Impact of prenatal manganese and selenium exposure on childhood thyroid hormone parameters up to 4 years of age: Japan environment and children's study.

Thyroid hormones are essential for fetal and early childhood development. Manganese (Mn) and selenium (Se) are involved in thyroid hormone homeostasis; however, the effects of prenatal Mn and Se exposure on thyroid function in offspring remain unclear. We analyzed 1,773 mother-child pairs from the Japan Environment and Children's Study, measuring Mn and Se in maternal whole blood during the second or third trimester and in cord blood at delivery. Neonatal thyroid-stimulating hormone (TSH) was measured on postnatal days 4-6, whereas plasma TSH and free thyroxine (FT4) were measured at ages 2 and 4 years. Log2-transformed exposure and outcome values were analyzed using multivariable linear regression, quartile models, restricted cubic spline analyses, and repeated-measures generalized estimating equation models. Cord-blood Mn was inversely associated with neonatal TSH, with adjusted β values (95% confidence interval) of -0.226 (-0.364 to -0.089) overall, -0.411 (-0.608 to -0.214) in males, and -0.031 (-0.225 to 0.163) in females. Quartile analyses supported this inverse pattern, particularly in males: the adjusted β values for the highest versus lowest quartil of cord-blood Mn were -0.210 (-0.361 to -0.059) overall and -0.436 (-0.658 to -0.214) in males. Repeated-measures, quartile, and nonlinear analyses partially supported an inverse or non-monotonic cord-blood Mn-TSH pattern across follow-up ages, although the findings at ages 2 and 4 years were weaker and less consistent. Maternal-blood Mn showed similar but weaker inverse associations with TSH, whereas maternal- and cord-blood Se showed no consistent associations with TSH or FT4. Higher prenatal Mn exposure, particularly cord-blood Mn, was associated with lower neonatal TSH levels, especially in males. Further studies are needed to clarify the clinical and public health relevance of these findings.