Iodine Status Modifies the Association between Fluoride Exposure in Pregnancy and Preschool Boys’ Intelligence

In animal studies, the combination of in utero fluoride exposure and low iodine has greater negative effects on offspring learning and memory than either alone, but this has not been studied in children. We evaluated whether the maternal urinary iodine concentration (MUIC) modifies the association between maternal urinary fluoride (MUF) and boys’ and girls’ intelligence. We used data from 366 mother–child dyads in the Maternal–Infant Research on Environmental Chemicals Study. We corrected trimester-specific MUF and MUIC for creatinine, and averaged them to yield our exposure variables (MUF_CRE, mg/g; MUIC_CRE, µg/g). We assessed children’s full-scale intelligence (FSIQ) at 3 to 4 years. Using multiple linear regression, we estimated a three-way interaction between MUF_CRE, MUIC_CRE, and child sex on FSIQ, controlling for covariates. The MUIC_CRE by MUF_CRE interaction was significant for boys (p = 0.042), but not girls (p = 0.190). For boys whose mothers had low iodine, a 0.5 mg/g increase in MUF_CRE was associated with a 4.65-point lower FSIQ score (95% CI: -7.67, -1.62). For boys whose mothers had adequate iodine, a 0.5 mg/g increase in MUF_CRE was associated with a 2.95-point lower FSIQ score (95% CI: -4.77, -1.13). These results suggest adequate iodine intake during pregnancy may minimize fluoride’s neurotoxicity in boys.

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4. Discussion

We examined whether gestational iodine status modifies the association between prenatal fluoride exposure and preschool boys’ and girls’ intelligence in the Maternal Infant Research on Environmental Chemicals (MIREC) Study. To do so, we estimated the three-way interaction between prenatal fluoride exposure, gestational iodine status, and sex on children’s FSIQ.We found that the association between prenatal fluoride exposure and FSIQ was stronger among boys whose mothers had low urinary iodine concentrations in pregnancy compared to boys whose mothers had adequate iodine concentrations in pregnancy. These findings are consistent with previous experimental and human epidemiological studies [27–30,45] and indicate that even mildly reduced iodine levels may have biological significance when interacting with fluoride. Importantly, our findings were observed in a Canadian pregnancy sample with, on average, sufficient iodine intake (median iodine = 294 ?g/g) and with 88% of women taking prenatal multi-vitamins.

Regarding potential mechanisms, experimental evidence demonstrates that prenatal exposure to both high fluoride and low iodine can induce neurochemical changes in offspring. For example, Ge et al., (2011) found that brains of rat offspring exposed to both high fluoride and low iodine in utero had different protein profiles compared with
controls; proteins involved in cellular signaling and metabolism were most affected [46]. Other studies with similar experimental designs found higher levels of superoxide dismutase and malondialdehyde (biomarkers of oxidative stress), apoptosis, and histopathological changes (e.g., elongation of neural dendrites and missing nuclei) in the brains of rat offspring exposed to high fluoride and low iodine compared with those exposed to either alone [29,47,48].

The combination of low iodine and high fluoride may also adversely impact thyroid function. A prior study conducted in Canada showed that higher urinary fluoride levels in adults were associated with higher thyroid stimulating hormone levels, but only among adults who had low urinary iodine concentrations (?0.38 ?mol/L) [49]. One potential mechanism by which fluoride may interact with iodine to affect thyroid function is by inhibiting
one or more enzymes involved in normal thyroid function, such as deiodinases [50]. This would increase the iodine requirement, such that the effect would be more severe in the presence of iodine deficiency. Another common hypothesis is that fluoride displaces thyroidal iodine uptake since it is more electronegative and has a lighter atomic weight than iodine [51].

Experimental studies have also shown that the effects of fluoride may be exacerbated by deficient or excess iodine [52]. For instance, Guan et al. (1988) observed decreases in T3 and T4 among adult Wistar rats with sufficient iodine intake who were exposed to fluoride at a concentration of 30 mg/L [53]. These same changes were observed among iodine-deficient rats who were exposed to fluoride at a lower concentration of only 10 mg/L. Another study with adult mice observed lower levels of triiodothyronine (T3) and thyroxine (T4) among mice with a deficient iodine intake coupled with low fluoride intake when compared with mice with a moderate iodine intake [52]. Thus, the relationship between fluoride exposure and thyroid function may differ as a function of iodine intake.

The impact of fluoride and iodine on thyroid hormones during pregnancy is especially relevant to cognitive abilities in offspring. The fetus is entirely dependent on maternal thyroid hormones until mid-gestation and continues to be partially dependent until birth [54]. Even subtle changes in maternal thyroid hormone levels in pregnancy can have adverse effects on brain structure [55–57] and neurodevelopment [55,56,58]. Low iodine and exposure to higher levels of fluoride in drinking water during pregnancy are both independently associated with a greater risk of developing hypothyroidism [59,60]. Our results are consistent with the combination of low iodine and high fluoride compounding thyroid disruption during fetal development, the most vulnerable period of brain development.

In our study, the interaction between fluoride and iodine was only evident in boys. This finding is consistent with a recent cross-sectional study conducted in China showing that iodine modified the susceptibility of the thyroid gland to fluoride exposure in school-aged boys, but not girls [45]. For boys with lower urinary levels of iodine, higher urinary fluoride was associated with larger thyroid volumes, whereas higher levels of iodine reduced the effects of fluoride on the thyroid. To our knowledge, no study has examined sex-specific effects of the interaction between prenatal fluoride and iodine on neurodevelopmental outcomes, but some epidemiological and animal studies of fluoride neurotoxicity found that boys are more vulnerable to prenatal fluoride exposure than girls [33]. Sex-specific effects in the interaction between fluoride and iodine, particularly among mothers with insufficient iodine intake, may disrupt in utero thyroid hormones. Given that the thyroid gland expresses estrogen and androgen receptors, boys and girls may respond differently to thyroid hormone insufficiency [61–63]. One study, for example, found that maternal trajectories of thyroid hormones were associated with preschool boys’ behavioural development but not girls’ [64]. Taken together, these findings indicate that future investigations of fluoride’s neurotoxicity should examine the roles of iodine intake and child sex, and whether thyroid hormones mediate the pathway for fluoride and iodine’s effects on boys’ IQ.

Strengths and Limitations

Our study has several strengths, including a modest-sized pregnancy cohort, prospective design, state-of-the-art biomarkers of fluoride exposure and iodine status, available information on a wide array of potential maternal and child confounders, and use of standardized and valid measures of child intelligence. Our study also has limitations.
Compared with the general Canadian population, women in the MIREC cohort were more educated, older, predominantly Caucasian, and more likely to be married or in common law relationships [34], which may limit the generalizability of our findings. The high use of prenatal multivitamins in our sample likely reduced the risk of moderate-to-severe iodine deficiency which may be observed in other populations. Even though we used state-of-  the-art biomarkers, fluoride and iodine both have short half-lives and could therefore be impacted by recent fluoride or iodine ingestion. Further, we measured iodine and fluoride in urine spot samples instead of 24 h urine samples. We attempted to minimize this limitation by averaging urine fluoride across all three trimesters of pregnancy, and urine iodine across two trimesters of pregnancy. Nonetheless, we acknowledge that up to ten repeat spot urine samples may be needed to accurately reflect individual iodine status [65].

5. Conclusions

This is the first prospective epidemiological study to estimate the interplay between prenatal fluoride exposure and maternal iodine status in relation to child IQ in boys and girls. Our findings indicate that the association between prenatal fluoride exposure and fullscale intelligence previously identified in this cohort [6] was exacerbated by low maternal iodine in pregnancy among boys. These results, which were found among mother-child pairs living in fluoridated and non-fluoridated communities in Canada, underscore the importance of sufficient iodine intake in pregnancy to minimize the neurotoxicity of fluoride in boys.

Funding: This research was funded by National Institute of Environmental Health Science, grant
numbers R21ES027044, 2016–2019; R01ES030365, 2020–2025 and the Maternal-Infant Research on
Environmental Chemicals Study was funded by the Chemicals Management Plan at Health Canada,
the Ontario Ministry of the Environment, and the Canadian Institute for Health Research, grant
number MOP-81285, 2006).

*Full text study online at https://www.mdpi.com/2072-6643/14/14/2920/html