Toxic metals, essential micronutrients, gestational thyroid hormones, and size at birth

The toxicity of the metals cadmium (Cd), lead (Pb), and methylmercury [MeHg; an organic and very toxic form of mercury (Hg)] in adults have long been recognized. It is also well-established that early-life exposure to Pb and MeHg is associated with neurodevelopmental toxicity. However, effects of commonly occurring low-level exposure from the diet on fetal growth has more recently gained some attention. Also, experimental studies have indicated that Cd, Pb, and MeHg may be endocrine disruptors that can interfere with thyroid function, which in pregnancy is critical for normal fetal development. Fetuses are particularly vulnerable to toxic insult, due to critical development in combination with undeveloped defense mechanisms. Effects on early development, such as impaired fetal growth, may adversely affect child health and have long-term health consequences later in life. Thus, a better understanding of the potential impact of commonly occurring dietary exposure to Cd, Pb, and MeHg on fetal development is of public health relevance.

The overarching aim of this thesis was to clarify if and how dietary exposure to Cd, Pb, and MeHg in pregnancy may influence fetal growth. Specifically, this thesis aimed to elucidate whether maternal metal exposure during pregnancy affect infant birth size. We also assessed the potential influence of both toxic metals and essential micronutrients on maternal thyroid function in pregnancy, which is a critical hormonal system for normal fetal development.

All studies within this thesis are based on data from an ongoing Swedish birth-cohort, called NICE (Nutritional impact on the Immunological maturation during Childhood in relation to the Environment), established in the catchment area of Sunderby hospital in northern Sweden. In total, 655 pregnancies are included in NICE. Recruited women (2015-2018) donated blood and urine in gestational week 27-36, which was used to assess the women’s exposure to metals during pregnancy. Erythrocyte concentrations of Cd, Pb, and total Hg (mainly consisting of MeHg) were measured to assess recent exposure, and Cd was also measured in urine (reflecting long-term exposure). Essential micronutrients were measured in urine (iodine) or plasma (selenium and zinc), all of which are short-term status markers. Thyroid hormones [thyroxine (T4) and triiodothyronine (T3)] and thyroid stimulating hormone (TSH) were measured in plasma. Information on birth anthropometry was obtained from hospital records.

We found that the women’s average exposure to Cd, Pb, and MeHg were low compared to most other populations of pregnant women in Europe, North America, and Asia. However, there were marked variations in all the exposures. In multivariable-adjusted regression analyses, the erythrocyte Cd and Hg concentrations in pregnancy were inversely associated with the infants’ birth weight and birth length, above the concentration of 0.5 μg/kg for Cd and of 1.0 μg/kg for Hg. Further, the women’s urinary Cd concentrations were positively associated with thyroid hormone levels in pregnancy, while erythrocyte Hg concentrations above 1.0 μg/kg were inversely associated with the T3 levels. Mediation analyses suggested that only a small part (about 12%) of the MeHg-birth size relationships was mediated via reduced total T3. We found no associations of maternal Pb exposure with birth size or maternal hormone levels. However, the Pb exposure was very low among most women. In Bayesian kernel machine regression analyses, we did not observe any interactions between the metals in relation to birth size or the maternal hormone levels. The metal-hormone associations appeared to be independent also of the women’s micronutrient status. Iodine and selenium concentrations were low compared to recommended levels. Still, zinc was most prominently associated with the maternal hormone concentrations, highlighting the importance of including other micronutrients than just iodine in studies of thyroid function in pregnancy.

Taken together, the results in this thesis provide evidence that exposure in pregnancy to Cd and MeHg from the Swedish diet may influence size at birth and circulating maternal thyroid hormone levels. For MeHg, these outcomes appeared to be related to a small degree, suggesting that changes in maternal thyroid hormone levels are not the main mode of action in the MeHg-birth size relationship. Further studies are warranted to elucidate the potential implications of these findings on the long-term health of women and children.

List of scientific papers

I. Gustin K, Barman M, Stråvik M, Levi M, Englund-Ögge L, Murray F, Jacobsson B, Sandberg A-S, Sandin A, Wold A E, Vahter M, Kippler M. Low-level maternal exposure to cadmium, lead, and mercury and birth outcomes in a Swedish prospective birth-cohort. (2020) Environmental Pollution. 265(Pt B):114986.
https://doi.org/10.1016/j.envpol.2020.114986

II. Gustin K, Barman M, Skröder H, Jacobsson B, Sandin A, Sandberg A-S, Wold A E, Vahter M, Kippler M. Thyroid hormones in relation to toxic metal exposure in pregnancy, and potential interactions with iodine and selenium. (2021) Environment International. 157:106869.
https://doi.org/10.1016/j.envint.2021.106869

III. Gustin K, Vahter M, Barman M, Jacobsson B, Skröder H, Filipsson Nyström H, Sandin H, Sandberg A-S, Wold A E, Kippler M. Assessment of joint impact of iodine, selenium, and zinc on women’s third-trimester plasma thyroid hormone levels. (2022) The Journal of Nutrition.
https://doi.org/10.1093/jn/nxac081

IV. Gustin K, Ekvall KO, Barman M, Jacobsson B, Sandin A, Sandberg A-S, Wold A E, Vahter M, Kippler M. Mediation by thyroid hormone in the relationships between maternal exposure to methylmercury and birth size. [Submitted]