Urinary Concentrations of Phthalate Metabolite Mixtures in Relation to Serum Biomarkers of Thyroid Function and Autoimmunity among Women from a Fertility Center.

BACKGROUND: Although previous epidemiological studies have explored associations of phthalate metabolites with thyroid function, no studies to date have assessed associations of mixtures with thyroid function and autoimmunity among potentially susceptible subgroups such as subfertile women. OBJECTIVE: We aimed to explore associations of mixtures of urinary phthalate metabolites with serum markers of thyroid function and autoimmunity. METHODS: This cross-sectional study included 558 women attending a fertility center who provided one spot urine and one blood sample at enrollment (2005-2015). We quantified urinary concentrations of eight phthalate metabolites using mass spectrometry, and biomarkers of thyroid function [thyroid-stimulating hormone (TSH), free and total thyroxine (fT4, TT4) and triiodothyronine (fT3, TT3), and autoimmunity [thyroid peroxidase and thyroglobulin antibodies (TPOAb and TgAb, respectively)] in serum using electrochemiluminescence assays. We applied principal component analysis (PCA) and Bayesian kernel machine regression (BKMR) to identify the main patterns of urinary phthalate metabolites. We used linear mixed models to assess the association between PCA-derived factor scores in quintiles and serum thyroid function and autoimmunity, adjusting for age, body mass index (BMI), specific gravity (SG), and, for the PCA, other factor scores. RESULTS: We observed two factors using PCA, one representing the di(2-ethylhexyl) (DEHP) and another non-DEHP metabolites. Compared to women in the lowest quintile of the DEHP factor scores, women in the highest quintile had significantly lower serum concentrations of fT4, TT4, fT3, and TT3 [absolute difference: -0.62; 95% confidence interval (CI): -0.12, -0.01; p=0.04; absolute difference: -8.31; 95% CI: -13.8, -2.85; p=0.003; absolute difference: -0.37; 95% CI: 0.54, -0.19; p<0.0001; and absolute difference: -0.21; 95% CI: -0.32, -0.10; p=0.003, respectively]. Using BKMR, we observed that mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) was the primary contributor to these negative associations. DEHP and non-DEHP factor scores were not associated with serum TSH, TgAb, or TPOAb. CONCLUSIONS: Mixtures of urinary DEHP metabolites were inversely associated with serum biomarkers of thyroid function but not with autoimmunity, which were within normal ranges for healthy adult women. https://doi.org/10.1289/EHP6740.

The Association of Maternal Iodine Status in Early Pregnancy with Thyroid Function in the Swedish Environmental Longitudinal, Mother and Child, Asthma and Allergy Study.

Background: Severe maternal iodine deficiency can impact fetal brain development through effects on maternal and/or fetal thyroid hormone availability. The effects of mild-to-moderate iodine deficiency on thyroid function are less clear. The aim was to investigate the association of maternal urinary iodine concentration corrected for creatinine (UI/Creat) with thyroid function and autoantibodies in a mild-to-moderate iodine-deficient pregnant population. Methods: This study was embedded within the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study. Clinical reference ranges were determined by the 2.5th and 97.5th population-based percentile cutoffs. The associations of UI/Creat with thyrotropin (TSH), free thyroxine (fT4), free triiodothyronine (fT3), total T4 (TT4), and total T3 (TT3) were studied using multivariable linear regression in thyroid peroxidase antibody (TPOAb)-negative women. The association of UI/Creat with TPOAb and thyroglobulin antibody (TgAb) positivity was analyzed using multivariable logistic regression. Results: Urinary iodine and thyroid function were measured at a median (95% range) gestational age of 10 (6-14) weeks in 2009 women. The median (95% range) UI/Creat was 85 µg/g (36-386) and the UI/Creat was below 150 µg/g in 80.1% of women. Reference ranges did not differ substantially by UI/Creat. A lower UI/Creat was associated with a lower TSH (p = 0.027), a higher TT4 (p = 0.032), and with a corresponding trend toward slightly higher fT4 (p = 0.081), fT3 (p = 0.079), and TT3 (p = 0.10). UI/Creat was not associated with the fT4/fT3 (p = 0.94) or TT4/TT3 ratios (p = 0.63). Women with a UI/Creat of 150-249 µg/g had the lowest prevalence of TPOAb positivity (6.1%), while women with a UI/Creat of <150 µg/g had a higher prevalence (11.0%, odds ratio [OR] confidence interval [95% CI] 1.84 [1.07-3.20], p = 0.029). Women with a UI/Creat ≥500 µg/g showed the highest prevalence and a higher risk of TPOAb positivity, however, only a small proportion of women had such a UI/Creat (12.5%, OR, [95% CI] 2.36 [0.54-10.43], p = 0.26). Conclusions: We could not identify any meaningful differences in thyroid function reference ranges. Lower iodine availability was associated with a slightly lower TSH and a higher TT4. Women with adequate iodine intake had the lowest risk of TPOAb positivity.

Cross-sectional associations between urinary triclosan and serum thyroid function biomarker concentrations in women.

INTRODUCTION: Exposure to the antimicrobial agent triclosan is ubiquitous. Research in animals shows that triclosan can cause decreases in thyroxine concentrations. However, the potential effects of triclosan on thyroid function in humans are unclear. OBJECTIVE: To estimate the association between urinary triclosan concentrations and serum thyroid function biomarkers in women seeking assisted reproduction treatment in the Environment and Reproductive Health (EARTH) Study. METHODS: We conducted a cross-sectional study of 317 women enrolled in the EARTH Study, a prospective preconception cohort that recruits Boston area couples. Using samples collected at study entry, we quantified urinary triclosan and serum thyroid function biomarker concentrations, specifically free and total thyroxine and triiodothyronine, thyroid-stimulating hormone (TSH), and thyroid antibodies. We estimated covariate-adjusted differences in thyroid function biomarkers per 10-fold increase in triclosan using linear regression models. We examined effect modification by body mass index (BMI) and infertility diagnosis. RESULTS: The median urinary triclosan concentration was 7.8 µg/L (IQR: 3.0-59 µg/L). Each 10-fold increase in triclosan was inversely associated with free triidothyronine (T3) (ß: -0.06 pg/mL; 95% CI: -0.1, -0.01), thyroperoxidase antibody (TPOAb) (-10%; 95% CI: -19, -0.4), and thyroglobulin antibody (TgAb) (-12%; 95% CI: -23,0.9) concentrations. BMI and infertility diagnosis modified the association of triclosan with free T3 and TPOAb, respectively. CONCLUSION: Urinary triclosan concentrations were inversely associated with specific serum thyroid function biomarkers in this cohort, suggesting that triclosan may affect thyroid homeostasis and autoimmunity.

Dibutyl-phthalate exposure from mesalamine medications and serum thyroid hormones in men.

BACKGROUND: Dibutyl phthalate (DBP) is an endocrine disruptor and used in some medication coatings, such as mesalamine for treatment inflammatory bowel disease (IBD). OBJECTIVES: To determine whether high-DBP from some mesalamine medications alters thyroid function. METHODS: Seventy men with IBD, without thyroid disease or any radiation history participated in a crossover-crossback prospective study and provided up to 6 serum samples (2:baseline, 2:crossover, 2:crossback). Men on non-DBP mesalamine (background exposure) at baseline crossed-over to DBP-mesalamine (high exposure) then crossed-back to non-DBP mesalamine (B1HB2-arm) and vice versa for men on DBP-mesalamine at baseline (H1BH2-arm). Serum concentrations of total triiodothyronine (T3), total thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb). RESULTS: After crossover in B1HB2-arm (26 men, 134 samples), T3 decreased 10% (95% confidence interval (CI): 14%,-5%), T3/T4 ratio decreased 8% (CI: 12%,-3%), TPOAb, and TgAb concentrations decreased, 11% (-20%, -2%) and 15% (-23%, -5%), respectively; after crossback, they increased. When men in the H1BH2-arm (44 men, 193 samples) crossed-over, T3 decreased 7% (CI: -11%, -2%) and T3/T4 ratio decreased 6% (CI: -9%, -2%). After crossback, only TgAb increased and FT4 decreased. CONCLUSIONS: High-DBP novel exposure or removal from chronic high-DBP exposure could alter elements of the thyroid system, and most probably alters the peripheral T4 conversion to T3 and thyroid autoimmunity, consistent with thyroid disruption. After exposure removal, these trends were mostly reversed.

Reference Ranges and Determinants of Thyroid Function During Early Pregnancy: The SELMA Study.

Context: Establishing reference ranges as well as identifying and quantifying the determinants of thyroid function during pregnancy is important for proper clinical interpretation and optimizing research efforts. However, such data are sparse, specifically for triiodothyronine measurements, and most studies do not take into account thyroid antibodies or human chorionic gonadotropin. Objective: To determine reference ranges and to identify/quantify determinants of TSH, free T4 (FT4), free triiodothyronine (FT3), total T4 (TT4), and total triiodothyronine (TT3). Design, Setting, and Participants: This study included 2314 participants of the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy study, a population-based prospective pregnancy cohort of mother-child pairs. Reference ranges were calculated by 2.5th to 97.5th percentiles after excluding thyroperoxidase antibody (TPOAb)-positive and/or thyroglobulin antibody (TgAb)-positive women. Intervention: None. Main Outcome Measures: TSH, FT4, FT3, TT4, and TT3 in prenatal serum. Results: After exclusion of TPOAb-positive women, reference ranges were as follows: TSH, 0.11 to 3.48 mU/L; FT4, 11.6 to 19.4 pmol/L; FT3, 3.72 to 5.92 pg/mL; TT4, 82.4 to 166.2 pmol/L; and TT3, 1.28 to 2.92 nmol/L. Additional exclusion of TgAb-positive women did not change the reference ranges substantially. Exposure to tobacco smoke, as assessed by questionnaires and serum cotinine, was associated with lower TSH and higher FT3 and TT3. Body mass index (BMI) and gestational age were the main determinants of TSH (only for BMI), FT4, FT3, TT4, and TT3. Conclusions: We show that the exclusion of TgAb-positive women on top of excluding TPOAb-positive women hardly affects clinical reference ranges. We identified various relevant clinical determinants of TSH, FT4, FT3, TT4, and TT3 that could reflect endocrine-disrupting effects and/or effects on thyroid hormone transport or deiodination.

Association of Thyroid Function and Autoimmunity with Ovarian Reserve in Women Seeking Infertility Care.

BACKGROUND: While overt thyroid disease is a well known risk factor for infertility, the potential consequences of mild thyroid dysfunction or thyroid autoimmunity remain unknown. Experimental studies suggest a considerable role for thyroid hormone in the physiological mechanisms of ovarian reserve, but translation of such findings to human studies remains rare. A potential role for thyroid function in female reproduction could be especially relevant when the cause of infertility remains unknown, such as in women with diminished ovarian reserve (DOR) or unexplained infertility. The aims of this study were to investigate the association of thyroid function and autoimmunity with markers of ovarian reserve day 3 follicle-stimulating hormone (FSH) concentrations and antral follicle count (AFC), and to investigate whether thyroid function or autoimmunity may have different effects in women with DOR or unexplained infertility. METHODS: Thyrotropin, free thyroxine, thyroxine, free triiodothyronine (fT3), triiodothyronine, thyroid peroxidase antibodies (TPOAbs), and thyroglobulin antibodies (TgAbs), as well as AFC and the day 3 FSH concentration, were measured among women seeking fertility treatment at the Massachusetts General Hospital Fertility Center. Multiple linear or mixed regression models were used to study the association of thyroid function or autoimmunity with AFC or day 3 FSH. RESULTS: In the total study population (436 women, 530 AFC measurements), there was no association of thyroid function or TPOAb positivity with AFC. However, TgAb positivity was associated with a higher AFC (mean difference = 3.4 [95% confidence interval (CI) 1.8-5.1], p < 0.001). In women with DOR or unexplained infertility, lower fT3 and TPOAb positivity were associated with a lower AFC (fT3: continuous nonlinear association, p = 0.009; TPOAb positivity: -2.3 follicles [confidence interval -3.8 to -0.5], p = 0.01), while TgAb positivity was not associated with AFC. Neither thyroid function nor thyroid antibody positivity was associated with the day 3 FSH concentration. CONCLUSIONS: This study found that lower fT3 and TPOAb positivity are associated with a lower AFC in women with DOR or unexplained infertility. Future studies are required to replicate these findings and further elucidate the role of TgAbs and underlying mechanisms through which thyroid function and autoimmunity is associated with ovarian reserve.