Abstract
BackgroundMaternal 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.MethodsThyroid 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.ResultsMaternal smoking was associated with significant changes in fetal plasma T4 and TSH levels during the second trimester. Smoke-exposed thyroids had reduced thyroid GATA6 and NKX2-1 transcript levels and altered developmental trajectories for ESR2 and AHR transcript 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.ConclusionsFor 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.
Highlights
Maternal lifestyle factors, including smoking and increased body weight, increase risks of adult diseases such as metabolic syndrome and infertility
The roles of fetal age and sex in the developing human fetal thyroid Total T3 and T4 levels in the fetal circulation increased with age, the T3/T4 ratio decreased with fetal age, and the thyroid hormone-binding proteins ALB and thyroxine-binding globulin (TBG) increased with increasing fetal age in both males and females regardless of smoke exposure or maternal body mass index (BMI) models (Additional file 6: Figure S2A, Table 1)
There was no difference in thyroid gland weight between males and females, but male thyroids tended to show more immature thyroid gland morphology compared to female thyroids and this approached statistical significance (P = 0.057, Additional file 4: Table S3)
Summary
Maternal lifestyle factors, including smoking and increased body weight, increase risks of adult diseases such as metabolic syndrome and infertility. Thyroid hormones control metabolic rate, cardiac output, and brain function and are critical for normal fetal brain development and growth [1]. Maternal smoking during pregnancy has immediate adverse effects including pre-term delivery and stillbirth and has been linked to metabolic syndrome [6, 7], low birth weight, reduced fertility [8, 9], increased miscarriage rates [10], and psychosomatic problems in the offspring [11]. High maternal body mass index (BMI) is the most prevalent adverse lifestyle factor in women of reproductive age, with 64% of women overweight and 35% obese in the USA and UK [12, 13]. Elevated BMI during pregnancy predisposes the offspring to the highest mortality-inducing diseases worldwide such as premature death from cardiovascular disease [14], obesity and metabolic syndrome [15], and respiratory complications [16] and to other conditions such as autism [17]
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