Around half of expectant mothers worldwide are overweight or obese and 20% smoke. Exposure to such factors during fetal life is linked to diseases including obesity, cardiovascular disease, and behavioural disorders. Because thyroid hormones control fetal metabolism, cardiac output and brain development, altered fetal thyroid signalling can contribute to future disease. We examined the impact of maternal smoking and overweight/obese (body mass index, BMI, ≥25) on the thyroid system in 2nd trimester human fetal tissues from normally progressing, electively-terminated pregnancies. We measured circulating thyroid hormones (THs), thyroid-stimulating hormone (TSH), and thyroid hormone-binding proteins, scored thyroid histology and examined the expression of developmentally-relevant proteins and transcripts in the human fetus and quantified TH transporter and signalling proteins and transcripts in placental plasma membrane preparations and fetal livers extracts. The fetal thyroid system is sexually dimorphic: male thyroids appeared more immature, lacking developmentally increased PAX8. The developmental increase of thyroid sodium-iodide importer NIS and a developmental decrease of the major placental TH transporter LAT1, in male fetuses only, suggest reduced reliance on maternal TH supply and increased fetal TH synthesis. Further, higher circulating triiodothyronine (T3) levels and reduced liver DIO3 transcript in males indicate decreased peripheral degradation of T3. Maternal smoke exposure increased the developmental trajectory of fetal circulating thyroxine and altered the developmental trajectory of TSH, reversed the negative T4:TSH correlation and decreased PAX8 staining in female fetuses. Fetal thyroids from high BMI mothers were heavier, had reduced PAX8 staining and, in female fetuses, thyroids appeared more immature. Circulating TSH was higher in female fetuses from high BMI mothers. In conclusion, we showed that physiologically the fetal thyroid system is highly sexually dimorphic and responds to maternal smoking and high maternal BMI in a sex-specific manner. Our findings imply that management of the fetal thyroid function in children at risk may minimize predisposition to disease.
18 May 2019 - 21 May 2019