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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2012

Comparative study on 2,2′,4,5,5′-pentachlorobiphenyl-mediated decrease in serum thyroxine level between C57BL/6 and its transthyretin-deficient mice

The relationships between the changes in the levels of serum total thyroxine (T{sub 4}), serum T{sub 4}-transthyretin (TTR) complex, and accumulation of T{sub 4} in tissues by 2,2′,4,5,5′-pentachlorobiphenyl (PentaCB) were examined using wild-type C57BL/6 (WT) and its TTR-deficient (TTR-null) mice. The constitutive level of serum total T{sub 4} was much higher in WT mice than in TTR-null mice. In WT mice 4 days after a single intraperitoneal injection with PentaCB (112 mg/kg), serum total T{sub 4} level was significantly decreased along with a decrease in serum T{sub 4}–TTR complex, and the levels of serum total T{sub 4} in the PentaCB-treated WT mice were almost the same to those in PentaCB-untreated (control) TTR-null mice. In addition, a slight decrease in serum total T{sub 4} by PentaCB treatment was observed in TTR-null mice. Furthermore, clearance of [{sup 125}I]T{sub 4} from the serum after [{sup 125}I]T{sub 4}-administration was promoted by the PentaCB-pretreatment in either strain of mice, especially WT mice. On the other hand, accumulation level of [{sup 125}I]T{sub 4} in the liver, but not in extrahepatic tissues, was strikingly enhanced in the PentaCB-pretreated WT and TTR-null mice. Furthermore, in both strains of mice, PentaCB-pretreatment led to significant increases in the steady-state distribution volume of [{sup 125}I]T{sub 4} and the concentration ratio of the liver to serum. The present findings demonstrate that PentaCB-mediated decrease in serum T{sub 4} level occurs mainly through increase in accumulation level of T{sub 4} in the liver and further indicate that the increased accumulation of T{sub 4} in the liver of WT mice is primarily dependent on the PentaCB-mediated inhibition of serum T{sub 4}–TTR complex formation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Combined effects of perchlorate, thiocyanate, and iodine on thyroid function in the National Health and Nutrition Examination Survey 2007–08

Perchlorate, thiocyanate, and low iodine intake can all decrease iodide intake into the thyroid gland. This can reduce thyroid hormone production since iodide is a key component of thyroid hormone. Previous research has suggested that each of these factors alone may decrease thyroid hormone levels, but effect sizes are small. We hypothesized that people who have all three factors at the same time have substantially lower thyroid hormone levels than people who do not, and the effect of this combined exposure is substantially larger than the effects seen in analyses focused on only one factor at a time. Using data from the 2007–2008 National Health and Nutrition Examination Survey, subjects were categorized into exposure groups based on their urinary perchlorate, iodine, and thiocyanate concentrations, and mean serum thyroxine concentrations were compared between groups. Subjects with high perchlorate (n=1939) had thyroxine concentrations that were 5.0% lower (mean difference=0.40 μg/dl, 95% confidence interval=0.14–0.65) than subjects with low perchlorate (n=2084). The individual effects of iodine and thiocyanate were even smaller. Subjects with high perchlorate, high thiocyanate, and low iodine combined (n=62) had thyroxine concentrations 12.9% lower (mean difference=1.07 μg/dl, 95% confidence interval=0.55–1.59) than subjects with low perchlorate, low thiocyanate, and adequate iodine (n=376). Potential confounders had little impact on results. Overall, these results suggest that concomitant exposure to perchlorate, thiocyanate, and low iodine markedly reduces thyroxine production. This highlights the potential importance of examining the combined effects of multiple agents when evaluating the toxicity of thyroid-disrupting agents. -- Highlights: ► Recent data suggest that essentially everyone in the US is exposed to perchlorate. ► Perchlorate exposure may be associated with lower thyroid hormone levels. ► Some groups may be more susceptible to perchlorate than others.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Normal Tissue Complication Probability Modeling of Radiation-Induced Hypothyroidism After Head-and-Neck Radiation Therapy

Purpose: To determine the dose-response relationship of the thyroid for radiation-induced hypothyroidism in head-and-neck radiation therapy, according to 6 normal tissue complication probability models, and to find the best-fit parameters of the models. Methods and Materials: Sixty-five patients treated with primary or postoperative radiation therapy for various cancers in the head-and-neck region were prospectively evaluated. Patient serum samples (tri-iodothyronine, thyroxine, thyroid-stimulating hormone [TSH], free tri-iodothyronine, and free thyroxine) were measured before and at regular time intervals until 1 year after the completion of radiation therapy. Dose-volume histograms (DVHs) of the patients' thyroid gland were derived from their computed tomography (CT)-based treatment planning data. Hypothyroidism was defined as increased TSH (subclinical hypothyroidism) or increased TSH in combination with decreased free thyroxine and thyroxine (clinical hypothyroidism). Thyroid DVHs were converted to 2 Gy/fraction equivalent doses using the linear-quadratic formula with {alpha}/{beta} = 3 Gy. The evaluated models included the following: Lyman with the DVH reduced to the equivalent uniform dose (EUD), known as LEUD; Logit-EUD; mean dose; relative seriality; individual critical volume; and population critical volume models. The parameters of the models were obtained by fitting the patients' data using a maximum likelihood analysis method. The goodness of fit of the models was determined by the 2-sample Kolmogorov-Smirnov test. Ranking of the models was made according to Akaike's information criterion. Results: Twenty-nine patients (44.6%) experienced hypothyroidism. None of the models was rejected according to the evaluation of the goodness of fit. The mean dose model was ranked as the best model on the basis of its Akaike's information criterion value. The D{sub 50} estimated from the models was approximately 44 Gy. Conclusions: The implemented normal tissue complication probability models showed a parallel architecture for the thyroid. The mean dose model can be used as the best model to describe the dose-response relationship for hypothyroidism complication.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Number, Proliferative Activity, and Expression of Thyroid Hormone Receptors in Dermal Fibroblasts in Mice with Changed Thyroid Status

We studied the intensity of age-specific changes in the dermis (number and proliferative activity of fibroblasts) in mice with normal and experimentally changed level of thyroid hormones. Receptors of thyroid hormones, TR-α and TR-β, in mouse dermal fibroblasts were identified by immunohistochemical methods. The relative expression of Thra, Thrb, and Dio2 genes was assessed by real-time PCR analysis. From the second to fifth month of life, the number of fibroblasts in the connective tissue layer of mouse skin decreased by 42.3%. The number of fibroblasts in the dermis of 5-month-old mice treated with Thyrozol significantly decreases by 25.9% (p<0.05), and vice versa, in mice receiving thyroxin this parameter increased by 4.7% in comparison with the control (p>0.05). TR-α and TR-β were identified in dermal fibroblasts in all groups of mice. No differences in the content TR-α and Thra gene expression in 2- and 5-month-old mice of the control and experimental were revealed. TR-β content in dermal fibroblasts of 2-month-old animals was maximum and exceeded this value in 5-month-old control mice by 25%. The number of these receptors decreased by 33.3% in mice treated with Thyrozol and increased by 25% in animals receiving thyroxin injection in comparison with the control. Relative expression of Thrb gene significantly increased only in mice treated with thyroxin. Comparative analysis of the relative expression of Dio2 gene revealed no differences between the experimental and control groups. Changes in the level of thyroid hormones, content of TR-β, and relative Thrb gene expression contribute to agerelated shifts in the number and proliferative activity of mouse dermal fibroblasts.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Association between thyroid profile and perfluoroalkyl acids: Data from NHNAES 2007–2008

The effect of six perfluoroalkyl acids (PFAAs), namely, perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDE), perfluorohexane sulfonic acid (PFHxS), 2-(N-methyl-perfluorooctane sulfonamide) acetic acid (MPAH), and perfluorononanoic acid (PFNA) on the levels of six thyroid function variables, namely, thyroid stimulating hormone (TSH), free and total thyroxine (FT4, TT4), free and total triiodothyronine (FT3, TT3), and thyroglobulin (TGN) was evaluated. Data from National Health and Nutrition Examination Survey for the years 2007–2008 were used for this evaluation. TSH levels increased with increase in levels of PFOA (p<0.01). There were no statistically significant associations between the levels of FT3, and FT4 with the levels of any of the six PFAAs. Levels of TT3 were found to increase with the levels of PFOA (p=0.01) and TT4 levels were found to increase with increase in PFHxS levels (p<0.01). Males had statistically significantly higher levels of FT3 than females and females had statistically significantly higher levels of TT4 than males. As compared to non-Hispanics whites and Hispanics, non-Hispanic blacks had lower levels of TSH, FT3, TT3, and TT4 but Hispanics had the lowest levels of TGN. Age was negatively associated with FT3 and TT3 but positively associated with FT4 and TT4. Non-smokers had higher levels of TSH and TT4 than smokers and smokers had higher levels of FT3 and TGN than non-smokers. Iodine deficiency was associated with increased levels of TSH, TT3, TT4, and TGN. -- Highlights: • Levels of total triiodothyronine were found to increase with the levels of PFOA. • Total thyroxine increased with increase in levels of perfluorohexane sulfonic acid. • There was a positive association between the levels of PFOA and TSH. • Iodine deficiency was associated with elevated levels of TSH, total T3 and T4. • Iodine deficiency was associated with elevated levels of thyroglobulin.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Sperm quality biomarkers complement reproductive and endocrine parameters in investigating environmental contaminants in common carp (Cyprinus carpio) from the Lake Mead National Recreation Area

Highlights: • Reproductive and endocrine biomarkers were differentially altered in carp in Lake Mead National Recreational Area. • Sex steroid hormone, sperm motility, and vitellogenin biomarker data pointed to lessened endocrine disrupting effects in 2006 versus late 1990's. • Among sub-basins, fish in Gregg Basin were least affected by endocrine disrupting compounds. • Compounds indicating risks in LMNRA included galaxolide, methyl triclosan, polybrominated diphenyl ether-47, hexachlorobenzene, and polychlorinated biphenyls. • Male germplasm provides pertinent cell and molecular biomarkers for endocrine disrupting compound studies. Lake Mead National Recreational Area (LMNRA) serves as critical habitat for several federally listed species and supplies water for municipal, domestic, and agricultural use in the Southwestern U.S. Contaminant sources and concentrations vary among the sub-basins within LMNRA. To investigate whether exposure to environmental contaminants is associated with alterations in male common carp (Cyprinus carpio) gamete quality and endocrine- and reproductive parameters, data were collected among sub-basins over 7 years (1999–2006). Endpoints included sperm quality parameters of motility, viability, mitochondrial membrane potential, count, morphology, and DNA fragmentation; plasma components were vitellogenin (VTG), 17ß-estradiol, 11-keto-testosterone, triiodothyronine, and thyroxine. Fish condition factor, gonadosomatic index, and gonadal histology parameters were also measured. Diminished biomarker effects were noted in 2006, and sub-basin differences were indicated by the irregular occurrences of contaminants and by several associations between chemicals (e.g., polychlorinated biphenyls, hexachlorobenzene, galaxolide, and methyl triclosan) and biomarkers (e.g., plasma thyroxine, sperm motility and DNA fragmentation). By 2006, sex steroid hormone and VTG levels decreased with subsequent reduced endocrine disrupting effects. The sperm quality bioassays developed and applied with carp complemented endocrine and reproductive data, and can be adapted for use with other species.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2014

Tris(2-butoxyethyl)phosphate and triethyl phosphate alter embryonic development, hepatic mRNA expression, thyroid hormone levels, and circulating bile acid concentrations in chicken embryos

The organophosphate flame retardants tris(2-butoxyethyl) phosphate (TBOEP) and triethyl phosphate (TEP) are used in a wide range of applications to suppress or delay the ignition and spread of fire. Both compounds have been detected in the environment and TBOEP was recently measured in free-living avian species. In this study, TBOEP and TEP were injected into the air cell of chicken embryos at concentrations ranging from 0 to 45,400 ng/g and 0 to 241,500 ng/g egg, respectively. Pipping success, development, hepatic mRNA expression of 9 target genes, thyroid hormone levels, and circulating bile acid concentrations were determined. Exposure to the highest doses of TBOEP and TEP resulted in negligible detection of the parent compounds in embryonic contents at pipping indicating their complete metabolic degradation. TBOEP exposure had limited effects on chicken embryos, with the exception of hepatic CYP3A37 mRNA induction. TEP exposure decreased pipping success to 68%, altered growth, increased liver somatic index (LSI) and plasma bile acids, and modulated genes associated with xenobiotic and lipid metabolism and the thyroid hormone pathway. Plasma thyroxine levels were decreased at all TEP doses, including an environmentally-relevant concentration (8 ng/g), and gallbladder hypotrophy was evident at ≥ 43,200 ng/g. Tarsus length and circulating thyroxine concentration emerged as potential phenotypic anchors for the modulation of transthyretin mRNA. The increase in plasma bile acids and LSI, gallbladder hypotrophy, and discoloration of liver tissue represented potential phenotypic outcomes associated with modulation of hepatic genes involved with xenobiotic and lipid metabolism. - Highlights: • TBOEP is not embryolethal to chicken embryos. • TEP affected embryonic viability, morphometric endpoints, and thyroid hormone levels. • TEP altered mRNA levels of xenobiotic and lipid metabolism genes. • TEP increased plasma bile acids and caused gallbladder hypotrophy. • TEP elicited more adverse molecular and phenotypic effects than TBOEP.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Estimation of iodine nutrition and thyroid function status in late-gestation pregnant women in the United States: Development and application of a population-based pregnancy model

Previously, a deterministic biologically-based dose-response (BBDR) pregnancy model was developed to evaluate moderate thyroid axis disturbances with and without thyroid-active chemical exposure in a near-term pregnant woman and fetus. In the current study, the existing BBDR model was adapted to include a wider functional range of iodine nutrition, including more severe iodine deficiency conditions, and to incorporate empirically the effects of homeostatic mechanisms. The extended model was further developed into a population-based model and was constructed using a Monte Carlo-based probabilistic framework. In order to characterize total (T4) and free (fT4) thyroxine levels for a given iodine status at the population-level, the distribution of iodine intake for late-gestation pregnant women in the U.S was reconstructed using various reverse dosimetry methods and available biomonitoring data. The range of median (mean) iodine intake values resulting from three different methods of reverse dosimetry tested was 196.5–219.9 μg of iodine/day (228.2–392.9 μg of iodine/day). There was minimal variation in model-predicted maternal serum T4 and ft4 thyroxine levels from use of the three reconstructed distributions of iodine intake; the range of geometric mean for T4 and fT4, was 138–151.7 nmol/L and 7.9–8.7 pmol/L, respectively. The average value of the ratio of the 97.5th percentile to the 2.5th percentile equaled 3.1 and agreed well with similar estimates from recent observations in third-trimester pregnant women in the U.S. In addition, the reconstructed distributions of iodine intake allowed us to estimate nutrient inadequacy for late-gestation pregnant women in the U.S. via the probability approach. The prevalence of iodine inadequacy for third-trimester pregnant women in the U.S. was estimated to be between 21% and 44%. Taken together, the current work provides an improved tool for evaluating iodine nutritional status and the corresponding thyroid function status in pregnant women in the U.S. This model enables future assessments of the relevant risk of thyroid hormone level perturbations due to exposure to thyroid-active chemicals at the population-level. - Highlights: • A population-based thyroid function model for pregnant women was developed. • The model was used specifically study the late-gestation pregnant women in the U.S. • The prevalence of iodine inadequacy was estimated in the sub-population studied. • Developed model well predicts trimester-specific thyroid hormone reference ranges. • The model can be further used to study thyroid perturbations at a population level.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Exposure to pyrethroids insecticides and serum levels of thyroid-related measures in pregnant women

Possible association between environmental exposure to pyrethroid insecticides and serum thyroid-related measures was explored in 231 pregnant women of 10–12 gestational weeks recruited at a university hospital in Tokyo during 2009–2011. Serum levels of free thyroxine (fT4), thyroid stimulating hormone (TSH) and thyroid biding globulin (TBG) and urinary pyrethroid insecticide metabolite (3-phenoxybenzoic acid, 3-PBA) were measured. Obstetrical information was obtained from medical records and dietary and lifestyle information was collected by self-administered questionnaire. Geometric mean concentration of creatinine-adjusted urinary 3-PBA was 0.363 (geometric standard deviation: 3.06) μg/g cre, which was consistent with the previously reported levels for non-exposed Japanese adult females. The range of serum fT4, TSH and TBG level was 0.83–3.41 ng/dL, 0.01–27.4 μIU/mL and 16.4–54.4 μg/mL, respectively. Multiple regression analysis was carried out by using either one of serum levels of thyroid-related measures as a dependent variable and urinary 3-PBA as well as other potential covariates (age, pre-pregnancy BMI, parity, urinary iodine, smoking and drinking status) as independent variables: 3-PBA was not found as a significant predictor of serum level of thyroid-related measures. Lack of association may be due to lower pyrethroid insecticide exposure level of the present subjects. Taking the ability of pyrethroid insecticides and their metabolite to bind to nuclear thyroid hormone (TH) receptor, as well as their ability of placental transfer, into consideration, it is warranted to investigate if pyrethroid pesticides do not have any effect on TH actions in fetus brain even though maternal circulating TH level is not affected. -- Highlights: • Pyrethroid exposure and thyroid hormone status was examined in pregnant women. • Urinary 3-phenoxybenzoic acid was used as a biomarker of exposure. • Iodine nutrition, age and other covariates were included in statistical models. • No association was found between levels of thyroid hormone and pyrethroid exposure. • The result may be ascribed to lower exposure level.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2015

Synergism between exposure to mercury and use of iodine supplements on thyroid hormones in pregnant women

Objective: To evaluate the association between mercury exposure and thyroid-stimulating hormone (TSH), total triiodothyronine (TT3) and free thyroxine (FT4) levels during pregnancy as well as to explore if there is any synergic action between mercury and intake of iodine from different sources. Methods: The study population was 1407 pregnant women participating in the Spanish INMA birth cohort study. Total mercury concentrations were analyzed in cord blood. Thyroid hormones (THs) were measured in serum samples collected at 13.2±1.5 weeks of gestation. The association between mercury and TH levels was evaluated with multivariate linear regression models. Effect modification caused by iodine intake from supplements and diet was also evaluated. Results: The geometric means of TSH, TT3, FT4 and mercury were 1.1 μU/L, 2.4 nmol/L, 10.5 pmol/L and 7.7 μg/L, respectively. Mercury levels were marginally significantly associated with TT3 (β: −0.05; 95%CI: −0.10, 0.01), but were neither associated with TSH nor FT4. The inverse association between mercury and TT3 levels was stronger among the iodine supplement consumers (−0.08; 95%CI: −0.15, −0.02, interaction p-value=0.07). The association with FT4 followed the same pattern, albeit not significant. Conclusion: Prenatal mercury exposure was inversely associated with TT3 levels among women who took iodine supplements during pregnancy. These results could be of public health concern, although further research is needed. - Highlights: • We studied the relationship between mercury and thyroid hormones among pregnant. • Mercury was marginally significantly associated with TT3, but not with TSH or FT4. • This association was stronger among the iodine supplement. • These results could be of public health concern, but further research is needed.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2015

Gestational urinary bisphenol A and maternal and newborn thyroid hormone concentrations: The HOME Study

Bisphenol A (BPA), an endocrine disruptor used in consumer products, may perturb thyroid function. Prenatal BPA exposure may have sex-specific effects on thyroid hormones (THs). Our objectives were to investigate whether maternal urinary BPA concentrations during pregnancy were associated with THs in maternal or cord serum, and whether these associations differed by newborn sex or maternal iodine status. We measured urinary BPA concentrations at 16 and 26 weeks gestation among pregnant women in the HOME Study (2003–2006, Cincinnati, Ohio). Thyroid stimulating hormone (TSH) and free and total thyroxine (T{sub 4}) and triiodothyronine (T{sub 3}) were measured in maternal serum at 16 weeks (n=181) and cord serum at delivery (n=249). Associations between BPA concentrations and maternal or cord serum TH levels were estimated by multivariable linear regression. Mean maternal urinary BPA was not associated with cord THs in all newborns, but a 10-fold increase in mean BPA was associated with lower cord TSH in girls (percent change=−36.0%; 95% confidence interval (CI): −58.4, −1.7%), but not boys (7.8%; 95% CI: −28.5, 62.7%; p-for-effect modification=0.09). We observed no significant associations between 16-week BPA and THs in maternal or cord serum, but 26-week maternal BPA was inversely associated with TSH in girls (−42.9%; 95% CI: −59.9, −18.5%), but not boys (7.6%; 95% CI: −17.3, 40.2%; p-for-effect modification=0.005) at birth. The inverse BPA–TSH relation among girls was stronger, but less precise, among iodine deficient versus sufficient mothers. Prenatal BPA exposure may reduce TSH among newborn girls, particularly when exposure occurs later in gestation. - Highlights: • Examined associations of BPA with thyroid hormones in pregnant women and newborns. • Assessed effect modification of BPA–thyroid hormone associations by newborn sex. • Greater BPA related to decreased thyroid stimulating hormone in girls' cord serum. • Results may suggest window of susceptibility to BPA in later gestation. • BPA potentially has greatest adverse effect on girls with iodine deficient mothers.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2016

Exposure to polychlorinated biphenyls and the thyroid gland – examining and discussing possible longitudinal health effects in humans

Background: Many previous studies have dealt with the effect of polychlorinated biphenyls (PCBs) on the thyroid gland, but their findings are inconsistent. One problem of these studies has been their use of cross-sectional designs. Objectives: The aim of the current study is to investigate longitudinal effects of PCBs on the thyroid gland, focusing on: morphological changes in thyroid tissue (i.e. thyroid volume), changes in thyroid hormones and in thyroid antibodies. Methods: A total of 122 individuals (M{sub age}=44.7) were examined over a period of four years (t{sup 1} until t{sup 4}). Medical history was collected via interviews, an ultrasound examination was performed and blood samples were taken to determine plasma PCB levels, thyroid stimulating hormone (TSH), free triiodthyronine (fT3), free thyroxine (fT4), thyroid peroxidase antibodies (TPOab), thyreoglobulin antibodies (TGab) and thyroid-stimulating hormone receptor antibodies (TSHRab). Rank correlation coefficients and mixed effect models were performed controlling for age and total lipids. Results: There were negative correlations between higher chlorinated biphenyls and fT3, cross-sectionally as well as longitudinally. We also found an interaction effect of higher-chlorinated PCBs over time for fT4 as well as TSHRab. In case of high exposure, a decrease in fT4 and an increase in TSHRab level were found over time. In regards to the other variables, our findings yielded no clear results in the examined time period. Conclusion: This is the first study to shows a PCB-related effect on fT3, fT4 and TSHRab over a four year period. The data also suggest that morphological and antibody findings remain inconsistent and do not allow for unambiguous interpretation. - Highlights: • This is a longitudinal study which includes data from four cross sections. • Higher-chlorinated biphenyls are negatively correlated with fT3. • There are interactions of time and higher-chlorinated biphenyls to TSHRab and fT4. • There is an interaction of time and dioxin-like polychlorinated biphenyls to fT4. • No consistent effects were found for thyroid volume, TSH, TPOab and TGab.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2016

Thyroid antagonists and thyroid indicators in U.S. pregnant women in the Vanguard Study of the National Children's Study

The sodium iodide-symporter (NIS) mediates uptake of iodide into thyroid follicular cells. This key step in thyroid hormone synthesis is inhibited by perchlorate, thiocyanate (SCN) and nitrate (NO{sub 3}) anions. When these exposures occur during pregnancy the resulting decreases in thyroid hormones may adversely affect neurodevelopment of the human fetus. Our objectives were to describe and examine the relationship of these anions to the serum thyroid indicators, thyroid stimulating hormone (TSH) and free thyroxine (FT4), in third trimester women from the initial Vanguard Study of the National Children's Study (NCS); and to compare urine perchlorate results with those in pregnant women from the National Health and Nutritional Examination Survey (NHANES). Urinary perchlorate, SCN, NO{sub 3}, and iodine, serum TSH, FT4, and cotinine were measured and a food frequency questionnaire (FFQ) was administered to pregnant women enrolled in the initial Vanguard Study. We used multiple regression models of FT4 and TSH that included perchlorate equivalent concentration (PEC, which estimates combined inhibitory effects of the anions perchlorate, SCN, and NO{sub 3} on the NIS). We used multiple regression to model predictors of each urinary anion, using FFQ results, drinking water source, season of year, smoking status, and demographic characteristics. Descriptive statistics were calculated for pregnant women in NHANES 2001–2012. The geometric mean (GM) for urinary perchlorate was 4.04 µg/L, for TSH 1.46 mIU/L, and the arithmetic mean for FT4 1.11 ng/dL in 359 NCS women. In 330 women with completed FFQs, consumption of leafy greens, winter season, and Hispanic ethnicity were significant predictors of higher urinary perchlorate, which differed significantly by study site and primary drinking water source, and bottled water was associated with higher urinary perchlorate compared to filtered tap water. Leafy greens consumption was associated with higher urinary NO{sub 3} and higher urinary SCN. There was no association between urinary perchlorate or PEC and TSH or FT4, even for women with urinary iodine <100 µg/L. GM urinary perchlorate concentrations in the full sample (n=494) of third trimester NCS women (4.03 µg/L) were similar to pregnant women in NHANES (3.58 µg/L). - Highlights: • Limited biomonitoring data are available in pregnant women. • We found no effect of perchlorate and related anions on thyroid indicators in third trimester women. • Leafy green vegetables were a dietary source for perchlorate, nitrate, and thiocyanate.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Associations of maternal exposure to triclosan, parabens, and other phenols with prenatal maternal and neonatal thyroid hormone levels

Highlights: • Triclosan was associated with lower maternal total T4 during pregnancy. • 2,4-Dichlorophenol was associated with lower maternal free T4 during pregnancy. • Propyl paraben was associated with lower maternal TSH during pregnancy. • No chemicals were associated with neonatal TSH. Environmental phenols and parabens are commonly used in personal care products and other consumer products and human exposure to these chemicals is widespread. Although human and animal studies suggest an association between exposure to phenols and parabens and thyroid hormone levels, few studies have investigated the association of in utero exposure to these chemicals and thyroid hormones in pregnant women and their neonates. We measured four environmental phenols (triclosan, benzophenone-3, and 2,4- and 2,5-dichlorophenol), and three parabens (methyl-, propyl-, and butyl paraben) in urine collected from mothers at two time points during pregnancy as part of the CHAMACOS (Center for the Health Assessment of Mothers and Children of Salinas) study. We measured free thyroxine (T4), total T4, and thyroid-stimulating hormone (TSH) in serum of the pregnant women (N = 454) and TSH in their neonates (N = 365). We examined potential confounding by a large number of additional chemical exposures and used Bayesian Model Averaging (BMA) to select the most influential chemicals to include in regression models. We observed negative associations of prenatal urinary concentrations of propyl paraben and maternal TSH (β for two-fold increase = −3.26%, 95% CI: −5.55, −0.90) and negative associations of 2,4-dichlorophenol and maternal free T4 (β for two-fold increase = −0.05, 95% CI: −0.08, −0.02), after controlling for other chemical exposures. We observed negative associations of triclosan with maternal total T4 after controlling for demographic variables, but this association became non-significant after controlling for other chemicals (β for two-fold increase = −0.05, 95% CI: −0.11, 0.00). We found evidence that environmental phenols and parabens are associated with lower TSH and free T4 in pregnant women after controlling for related chemical exposures.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Exposure to perfluoroalkyl substances and associations with serum thyroid hormones in a remote population of Alaska Natives

Highlights: • Serum concentrations PFOA, PFNA, PFUnA and PFDA were positively associated with TSH in individual models. • No serum PFASs are associated with total or free T{sub 4}. • The associations between serum PFOA and PFNA and free T{sub 3,} as well as PFNA and total T3 are modified by sex. • The effect of PFAS exposure on thyroid hormone homeostasis differs between sexes. Perfluoroalkyl substances (PFASs) are known to accumulate in traditional food animals of the Arctic, and arctic indigenous peoples may be exposed via consumption of subsistence-harvested animals. PFASs are suspected of disrupting thyroid hormone homeostasis in humans. The aim of this study is to assess the relationship between serum PFASs and thyroid function in a remote population of Alaska Natives. Serum samples were collected from 85 individuals from St. Lawrence Island, Alaska. The concentrations of 13 PFASs, as well as free and total thyroxine (T{sub 4}), free and total triiodothyronine (T{sub 3}), and thyrotropin (TSH) were quantified in serum samples. The relationships between circulating concentrations of PFASs and thyroid hormones were assessed using multiple linear regression fit with generalized estimating equations. Several PFASs, including perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA), were positively associated with TSH concentrations when modeled individually. PFOS and PFNA were significantly associated with free T{sub 3} and PFNA was significantly associated with total T{sub 3} in models with PFAS*sex interactive terms; these associations suggested negative associations in men and positive associations in women. PFASs were not significantly associated with concentrations of free or total T{sub 4}. Serum PFASs are associated with circulating thyroid hormone concentrations in a remote population of Alaska Natives. The effects of PFAS exposure on thyroid hormone homeostasis may differ between sexes.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Exposure to environment chemicals and its possible role in endocrine disruption of children from a rural area

Highlights: • Rural children had elevated blood and hair Mn and Cr levels. • Disruption on thyroid function can be related to metals exposure in rural areas. • Dyslipidemia is associated to thyroid dysfunction in children exposed to metals. • Cholinesterase inhibitors insecticides affect the glucose homeostasis of children. • Children exposed to high levels of Mn can be evaluated through the prolactin. Endocrine disrupting chemicals (EDCs), including pesticides and metals, are present in rural areas, endangering the health of exposed populations. This work aimed to investigate the possible association between the exposure to these xenobiotics and thyroid dysfunction in children living in a rural community of Southern Brazil. Fifty-four children aged 5–16 years participated in this study. Peripheral biomarker evaluations were performed in periods of low and high exposure to pesticides. Thyroid ultrasonography was evaluated in the high exposure period. Blood levels of chromium (Cr), manganese (Mn), mercury (Hg), and lead (Pb), as well as hair Pb levels were positively correlated with thyroid stimulating hormone (TSH) concentrations and negatively associated with free thyroxine (fT4) levels in the low exposure period. Prolactin was positively associated with hair Mn in both periods. In the ultrasound tests, the majority of children presented a normal echogenicity of thyroid. Glucose was inversely associated with the biomarker of exposure to cholinesterase inhibitor insecticides, butyrylcholinesterase (BuChE). Lipid profile was above the recommended levels in both periods. In summary, our results show that children environmentally exposed to a mixture of xenobiotics in an agricultural community may have health impairments, especially on thyroid function, dyslipidemia, and glucose homeostasis disruption.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2012

The effects of clobazam treatment in rats on the expression of genes and proteins encoding glucronosyltransferase 1A/2B (UGT1A/2B) and multidrug resistance‐associated protein-2 (MRP2), and development of thyroid follicular cell hypertrophy

Clobazam (CLB) is known to increase hepatobiliary thyroxine (T4) clearance in Sprague–Dawley (SD) rats, which results in hypothyroidism followed by thyroid follicular cell hypertrophy. However, the mechanism of the acceleration of T4-clearance has not been fully investigated. In the present study, we tried to clarify the roles of hepatic UDP-glucronosyltransferase (UGT) isoenzymes (UGT1A and UGT2B) and efflux transporter (multidrug resistance–associated protein-2; MRP2) in the CLB-induced acceleration of T4-clearance using two mutant rat strains, UGT1A-deficient mutant (Gunn) and MRP2-deficient mutant (EHBR) rats, especially focusing on thyroid morphology, levels of circulating hormones (T4 and triiodothyronine (T3)) and thyroid-stimulating hormone (TSH), and mRNA or protein expressions of UGTs (Ugt1a1, Ugt1a6, and Ugt2b1/2) and MRP2 (Mrp). CLB induced thyroid morphological changes with increases in TSH in SD and Gunn rats, but not in EHBR rats. T4 was slightly decreased in SD and Gunn rats, and T3 was decreased in Gunn rats, whereas these hormones were maintained in EHBR rats. Hepatic Ugt1a1, Ugt1a6, Ugt2b1/2, and Mrp2 mRNAs were upregulated in SD rats. In Gunn rats, UGT1A mRNAs (Ugt1a1/6) and protein levels were quite low, but UGT2B mRNAs (Ugt2b1/2) and protein were prominently upregulated. In SD and Gunn rats, MRP2 mRNA and protein were upregulated to the same degree. These results suggest that MRP2 is an important contributor in development of the thyroid cellular hypertrophy in CLB-treated rats, and that UGT1A and UGT2B work in concert with MRP2 in the presence of MRP2 function to enable the effective elimination of thyroid hormones. -- Highlights: ► Role of UGT and MRP2 in thyroid pathology was investigated in clobazam-treated rats. ► Clobazam induced thyroid cellular hypertrophy in SD and Gunn rats, but not EHBR rats. ► Hepatic Mrp2 gene and protein were upregulated in SD and Gunn rats, but not EHBR rats. ► Neither serum thyroid hormones (T3/T4) nor thyroid pathology changed in EHBR rats. ► Mrp2 was implied to be a key molecule in clobazam-induced thyroid pathology in rats.

60 APPLIED LIFE SCIENCES↗