Factors Modifying the Biological Impact of Maternal Thyroid Function

Maternal and fetal deiodinases. Deiodinase type 1 (located in cell plasma

membranes) and deiodinase type 2 (located in the endoplasmic reticulum of cells) both mainly convert T4 to the more biologically active thyroid hormone T3. Deiodinase type 1 is expressed in the liver, kidney, gut, lungs, thyroid, pituitary,78,91 _{and possibly the placenta.}88 _{There is minimal} evidence that deiodinase type 1 is expressed in the fetus sufficiently early in gestation to

influence the effect of maternal thyroid function on fetal neurodevelopment. Deiodinase type 2 is expressed in the pituitary, brain, brown adipose tissue, adrenal, liver, thyroid, heart, skeletal muscle,78,91 _{as well as in maternal uterine decidual cells}92 _{and in the fetal cerebral cortex.}86,87

Deiodinases modify the local intracellular levels of thyroid hormones, affecting the concentration of T3 that is available to influence gene expression within cells.83,93,94 _{In this way,} deiodinases modify the association between circulating levels of thyroid hormones and their biological impact: intracellular T3 availability can vary somewhat independently from T3 levels circulating in the bloodstream. That being said, T3 produced by deiodinases can be released back into circulation.93 _{In fact, the main source of circulating T3 comes from local conversion of} T4 to T3 by deiodinases, and not synthesis in the thyroid hormone gland.94

Therefore, deiodinase activity in the maternal liver, for example, would not be expected to modify the association between circulating maternal thyroid function biomarkers and fetal neurodevelopment because deiodinases in the liver would directly affect maternal circulating thyroid function biomarkers. In other words, maternal thyroid function biomarker levels would be an intermediate variable on the path from maternal deiodinase activity and fetal

neurodevelopment. However, maternal deiodinases in the placenta—which consists of both maternal and fetal cells and is a place of maternal-fetal transfer—could possibly alter the supply of maternal thyroid hormones that reach the fetus, independent of circulating maternal levels. Maternal deiodinase type 2 is expressed in maternal uterine decidual cells, which form the maternal portion of the placenta.92 _{The presence of deiodinase type 1 in the placenta is}

15 debated.95

Deiodinase type 2 and deiodinase type 3 (the deactivating deiodinase) are expressed in the fetus, with deiodinase type 2 expression occurring in the fetal cerebral cortex as early as 7 weeks’ gestation.86,87 _{Mostly maternal T4 is transferred to the fetus, where it can be converted to} the more biologically active T3 by fetal deiodinase type 2.85 _{Thus, fetal deiodinase type 2 may} modify the association between circulating maternal thyroid function biomarkers and fetal neurodevelopment.

Maternal Iodine and Selenium Intake. Nutritional elements iodine and selenium influence the synthesis of thyroid hormones in the thyroid gland as well as the conversion of thyroid hormones by deiodinases. Iodine can be found in small amounts in natural sources such as seafood, water, and some vegetables, whereas selenium can be found in fish, eggs, meat, mushroom, and cereals.96 _{The selenium level in crops is partly dependent on soil content, which} varies geographically and seasonally.97

Iodine deficiency is the most common preventable cause of neurocognitive deficits worldwide.98 _{To combat the adverse outcomes associated with iodine deficiency, many countries} (including Norway) fortify table salt.99 _{Yet, even in countries with universal salt iodization,} iodine insufficiency persists, and iodine deficiency remains the most common cause of endocrine disorders.100 _{Women who are pregnant are at a higher risk of iodine deficiency for} three main reasons.69 _{First, there is an increased synthesis of T3 and T4 during pregnancy} (particularly during the first trimester), and iodine is required for this synthesis. Second, the renal clearance of iodine is greater in pregnant women compared to those who are not pregnant. Third, some of the maternal iodine supply is transferred to the fetus.69 _{Because of these reasons,} pregnant women require approximately 50% more iodine than those who are not pregnant.69

Iodine deficiency alters thyroid hormone synthesis and conversion. When iodine levels are insufficient, the thyroid gland synthesizes relatively more T3 and less T4, leading to

up-regulated (and deiodinase type 3 is downregulated) in the central nervous sytem.102 _This altered regulation would have the effect of converting more T4 to the more biologically active T3.

Selenium is a constituent of deiodinase enzymes, making it essential for the local conversion of thyroid hormones.98 _{Like iodine, selenium requirements increase during} pregnancy, with 60 µg/day intake recommended for women who are pregnant.103 _Selenium supplementation is associated with reduced thyroid peroxidase antibodies, allowing for more thyroid hormone synthesis.104–106 _{Selenium supplementation is also associated with increased} deiodinase activity leading to higher levels of T3,107 _{while selenium deficiency is associated with} increased T4 and decreased T3 levels. Whereas iodine deficiency has been recognized as an important preventable threat to fetal and child development, selenium deficiency is relatively understudied.

Fetal/Child Sex. There are a number of mechanisms that might lead to sex-related differences in maternal thyroid function’s effect on neurodevelopment. First, as early as 3 weeks post-fertilization, maternal serum human chorionic gonadotropin (hCG) levels are higher in pregnant women carrying female than male fetuses.108 _{Because hCG is structurally similar to} TSH and thus also stimulates thyroid hormone synthesis, the sexually dimorphic levels of hCG may differentially alter the balance of maternal TSH, T4, and T3 by fetal sex. Second, animal research has demonstrated that sex hormones can affect deiodinase activity.109 _Different deiodinase activity in male versus female fetuses could lead to different local T3 availability to male versus female fetuses, modifying the association between maternal thyroid function and fetal neurodevelopment.

Attention deficit disorder is more commonly diagnosed in male children, and the most frequently subtype of ADHD diagnosis varies by sex: male children are more likely to be diagnosed with the hyperactive/inattentive subtype whereas female children are more likely to be diagnosed with the inattention subtype.13–15 _{Part of this this sex difference may be due to}

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cultural norms and expectations regarding the behavior of male and female children. However, part of this difference may also reflect biological mechanisms such as the interaction of hCG, sex hormones, and thyroid hormones during gestation.