱乙酰胆碱受体改变肺分支形态发生。Am.J.Physiol。肺细胞。分子生理学。293，L611–L618（2007）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Kyrklund-Blomberg, N. B., Hu, J. & Gennser, G. Chronic effects of maternal smoking on pulse waves in the fetal aorta. J. Matern Fetal Neonatal Med. 19, 495–501 (2006).Article

Kyrklund Blomberg，N.B.，Hu，J。＆Gennser，G。母亲吸烟对胎儿主动脉脉搏波的慢性影响。J、 Matern胎儿新生儿医学19495-501（2006）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Pulvers, K. et al. Light and intermittent smoking among California Black, Hispanic/Latino, and non-hispanic white men and women. Nicotine Tob. Res. 17, 755–759 (2015).Article

Pulvers，K.等人。加利福尼亚黑人、西班牙裔/拉丁裔和非西班牙裔白人男女之间的轻度和间歇性吸烟。尼古丁Tob。第17755-759号决议（2015年）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Schauer, G. L., Malarcher, A. M. & Mowery, P. National trends in frequency and amount of nondaily smoking, and relation to quit attempts, 2000–2012. Nicotine Tob. Res. 18, 1539–1544 (2016).Article

Schauer，G.L.、Malarcher，A.M.&Mowery，P.《非日常吸烟频率和数量的国家趋势以及与戒烟尝试的关系，2000-2012年》。尼古丁Tob。第181539-1544号决议（2016年）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Alptekin, H. et al. A prospective comparative study to assess the effect of maternal smoking at 37 weeks on doppler flow velocity waveforms as well as foetal birth weight and placental weight. J. Obstet. Gynaecol. 37, 146–150 (2017).PubMed

Alptekin，H.等人。一项前瞻性比较研究，旨在评估母亲在37周时吸烟对多普勒血流速度波形以及胎儿出生体重和胎盘重量的影响。J、 障碍。妇科。37146-150（2017）。PubMed出版社

Google Scholar

谷歌学者

Jobe, A. H. Effects of chorioamnionitis on the fetal lung. Clin. Perinatol. 39, 441–457 (2012).Article

Jobe，A.H。绒毛膜羊膜炎对胎儿肺的影响。临床。围产期。39441-457（2012）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kramer, B. W., Kallapur, S., Newnham, J. & Jobe, A. H. Prenatal inflammation and lung development. Semin Fetal Neonatal Med. 14, 2–7 (2009).Article

Kramer，B.W.，Kallapur，S.，Newnham，J。＆Jobe，A.H。产前炎症和肺部发育。Semin胎儿新生儿医学14,2-7（2009）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Sotiriou, S. et al. Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival. Nat. Med. 8, 514–517 (2002).Article

抗坏血酸转运蛋白Slc23a1对于维生素C转运到大脑和围产期存活至关重要。《自然医学》8514-517（2002）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Holbourn, K. P., Acharya, K. R. & Perbal, B. The CCN family of proteins: structure-function relationships. Trends Biochem. Sci. 33, 461–473 (2008).Article

Holbourn，K.P.，Acharya，K.R。和Perbal，B。CCN蛋白质家族：结构-功能关系。趋势生物化学。科学。33461-473（2008）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Grzeszkiewicz, T. M., Lindner, V., Chen, N., Lam, S. C. & Lau, L. F. The angiogenic factor cysteine-rich 61 (CYR61, CCN1) supports vascular smooth muscle cell adhesion and stimulates chemotaxis through integrin alpha(6)beta(1) and cell surface heparan sulfate proteoglycans. Endocrinology.

Grzeszkiewicz，T.M.，Lindner，V.，Chen，N.，Lam，S.C。＆Lau，L.F。富含半胱氨酸的血管生成因子61（CYR61，CCN1）支持血管平滑肌细胞粘附并通过整合素α（6）β（1）和细胞表面硫酸乙酰肝素蛋白聚糖刺激趋化性。内分泌学。

143, 1441–1450 (2002).Article .

1431441-1450（2002）。。

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Mo, F. E. et al. CYR61 (CCN1) is essential for placental development and vascular integrity. Mol. Cell. Biol. 22, 8709–8720 (2002).Article

Mo，F.E.等人CYR61（CCN1）对于胎盘发育和血管完整性至关重要。摩尔电池。生物学228709-8720（2002）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Lopez-Lluch, G. et al. Cellular redox state and activating protein-1 are involved in ascorbate effect on calcitriol-induced differentiation. Protoplasma. 217, 129–136 (2001).Article

Lopez-Lluch，G。等人。细胞氧化还原状态和活化蛋白-1参与抗坏血酸对骨化三醇诱导的分化的影响。原生质体。217129-136（2001）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Yu, H. F. et al. HB-EGF ameliorates oxidative stress-mediated uterine decidualization damage. Oxid. Med. Cell Longev. 6170936 (2019). (2019).Stejskalova, L. & Pavek, P. The function of cytochrome P450 1A1 enzyme (CYP1A1) and aryl hydrocarbon receptor (AhR) in the placenta. Curr. Pharm.

Yu，H.F。等人。HB-EGF改善氧化应激介导的子宫蜕膜化损伤。氧化剂。医学Cell Longev。6170936（2019）。（2019年）。Stejskalova，L。＆Pavek，P。细胞色素P450 1A1酶（CYP1A1）和芳烃受体（AhR）在胎盘中的功能。货币。药学。

Biotechnol. 12, 715–730 (2011).Article .

生物技术。12, 715-730 (2011).第[UNK]条。

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Fa, S. et al. Changes in first trimester fetal CYP1A1 and AHRR DNA methylation and mRNA expression in response to exposure to maternal cigarette smoking. Environ. Toxicol. Pharmacol. 57, 19–27 (2018).Article

Fa，S.等人。暴露于母亲吸烟后，孕早期胎儿CYP1A1和AHRR DNA甲基化和mRNA表达的变化。环境。毒理学。药理学。。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Suter, M. A. & Aagaard, K. What changes in DNA methylation take place in individuals exposed to maternal smoking in utero? Epigenomics. 4, 115–118 (2012).Article

Suter，M.A。＆Aagaard，K。在子宫内暴露于母亲吸烟的个体中，DNA甲基化发生了什么变化？表观基因组学。4115-118（2012）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Suter, M. et al. In utero tobacco exposure epigenetically modifies placental CYP1A1 expression. Metabolism. 59, 1481–1490 (2010).Article

Suter，M。等人在子宫内烟草暴露表观遗传修饰胎盘CYP1A1表达。新陈代谢。591481-1490（2010）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Huuskonen, P. et al. The human placental proteome is affected by maternal smoking. Reprod. Toxicol. 63, 22–31 (2016).Article

Huuskonen，P。等人。人类胎盘蛋白质组受母亲吸烟的影响。重新编程。毒理学。63,22-31（2016）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Zhou, H., Fu, G., Yu, H. & Peng, C. Transforming growth factor-beta inhibits aromatase gene transcription in human trophoblast cells via the Smad2 signaling pathway. Reprod. Biol. Endocrinol. 7, 146 (2009).Article

Zhou，H.，Fu，G.，Yu，H。＆Peng，C。转化生长因子β通过Smad2信号通路抑制人滋养层细胞中芳香化酶基因的转录。重新编程。生物内分泌。7146（2009）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Goumans, M. J. et al. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J. 21, 1743–1753 (2002).Article

Goumans，M.J.等人，通过两种不同的TGF-βI型受体平衡内皮的激活状态。。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Shorey-Kendrick, L. E. et al. Impact of vitamin C supplementation on placental DNA methylation changes related to maternal smoking: association with gene expression and respiratory outcomes. Clin. Epigenet. 13, 177 (2021).Article

。临床。表观遗传学。13177（2021）。文章

CAS

中科院

Google Scholar

谷歌学者

Houston, M. C. The role of cellular micronutrient analysis, nutraceuticals, vitamins, antioxidants and minerals in the prevention and treatment of hypertension and cardiovascular disease. Ther. Adv. Cardiovasc. Dis. 4, 165–183 (2010).Article

细胞微量营养素分析、营养保健品、维生素、抗氧化剂和矿物质在预防和治疗高血压和心血管疾病中的作用。他们。心血管高级医师。Dis。4165-183（2010）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Lo, J. O. et al. First trimester alcohol exposure alters placental perfusion and fetal oxygen availability affecting fetal growth and development in a non-human primate model. Am. J. Obstet. Gynecol. 216, 302 (2017).PubMed Central

Lo，J.O.等人。在非人灵长类动物模型中，妊娠早期酒精暴露会改变胎盘灌注和胎儿氧气的可用性，从而影响胎儿的生长发育。美国J.Obstet。妇科。216302（2017）。公共医学中心

Google Scholar

谷歌学者

Najafzadeh, A. & Dickinson, J. E. Umbilical venous blood flow and its measurement in the human fetus. J. Clin. Ultrasound. 40, 502–511 (2012).Article

Najafzadeh，A。＆Dickinson，J。E。人胎儿脐静脉血流量及其测量。J、 临床。超声波。40502-511（2012）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Ford, I. & Norrie, J. Pragmatic trials. N Engl. J. Med. 375, 454–463 (2016).Article

Ford，I。＆Norrie，J。实用试验。英格兰。J、 医学375454-463（2016）。文章

PubMed

PubMed

Google Scholar

谷歌学者

McEvoy, C. T. et al. Vitamin C to pregnant smokers persistently improves infant airway function to 12 months of age: a randomised trial. Eur. Respir J. (2020).McEvoy, C. T. et al. Vitamin C to decrease the effects of smoking in pregnancy on infant lung function (VCSIP): Rationale, design, and methods of a randomized, controlled trial of vitamin C supplementation in pregnancy for the primary prevention of effects of in utero tobacco smoke exposure on infant lung function and respiratory health.

McEvoy，C.T.等人。孕妇吸烟者服用维生素C持续改善12个月大婴儿的气道功能：一项随机试验。《欧洲呼吸杂志》（2020）。McEvoy，C.T.等人，《维生素C降低妊娠期吸烟对婴儿肺功能（VCSIP）的影响：妊娠期补充维生素C的随机对照试验的基本原理，设计和方法，用于一级预防子宫内烟草烟雾暴露对婴儿肺功能和呼吸健康的影响。

Contemp. Clin. Trials. 58, 66–77 (2017).Article .

康坦普。临床。试验。58,66-77（2017）。。

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Acharya, G., Wilsgaard, T., Berntsen, G. K., Maltau, J. M. & Kiserud, T. Doppler-derived umbilical artery absolute velocities and their relationship to fetoplacental volume blood flow: a longitudinal study. Ultrasound Obstet. Gynecol. 25, 444–453 (2005).Article

Acharya，G.，Wilsgaard，T.，Berntsen，G.K.，Maltau，J.M。＆Kiserud，T。多普勒衍生的脐动脉绝对速度及其与胎儿胎盘体积血流量的关系：一项纵向研究。超声波障碍。妇科。25444-453（2005）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Frias, A. E. et al. Maternal high-fat diet disturbs uteroplacental hemodynamics and increases the frequency of stillbirth in a nonhuman primate model of excess nutrition. Endocrinology. 152, 2456–2464 (2011).Article

Frias，A.E.等人，在营养过剩的非人灵长类动物模型中，母体高脂肪饮食会干扰子宫胎盘血流动力学并增加死胎的频率。内分泌学。1522456-2464（2011）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Konje, J. C., Kaufmann, P., Bell, S. C. & Taylor, D. J. A longitudinal study of quantitative uterine blood flow with the use of color power angiography in appropriate for gestational age pregnancies. Am. J. Obstet. Gynecol. 185, 608–613 (2001).Article

Konje，J.C.，Kaufmann，P.，Bell，S.C。＆Taylor，D.J。使用彩色能量血管造影对适合胎龄妊娠的定量子宫血流进行纵向研究。美国J.Obstet。妇科。185608-613（2001）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Acharya, G., Wilsgaard, T., Rosvold Berntsen, G. K., Maltau, J. M. & Kiserud, T. Reference ranges for umbilical vein blood flow in the second half of pregnancy based on longitudinal data. Prenat Diagn. 25, 99–111 (2005).Article

Acharya，G.，Wilsgaard，T.，Rosvold-Berntsen，G.K.，Maltau，J.M。＆Kiserud，T。根据纵向数据，妊娠后半期脐静脉血流的参考范围。Prenat诊断。25，99-111（2005）。文章

PubMed

PubMed

Google Scholar

谷歌学者

ISUOG Education Committee recommendations. For basic training in obstetric and gynecological ultrasound. Ultrasound Obstet. Gynecol. 43, 113–116 (2014).Article

ISUOG教育委员会建议。妇产科超声基础培训。超声波障碍。妇科。43113-116（2014）。文章

Google Scholar

谷歌学者

Campbell, K. A. et al. Placental cell type deconvolution reveals that cell proportions drive preeclampsia gene expression differences. Commun. Biol. 6, 264 (2023).Article

Campbell，K.A。等人的胎盘细胞类型去卷积揭示了细胞比例驱动先兆子痫基因表达差异。Commun公司。生物学杂志6264（2023）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 26, 139–140 (2010).Article

Robinson，M.D.，McCarthy，D.J。＆Smyth，G.K.edgeR：用于数字基因表达数据差异表达分析的生物导体软件包。生物信息学。26139-140（2010）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Kamburov, A., Stelzl, U., Lehrach, H. & Herwig, R. The ConsensusPathDB interaction database: 2013 update. Nucleic Acids Res. 41, D793–D800 (2013).Article

Kamburov，A.，Stelzl，U.，Lehrach，H。＆Herwig，R。ConsensusPathDB交互数据库：2013年更新。核酸研究41，D793–D800（2013）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Kramer, A., Green, J., Pollard, J. Jr. & Tugendreich, S. Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics. 30, 523–530 (2014).Article

Kramer，A.，Green，J.，Pollard，J。Jr。和Tugendreich，S。创造力途径分析中的因果分析方法。生物信息学。30523-530（2014）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Kalinka, J., Hanke, W. & Sobala, W. Impact of prenatal tobacco smoke exposure, as measured by midgestation serum cotinine levels, on fetal biometry and umbilical flow velocity waveforms. Am. J. Perinatol. 22, 41–47 (2005).Article

Kalinka，J.，Hanke，W。＆Sobala，W。通过妊娠中期血清可替宁水平测量的产前烟草烟雾暴露对胎儿生物测量和脐血流速度波形的影响。Am.J.Perinatol。22,41-47（2005）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Download referencesAcknowledgementsWe would like to thank the women and their infants who participated in the VCSIP RCT to make this study possible. We also thank all VCSIP team members who contributed to clinical data and sample collection.FundingSupported by the NHLBI (R01 HL105447 and R01 HL 105460) with co-funding from the Office of Dietary Supplements (ODS) and by P51 OD0110925 and NIH grant UH3 OD023288 from the Environmental influences on Child Health Outcomes Program.

下载参考文献致谢我们要感谢参与VCSIP RCT的女性及其婴儿，使这项研究成为可能。我们还要感谢所有为临床数据和样本收集做出贡献的VCSIP团队成员。由NHLBI（R01 HL105447和R01 HL 105460）资助，由膳食补充剂办公室（ODS）共同资助，由P51 OD0110925和NIH grant UH3 OD023288资助，由环境影响儿童健康结果计划资助。

Additional support from the Oregon Clinical Translational Research Institute funded by the National Center for Advancing Translational Sciences (UL1TR000128).Author informationAuthors and AffiliationsDivision of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Ave, Beaverton, OR, 97006, USALyndsey E.

俄勒冈州临床转化研究所（National Center for Advanced Translation Sciences，UL1TR000128）资助的额外支持。作者信息作者和附属机构俄勒冈州健康与科学大学俄勒冈州国家灵长类动物研究中心神经科学部，俄勒冈州比弗顿西北185大街505号，俄勒冈州，97006，USALyndsey E。

Shorey-Kendrick, Shannon M. O’Sullivan & Eliot R. SpindelDepartment of Pediatrics, Papé Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USACindy T. McEvoy, Kristin Milner & Brittany VuylstekeDepartment of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USARobert S.

Shorey Kendrick，Shannon M.O'Sullivan＆Eliot R.SpindelDepartment of Pediatrics，PapéPediatric Research Institute，Oregon Health&Science University，Portland，OR，USACindy T.McEvoy，Kristin Milner＆Brittany VuylstekeDepartment of Pediatrics，Herman B Wells Center for Pediatric Research，Indiana University School of Medicine，Indianapolis，IN。

TepperDepartment of Pathology, Oregon Health & Science University, Portland, OR, USATerry K. MorganDepartment of Obstetrics and Gynecology, Oregon Health & Science University, Beaverton, OR, USATerry K. Morgan, Jamie O. Lo & Antonio E. FriasDivision of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USAVictoria H.

Tepper俄勒冈州波特兰市俄勒冈州健康与科学大学病理学系，俄勒冈州比弗顿市俄勒冈州健康与科学大学妇产科，俄勒冈州比弗顿，俄勒冈州比弗顿市俄勒冈州健康与科学大学生殖与发育科学系，Jamie O.Lo＆Antonio E.Frias，美国维多利亚H。

J. Roberts & Jamie O. LoDepartment of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, USADavid M. HaasOregon Health & Science University-Portlan.

J、 罗伯茨（Roberts）和杰米（JamieO.LoDepartment）美国印第安纳州印第安纳波利斯市印第安纳大学医学院妇产科DavidM.HaasOregon健康与科学大学波特兰分校。

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PubMed Google ScholarContributionsConception and design: L.E.S., C.T.M., R.S.T., T.K.M., V.H.R., J.O.L., A.E.F., D.M.H., B.P., L.G., A.V., C.D.M., E.R.S. Acquisition, analysis or interpretation of data: all authors. Drafting of manuscript: L.E.S., C.T.M., R.S.T., T.K.M., V.H.R., J.O.L., A.E.F., D.M.H., B.P., L.G., A.V., C.D.M., E.R.S.Corresponding authorCorrespondence to.

PubMed谷歌学术贡献概念与设计：L.E.S.，C.T.M.，R.S.T.，T.K.M.，V.H.R.，J.O.L.，A.E.F.，D.M.H.，B.P.，L.G.，A.V.，C.D.M.，E.R.S.数据的获取，分析或解释：所有作者。手稿的起草：L.E.S.，C.T.M.，R.S.T.，T.K.M.，V.H.R.，J.O.L.，A.E.F.，D.M.H.，B.P.，L.G.，A.V.，C.D.M.，E.R.S。对应作者。

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Reprints and permissionsAbout this articleCite this articleShorey-Kendrick, L.E., McEvoy, C.T., O’Sullivan, S.M. et al. Vitamin C supplementation improves placental function and alters placental gene expression in smokers.

转载和许可本文引用本文Shorey Kendrick，L.E.，McEvoy，C.T.，O'Sullivan，S.M.等人补充维生素C可改善吸烟者的胎盘功能并改变胎盘基因表达。

Sci Rep 14, 25486 (2024). https://doi.org/10.1038/s41598-024-73005-7Download citationReceived: 11 January 2024Accepted: 12 September 2024Published: 26 October 2024DOI: https://doi.org/10.1038/s41598-024-73005-7Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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NeonatologyNutritional supplementsOutcomes researchPaediatricsRisk factorsTranslational research