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 2nd trimester.
Methods: Thyroid glands and plasma were collected from fetuses electively terminated in the 2nd 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 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.
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.
- maternal smoking
- maternal obesity
- thyroid hormones