论文标题：Maternal smoking and high BMI disrupt thyroid gland development

期刊：

作者：Panagiotis Filis, Sabine Hombach-Klonisch, Pierre Ayotte, Nalin Nagrath, Ugo Soffientini, Thomas Klonisch, Peter O’Shaughnessy and Paul A. Fowler

发表时间：2018/10/23

数字识别码：s12916-018-1183-7

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众所周知，母亲在孕期的一举一动，各种不良的生活方式均会牵动腹中胎儿的健康，近期发表在BMC Medicine上的一篇文章揭露了孕中期母亲吸烟和体重增加对胎儿甲状腺功能的影响。

“成人疾病的胎儿起源”假说指出，从代谢综合征和肥胖到心血管或行为失调的各种成年人疾病均起源于胎儿时期。在孕妇中，众所周知，诸如体重过重、药物使用和滥用、压力过大、饮酒和吸烟等生活方式对后代的健康都有很大的影响。一般来说，31%的30岁以下妇女在第一次怀孕时吸烟，而少于4%的孕妇在怀孕期间停止吸烟。孕妇在怀孕期间吸烟对胎儿具有直接的副作用：包括早产和可能导致死胎，并且还与代谢综合征、胎儿出生体重过低、生育力下降、流产率增加和后代的心理健康问题有关。高母亲体重指数（BMI）是生育年龄妇女最普遍的不良生活方式，美国和英国有64%的妇女超重和35%的妇女肥胖。孕期BMI升高使后代易患全世界致死率最高的疾病，如心血管疾病、肥胖和代谢综合征、呼吸系统并发症以及孤独症等其他疾病。

甲状腺的内分泌功能对于控制代谢率和大脑发育至关重要，并且是胎儿正常发育所必需的，也是三碘甲状腺原氨酸（T3）和甲状腺素（T4）的来源。甲状腺激素控制着代谢率、心输出量和脑功能，对胎儿大脑的正常发育和生长至关重要。在孕早期，人类胎儿循环中的T3和T4是母源性的，但从孕中期开始，胎儿甲状腺的发育对胎儿血液循环中T3和T4水平的贡献越来越大。

胎儿期甲状腺功能的改变可能改变后代患儿期和成年期疾病的倾向。尽管如此，在母亲不良生活方式对胎儿甲状腺发育的影响方面却知之甚少。之前的研究表明，暴露于宫内香烟烟雾的新生儿甲状腺肿大，而母亲吸烟增加了母亲血清中游离T3水平，降低了新生儿脐带血清促甲状腺激素（TSH）水平。同样，孕妇和新生儿体重增加与新生儿脐带血清游离T3水平的增加有关。然而，目前还不清楚是在妊娠的哪个阶段，母亲吸烟或母亲体重增加开始对胎儿甲状腺在子宫中的发育和功能产生了影响。

在本研究中，作者从妊娠中期（正常进展期妊娠）选择性终止的胎儿中采集甲状腺和血浆。通过固相萃取 - 液相色谱 - 串联质谱联用法测量T3和T4的含量。使用针对人垂体激素的多重测定法测量胎儿血浆中促甲状腺激素（TSH）的水平，以及甲状腺激素结合蛋白(ALB)、转甲状腺素(TTR)和甲状腺素结合球蛋白(TBG)的水平。此外，还检测了胎儿甲状腺的形态学变化并量化了与甲状腺发育和功能相关基因的转录水平。

研究发现，母亲吸烟与妊娠中期胎儿血浆T4和TSH水平的显着变化有关。烟雾暴露的甲状腺减少了甲状腺GATA6和NKX2-1的转录水平，并改变了ESR2和AHR转录水平的发育轨迹，同时，AHR和ESR1转录物表达的发育变化也出现了异常。

图2. 胎儿暴露在烟雾中对其循环血液中甲状腺相关激素（A）、免疫组化标志物评分（B）以及甲状腺基因相关转录本的影响均具有统计学意义（P < 0.05）。

除此之外，母体BMI> 25与胎儿甲状腺重量增加、血浆TSH水平升高和女性胎儿甲状腺组织学异常有关

图3. 甲状腺重量和组织形态学评分比例（不成熟与成熟）与母体BMI呈显著正相关（P＜0.05）。

简而言之，母亲吸烟和母亲体重过高在妊娠中期触发了复杂和性别特异性的效应，影响了胎儿甲状腺形态和内分泌的功能。作者最后指出，提前了解到胎儿在发育过程中的敏感反应可有助于父母提早改变孕期生活方式，并适当采取预防措施来规避儿童以后患病的风险。

摘要：

Background

Maternal lifestyle factors, including smoking and increased body weight, increase risks of adult diseases such as metabolic syndrome and infertility. The fetal thyroid gland is essential for the control of fetal metabolic rate, cardiac output, and brain development. Altered fetal thyroid function may contribute to increased disease onset later in life. Here, we investigated the impact of maternal smoking and high maternal weight on human fetal thyroid function during the second trimester.

Methods

Thyroid glands and plasma were collected from fetuses electively terminated in the second trimester (normally progressing pregnancies). Plasma total triiodothyronine (T3) and total thyroxine (T4) were measured by solid-phase extraction-liquid chromatography-tandem mass spectrometry. Fetal plasma thyroid-stimulating hormone (TSH) levels were measured using a multiplex assay for human pituitary hormones. Histology and immunolocalization of thyroid developmental markers were examined in thyroid sections. Transcript levels of developmental, functional, apoptotic, and detoxification markers were measured by real-time PCR. Statistical analyses were performed using multivariate linear regression models with fetal age, sex, and maternal smoking or maternal body mass index (BMI) as covariates.

Results

Maternal smoking was associated with significant changes in fetal plasma T4 and TSH levels during the second trimester. Smoke-exposed thyroids had reduced thyroid GATA6and NKX2-1 transcript levels and altered developmental trajectories for ESR2 and AHRtranscript levels. Maternal BMI > 25 was associated with increased fetal thyroid weight, increased plasma TSH levels, and abnormal thyroid histology in female fetuses. Normal developmental changes in AHR and ESR1 transcript expression were also abolished in fetal thyroids from mothers with BMI > 25.

Conclusions

For the first time, we show that maternal smoking and high maternal BMI are associated with disturbed fetal thyroid gland development and endocrine function in a sex-specific manner during the second trimester. These findings suggest that predisposition to post-natal disease is mediated, in part, by altered fetal thyroid gland development.

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期刊介绍:

BMC Medicine(, 9.088 - 2, 9.41 - ) is the flagship medical journal of the BMC series. An open access, open peer-reviewed general medical journal, BMC Medicine publishes outstanding and influential research in all areas of clinical practice, translational medicine, medical and health advances, public health, global health, policy, and general topics of interest to the biomedical and sociomedical professional communities. We also publish stimulating debates and reviews as well as unique forum articles and concise tutorials.

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