Altered Thyroid Hormone Levels Research Articles

A Novel Deletion Mutation of SLC16A2 Encoding Monocarboxylate Transporter (MCT) 8 in a 26-year-old Japanese Patient with Allan-Herndon-Dudley Syndrome.

Allan-Herndon-Dudley Syndrome (AHDS), an X linked condition, is characterized by congenital hypotonia that progresses to spasticity with severe psychomotor delays, in combination with altered thyroid hormone levels, in particular, high serum T3 levels. Recently, this disease was proved to be caused by mutations in SLC16A2 coding for the monocarboxylate thyroid hormone transporter 8 (MCT8). Here we describe a 26-year -old Japanese patient with AHDS who had deletion of exon 3 of SLC16A2.

Thyroid endocrine disruption in zebrafish larvae following exposure to hexaconazole and tebuconazole

The widely used triazole fungicides have the potential to disrupt endocrine system, but little is known of such effects or underlying mechanisms of hexaconazole (HEX) and tebuconazole (TEB) in fish. In the present study, zebrafish (Danio rerio) embryos were exposed to various concentrations of HEX (0.625, 1.25 and 2.5mg/L) and TEB (1, 2 and 4mg/L) from fertilization to 120h post-fertilization (hpf). The whole body content of thyroid hormone and transcription of genes in the hypothalamic-pituitary-thyroid (HPT) axis were analyzed. The results showed that thyroxine (T4) levels were significantly decreased, while triiodothyronine (T3) concentrations were significantly increased after exposure to HEX and TEB, indicating thyroid endocrine disruption. Exposure to HEX significantly induced the transcription of all the measured genes (i.e., corticotrophin-releasing hormone (CRH), thyroid-stimulating hormone (TSHβ), sodium/iodide symporter (NIS), transthyretin (TTR), uridine diphosphate glucuronosyltransferase (UGT1ab), thyronine deiodinase (Dio1 and Dio2), thyroid hormone receptors (TRα and TRβ)) in the HPT axis, but did not affect the transcription of thyroglobulin (TG). However, TEB exposure resulted in the upregulation of all the measured genes, excepting that TG, Dio1and TRα had not changed significantly. The overall results indicated that exposure to HEX and TEB could alter thyroid hormone levels as well as gene transcription in the HPT axis in zebrafish larvae.

Relationship between urinary triclosan and paraben concentrations and serum thyroid measures in NHANES 2007–2008

Triclosan and parabens are broad spectrum antimicrobials used in a range of consumer products. In vitro and animal studies have suggested the potential for these compounds to disrupt thyroid function, though studies in humans have been limited. The objective of the study was to assess the relationship of urinary concentrations of triclosan and parabens with serum thyroid measures in a large, representative sample of the US population. We conducted an exploratory, cross-sectional analysis of data on urinary biomarkers of triclosan and paraben exposure and serum thyroid measures obtained from 1831 subjects (ages≥12years) as part of the 2007–2008 National Health and Nutrition Examination Survey (NHANES). We found evidence of some inverse associations between parabens and circulating thyroid hormone levels in adults, with the strongest and most consistent associations among females. We also observed a positive association between triclosan and total triiodothyonine (T3) concentrations in adolescents. These results, in accordance with the in vitro and animal literature, suggest that paraben, and potentially triclosan, exposures may be associated with altered thyroid hormone levels in humans. Further research is needed for confirmation and to determine the potential clinical and public health significance of these findings.

A Novel Deletion Mutation of <i>SLC16A2</i> Encoding Monocarboxylate Transporter (MCT) 8 in a 26-year-old Japanese Patient with Allan-Herndon-Dudley Syndrome

Allan-Herndon-Dudley Syndrome (AHDS), an X linked condition, is characterized by congenital hypotonia that progresses to spasticity with severe psychomotor delays, in combination with altered thyroid hormone levels, in particular, high serum T3 levels. Recently, this disease was proved to be caused by mutations in SLC16A2 coding for the monocarboxylate thyroid hormone transporter 8 (MCT8). Here we describe a 26-year -old Japanese patient with AHDS who had deletion of exon 3 of SLC16A2.

Alternative complement pathway and factor B activities in rats with altered blood levels of thyroid hormone

Evaluating the activity of the complement system under conditions of altered thyroid hormone levels might help elucidate the role of complement in triggering autoimmune processes. Here, we investigated alternative pathway (AP) activity in male Wistar rats (180 ± 10 g) after altering their thyroid hormone levels by treatment with triiodothyronine (T3), propylthiouracil (PTU) or thyroidectomy. T3 and thyroxine (T4) levels were determined by chemiluminescence assays. Hemolytic assays were performed to evaluate the lytic activity of the AP. Factor B activity was evaluated using factor B-deficient serum. An anti-human factor B antibody was used to measure factor B levels in serum by radial immunodiffusion. T3 measurements in thyroidectomized animals or animals treated with PTU demonstrated a significant reduction in hormone levels compared to control. The results showed a reduction in AP lytic activity in rats treated with increasing amounts of T3 (1, 10, or 50 µg). Factor B activity was also decreased in the sera of hyperthyroid rats treated with 1 to 50 µg T3. Additionally, treating rats with 25 µg T3 significantly increased factor B levels in their sera (P < 0.01). In contrast, increased factor B concentration and activity (32%) were observed in hypothyroid rats. We conclude that alterations in thyroid hormone levels affect the activity of the AP and factor B, which may in turn affect the roles of AP and factor B in antibody production.

Waterborne exposure to microcystin-LR alters thyroid hormone levels and gene transcription in the hypothalamic–pituitary–thyroid axis in zebrafish larvae

Microcystin–leucine–arginine (MCLR) is the most toxic and the most commonly encountered variant of microcystins (MCs) in aquatic environment, and it has the potential for disrupting thyroid hormone homeostasis, but the molecular mechanisms underlying this process have not yet been clarified. In the present study, we observed body growth retardation associated with decreased levels of thyroid hormones (THs) in zebrafish larvae, highlighting the interferences of MCLR with the growth of fish larvae. To further our understanding of mechanisms of MCLR-induced endocrine toxicity, quantitative real-time PCR analysis was performed on hypothalamic–pituitary–thyroid (HPT) axis related genes of developing zebrafish embryos exposed to 100, 300 and 500μgL−1 MCLR until 96h post-fertilization. The expression of several genes in the HPT system, i.e., corticotropin-releasing factor (CRF), thyroid-stimulating hormone (TSH), sodium/iodide symporter (NIS), thyroglobulin (TG), thyroid receptors (TRα and TRβ) and iodothyronine deiodinases (Dio1 and Dio2) was examined using quantitatively real-time PCR. The gene expression levels of CRF, TSH, NIS and TG were significantly induced after exposure to 500μgL−1 MCLR. The transcription of TRs gene was down-regulated in a concentration-dependent manner. Up-regulation and down-regulation of Deio1 and Deio2 gene expression, respectively, were observed upon exposure to MCLR. The above results indicated that MCLR could alter gene expression in the HPT axis which might subsequently contribute to MCLR-induced thyroid disruption.

THYROID FUNCTION, PFOA AND PFOS IN CHILDREN LIVING NEAR A CHEMICAL PLANT

Background and Aims: Altered thyroid hormone levels following exposure to perfluorocarbons (PFCs) have been found in some animal studies. Published epidemiological findings are not consistent and most prior studies have focused on adults. We investigated if concentrations of two PFCs, perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS), were associated with thyroid function among 10,725 children (aged 1-18 years) living near a Teflon manufacturing facility in the Mid-Ohio Valley, USA. Methods: Serum levels of thyroid-stimulating hormone (TSH), total thyroxine (TT4), and T3 uptake were measured and free thyroxine index (FTI) was calculated as biomarkers of thyroid function during 2005-2006, at the same time as serum levels of PFCs were measured. We estimated modeled in utero PFOA concentrations. Child-mother pairing allowed maternal serum concentrations of PFOA estimated at pregnancy to be used as a proxy for in utero exposure to PFOA for 52% of children. We performed multivariate regression analyses between thyroid disease status or thyroid hormone levels and PFOA/PFOS concentrations. Results: At survey, median serum PFOA and PFOS concentrations were 29.3 and 20 ng/mL, respectively, and modeled in utero PFOA concentration was 17.1 ng/mL. The prevalence of reported thyroid disease was 0.5%, and the prevalence of subclinical hypothyroidism and hyperthyroidism based on thyroid hormone levels was 2.6 and 1.0%, respectively. We found a positive association between serum TT4 or FTI and LnPFOS in children (TT4: β=0.19, 95% CI=0.12, 0.26; FTI: β=0.04, 95% CI=0.02, 0.06). Findings for PFOA will also be presented in the conference but must first be shown to the local community. Conclusions: Our results demonstrate a possible association between altered thyroid hormone levels and PFOS concentrations. This study comprises by far the largest population to date of children studied with such levels of PFOA, in relation to markers of thyroid function.

Effect of stocking density on growth and serum concentrations of thyroid hormones and cortisol in Amur sturgeon, Acipenser schrenckii

This study investigated the effects of different stocking densities on growth and serum concentrations of thyroid hormones and cortisol in Amur sturgeon, Acipenser schrenckii. Fish were reared at low, medium, and high stocking densities (initial experimental densities were 0.30, 0.75, and 1.78 kg m(-2), respectively) for 70 days. The results showed that high stocking density had negative effects on growth and feeding efficiency, and altered serum levels of thyroid hormones and cortisol in Amur sturgeon. A significant decrease in specific growth rate was observed as stocking density was increased. The feeding rate decreased significantly in the medium and high density groups, indicating that high stocking density reduced the food consumption of sturgeon. Food conversion ratio increased with increasing stocking density, suggesting that high stocking density might inhibit fish growth through decreasing food conversion efficiency. Serum concentrations of total triiodothyronine, free thyroxine, and free triiodothyronine were inversely related to stocking densities, whereas serum total thyroxine level of sturgeon stocked at different densities remained stable. Also, higher stocking density resulted in an elevation of serum cortisol level, indicating that the sturgeon stocked at the higher density experienced density-dependent physiological stress. These results suggest growth suppression caused by high stocking density might be related to both crowding stress and the declines in peripheral circulating levels of thyroid hormones, as well as associated with the reductions in both food consumption and food conversion efficiency.

T 3 fails to restore mitochondrial thiol redox status altered by experimental hypothyroidism in rat testis

Oxidative stress impaired sperm function might lead to infertility. The objective of this study was to evaluate the effects of altered thyroid hormone levels on regulation of mitochondrial glutathione redox status and its dependent antioxidant defense system in adult rat testis and their correlation with testicular function. Adult male Wistar rats were rendered hypothyroid by administration of 6- n-propyl-2-thiouracil in drinking water for six weeks. At the end of the treatment period, a subset of the hypothyroid rats was treated with T 3 (20 μg/100 g body weight/day for 3 days). Mitochondria were isolated from euthyroid, hypothyroid and hypothyroid + T 3-treated rat testes, and sub-fractionated into sub-mitochondrial particles and matrix fractions. Mitochondrial respiration, oxidative stress indices and antioxidant defenses were assayed. The results were correlated with daily testicular sperm production and epididymal sperm viability. Increased pro-oxidant level and reduced antioxidant capacity rendered the hypothyroid mitochondria susceptible to oxidative injury. The extent of damage was more evident in the membrane fraction. This was reflected in higher degree of oxidative damages inflicted upon membrane lipids and proteins. While membrane proteins were more susceptible to carbonylation, thiol residue damage was evident in matrix fraction. Reduced levels of glutathione and ascorbate further weakened the antioxidant defenses and impaired testicular function. Hypothyroid condition disturbed intra-mitochondrial thiol redox status leading to testicular dysfunction. Hypothyroidism-induced oxidative stress condition could not be reversed with T 3 treatment.

Exposure to DE-71 alters thyroid hormone levels and gene transcription in the hypothalamic–pituitary–thyroid axis of zebrafish larvae

Polybrominated diphenyl ethers (PBDEs) have the potential to disrupt thyroid hormone homeostasis, but the molecular mechanisms underlying this process have not yet been clarified. In the present study, zebrafish ( Danio rerio) embryos were exposed to a low concentration (0, 1, 3, and 10 μg/L) of DE-71 from fertilization to 14 days thereafter. The whole-body content of thyroid hormone and transcription of genes in the hypothalamic–pituitary–thyroid (HPT) axis were analyzed. Exposure to up to 10 μg/L of DE-71 significantly reduced thyroxine (T4) levels and significantly upregulated the transcription of corticotrophin-releasing hormone (CRH) and thyroid-stimulating hormone (TSHβ) genes in a concentration-dependent manner. The transcription of genes involved in the synthesis of TH proteins, sodium/iodide symporter (Slc5a5), and thyroglobulin (TG) and the transcription of marker genes associated with early thyroid development (Pax8 and Nkx2.1) were significantly upregulated upon DE-71 exposure. The expression of thyronine deiodinase (Deio1 and Deio2) mRNAs was also significantly upregulated, possibly as a compensatory response to the decreased T4 levels. However, DE-71 exposure resulted in the downregulation of transthyretin (TTR) gene transcription and did not affect the transcription of thyroid hormone receptors (TRs). Exposure to DE-71 significantly induced the transcription of the uridinediphosphate-glucuronosyltransferase (UGT1ab) gene. The results of our study confirmed the reliability of the zebrafish larvae as models for assessment of the developmental toxicity of PBDEs and transcription of genes of the HPT axis can evaluate the potential mechanisms of thyroid disruption.

Relationship between urinary metabolites of polycyclic aromatic hydrocarbons and thyroid hormone levels in Chinese non-occupational exposure adult males

Polycyclic aromatic hydrocarbons (PAH) are ubiquitous global pollutants. Limited studies suggested that PAH may interfere with thyroid function in animals, but little is known about humans. A population of 480 Chinese males was recruited. Using LC–MS/MS, four urinary metabolites of PAH including 1-hydroxynaphthalene (1-N), 2-hydroxynaphthalene (2-N), 1-hydroxypyrene (1-P) and 2-hydroxyfluorene (2-F) were measured in spot urinary samples, which were adjusted by urinary creatinine (CR). Blood samples were collected for measuring serum levels of thyroid hormones including total thyroxine (TT4), free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH). The median CR-adjusted urine PAH concentrations of 1-N, 2-N, 1-P, 2-F were 2.306, 4.047, 1.155 and 2.899 μg g −1 of CR, respectively. Significant p-values for trend were found for men with higher 2-F tertiles and were more likely to possess high-reference TSH levels. In addition, the multivariate linear regression models showed significant positive correlations for TSH levels with increased CR-adjusted 2-F concentration. No significant associations were found between other thyroid hormones levels and PAH metabolite concentrations. These results indicated that PAH exposure might be related to altered male thyroid hormone levels, but further study is needed to confirm these observed findings.

Competitive Binding of Poly- and Perfluorinated Compounds to the Thyroid Hormone Transport Protein Transthyretin

Due to their unique surfactant properties, poly- and perfluorinated compounds (PFCs) have been extensively used and can be found all over the environment. Concern about their environmental fate and toxicological properties has initiated several research projects. In the present study, we investigated if PFCs can compete with thyroxine (T(4), i.e., the transport form of thyroid hormone) for binding to the human thyroid hormone transport protein transthyretin (TTR). Such competitive capacity may lead to decreased thyroid hormone levels as previously reported for animals exposed to PFCs. Twenty-four PFCs, together with 6 structurally similar natural fatty acids, were tested for binding capacity in a radioligand-binding assay. The binding potency decreased in the order: perfluorohexane sulfonate > perfluorooctane sulfonate/perfluorooctanoic acid > perfluoroheptanoic acid > sodium perfluoro-1-octanesulfinate > perfluorononanoic acid, with TTR binding potencies 12.5-50 times lower than the natural ligand T(4). Some lower molecular weight compounds with structural similarity to these PFCs were > 100 times less potent than T(4). Simple descriptors based on the two-dimensional molecular structures of the compounds were used to visualize the chemical variation and to model the structure-activity relationship for the competitive potencies of the TTR-binding compounds. The models indicated the dependence on molecular size and functional groups but demanded a more detailed description of the chemical properties and data for validation and further quantitative structure-activity relationship (QSAR) development. Competitive binding of PFCs to TTR, as observed for human TTR in the present study, may explain altered thyroid hormone levels described for PFC-exposed rats and monkeys. Median human blood levels of the most potent TTR-binding PFCs are one to two orders of magnitude lower than concentration at 50% inhibition (IC(50)) values determined in the present study. In addition, this study contributes to the understanding of the bioaccumulation of PFCs in man and possibly in other wildlife species.

Importance of Monocarboxylate Transporter 8 for the Blood-Brain Barrier-Dependent Availability of 3,5,3′-Triiodo-l-Thyronine

Mutations of the gene expressing plasma membrane transporter for thyroid hormones MCT8 (SLC16A2) in humans lead to altered thyroid hormone levels and a severe neurodevelopmental disorder. Genetically engineered defect of the Mct8 gene in mice leads to similar thyroid hormone abnormalities but no obvious impairment of brain development or function. In this work we studied the relative role of the blood-brain barrier and the neuronal plasma cell membrane in the restricted access of T(3) to the target neurons. To this end we compared the effects of low doses of T(4) and T(3) on cerebellar structure and gene expression in wild-type (Wt) and Mct8 null male mice [Mct8-/y, knockout (KO)] made hypothyroid during the neonatal period. We found that compared with Wt animals, T(4) was considerably more potent than T(3) in the Mct8KO mice, indicating a restricted access of T(3), but not T(4), to neurons after systemic administration in vivo. In contrast, T(3) action in cultured cerebellar neurons was similar in Wt cells as in Mct8KO cells. The results suggest that the main restriction for T(3) entry into the neural target cells of the mouse deficient in Mct8 is at the blood-brain barrier.

Effect of Thyroid Hormone on the Gene Expression of Myostatin in Rat Skeletal Muscle

Modification of thyroid hormone levels has a profound effect on skeletal muscle differentiation, predominantly through direct regulation involving thyroid hormone receptors. Nevertheless, little is known about the regulation of myostatin gene expression in skeletal muscle due to altered concentrations of thyroid hormone. Thus, the goal of our study was to find out whether altered thyroid states could change the gene expression of myostatin, the most powerful inhibitor of skeletal muscle development. A hyperthyroid state was induced in rats by daily injections of L-thyroxine 20 mg/100 g body weight for 14 days, while a hypothyroid state was induced in another group of rats by administering methimazole (0.04%) in drinking water for 14 days. After a period of 14 days of L-thyroxine treatment we observed a significant increase of myostatin expression both in mRNA and protein level. However, decreased expression of myostatin mRNA and protein were observed in hypothyroid rats. Furthermore, our studies demonstrated that the upregulation of myostatin gene expression might be responsible for the loss of body weight induced by altered thyroid hormone levels. We concluded that myostatin played a role in a metabolic process in muscle that was regulated by thyroid hormone.

EFFECT OF EXPERIMENTALLY INDUCED SUBCHRONIC SELENOSIS ON THYROID HORMONES AND BIOCHEMICAL INDICES IN CALVES

Summary The present investigation was performed to determine the effect of long-term administration of sodium selenite on the biochemical indices and concentration of thyroid hormones in calves. Sodium selenite solution was drenched at 0.1 and 0.25 mg per kg body weight for 12 weeks. Higher dose produced characteristic symptoms of selenosis whereas mild symptoms were observed with lower dose. The toxic symptoms appeared when blood selenium level was 1.68 ± 0.13 µg per ml. There was a significant (P<0.05) increase in the activities of the aspartate aminotransferase, alkaline phosphatase, blood urea nitrogen and creatinine levels in the treated animals. The repeated administration of sodium selenite resulted in a significant p-value decline in thyroxine levels on the 10th week and increase in triiodothyronine on the 8th week of treatment. The findings of the present study suggested that sodium selenite induced selenosis alters thyroid hormone levels in plasma.

Organochlorine compounds and thyroid dysfunction in children: is there a link with neurotoxicity?

Recent epidemiological and experimental studies have suggested that persistent organochlorine compounds (OCs) such as polychlorinated biphenyls (PCBs) and dioxins may alter thyroid hormone levels in animals and humans. As neurological...

Chemical Exposures: Cats as Sentinel Species

Pet cats may be like canaries in coal mines when it comes to evaluating the health impacts of polybrominated diphenyl ethers (PBDEs), persistent chemicals used in carpet pads, furniture, and electronics. Chronic PBDE exposure may partly explain an epidemic of hyperthyroid disease in older cats, says Janice Dye, a U.S. EPA research biologist. In turn, studying the effects of chronic PBDE exposure in cats could offer clues as to the effects in their human counterparts. Veterinarians first noticed a dramatic surge in feline hyperthyroidism (FH) in the 1980s, coinciding with the use of PBDEs as flame retardants in consumer products. FH, the most common endocrine disorder in cats, causes rapid weight loss due to increased concentrations of thyroxine. Histologic changes in FH mirror those seen in older humans experiencing toxic nodular goiter (TNG), in which an enlarged thyroid gland overproduces thyroxine. The causes of FH and TNG remain unknown. Dye looked at whether hyperthyroidal cats had greater body burdens of PBDEs. She and her colleagues measured numerous PBDE congeners in serum samples collected from 23 cats, 11 of which were positive for FH. They report in the 15 September 2007 Environmental Science & Technology that total average PBDE levels were three times higher in older cats with FH than in younger cats without FH, but the difference was not statistically significant because of high within-group variability. “All cats are high [compared with humans], and some cats are incredibly high,” Dye notes. She also found that cat food, particularly canned fish-flavored brands, contains high levels of PBDEs. Cats swallow PBDEs in food and by licking PBDE-laden house dust from their fur. PBDE congeners contain bromine atoms that mimic the iodine in thyroxine. PBDEs may interact with thyroid-binding proteins to displace thyroxine, and chronic exposure may lead to sustained increases in secretion of thyroid-stimulating hormone and thyroid hyperplasia. “When that happens,” says Dye, “it’s pedal to the metal, and the cat’s thyroid makes too much thyroxine.” The potential link between FH and PBDEs suggests that house cats may be sentinels for chronic indoor PBDE exposure in people. By understanding more completely how PBDEs alter thyroid hormone levels in cat sentinels, “we can assess whether comparable risk exists for exposed people, especially children,” Dye says. Like cats, toddlers may be inordinately exposed to PBDEs in dust by crawling on floors and placing objects in their mouths. A case study of one family, described in the October 2006 EHP, found that a toddler had PBDE levels up to 10 times higher than those of his parents. “We don’t know what PBDEs do to children during critical stages of development,” says Dye, but cats offer hints about “where chronic exposure may lead.” People in the United States have the highest PBDE levels reported worldwide, according to a meta-analysis published in the 15 February 2004 Environmental Science & Technology. Heather Stapleton, an environmental chemist at Duke University, points out that the link between PBDEs and health problems in cats is reminiscent of the revelation 25 years ago that children ingesting lead in household dust experienced learning problems. Says Stapleton, “It’s important to understand the effects of exposure to these brominated flame retardants in humans.”

Hypermetabolism in Gaucher disease type I is not associated with altered thyroid hormone levels

Type I Gaucher disease (OMIM 231000) is an inherited storage disorder in which deficiency of the enzyme glucocerebrosidase (EC 32145) leads to accumulation of glucocerebroside in lysosomes of macrophages. These storage cells are present in liver, spleen and bone marrow resulting in hepatosplenomegaly, cytopenia and bone complications. Metabolic abnormalities in Gaucher patients include hypermetabolism, possibly caused by elevated levels of pro-inflammatory cytokines. Nonthyroidal illness (NTI) is a combination of changes in circulating thyroid hormone levels (decreased T(3), elevated rT(3), normal or mildly depressed TSH) present in different illnesses and might be an adaptation to protect the organism from harmful catabolic effects of hypermetabolism. The hypermetabolism and the elevated cytokine levels in Gaucher disease led us to hypothesize that the alterations in thyroid hormone levels as seen in NTI might also occur in Gaucher patients. We studied thyroid hormone levels before and during treatment in 22 adult type I Gaucher patients and resting energy expenditure (REE) and correlations with thyroid hormone levels in 12 patients. Baseline thyroid hormone levels were normal in the majority (17) of patients. No cases of nonthyroidal illness were detected. Baseline REE (kcal/kg per 24 h) was not correlated with circulating levels of T(3), rT(3) or fT(4). Treatment of Gaucher disease with enzyme replacement therapy for several years resulted in a decrease in circulating fT(4) levels. After several months of treatment most patients showed a decrease in REE. There was no correlation between the changes in REE and changes in fT(4) and T(3).

New Phthalate Link?: DEHP Metabolites and Altered Thyroid Hormone Levels in Men

Vol. 115, No. 7 EnvironewsOpen AccessNew Phthalate Link?: DEHP Metabolites and Altered Thyroid Hormone Levels in Men Rebecca Renner Rebecca Renner Search for more papers by this author Published:1 July 2007https://doi.org/10.1289/ehp.115-a363bAboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Human studies have shown widespread exposure to phthalates, compounds used in the manufacture of household, consumer, and medical products. The plasticizer DEHP is one of the most widely used chemicals in this class. A limited number of rat studies have linked DEHP exposure to alterations in thyroid signaling and lower plasma thyroxine (T4) concentrations. Now a study of adult men for the first time shows an association between higher urinary levels of the metabolite MEHP and reduced thyroid hormone in blood serum [EHP 115:1029–1034; Meeker et al.].Phthalates are metabolized and excreted quickly; these metabolites, rather than the parent diesters, are believed to be the active toxicants. Ingested DEHP is initially hydrolyzed in the intestine to MEHP. The metabolites MEOHP and MEHHP are then produced by the oxidation of MEHP.The study participants included 408 men between the ages of 18 and 55. All were partners in subfertile couples who visited a Boston fertility center between January 2000 and May 2004. Each man completed a questionnaire and provided urine and blood samples on the same day. Blood samples were analyzed for free T4, total tri-iodothyronine (T3), and thyroid-stimulating hormone. Urine analysis provided data on concentrations of DEHP metabolites.MEHP was detected in 83% of the 408 samples. MEOHP and MEHHP were found in more than 95% of 208 samples tested (the sample size was smaller because methods for analyzing these metabolites became available only later in the study).Multivariate regression analysis revealed a statistically significant inverse association between urine MEHP concentrations and serum total T3 levels. In an effort to determine whether individual differences in the ability to further metabolize and neutralize MEHP might explain this relationship, the researchers also calculated the percentage of MEHP relative to the other metabolites. They found a weaker though still statistically significant inverse association between the percentage of MEHP relative to the other metabolites and free T4 levels.This suggests that an individual’s ability to metabolize and neutralize MEHP may play a role in determining effects. The researchers urge other scientists to consider whether MEHP levels relative to other metabolite concentrations might serve as potential markers for metabolic vulnerability to adverse effects from DEHP exposure.FiguresReferencesRelatedDetails Vol. 115, No. 7 July 2007Metrics About Article Metrics Publication History Originally published1 July 2007Published in print1 July 2007 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

Di(2-ethylhexyl) Phthalate Metabolites May Alter Thyroid Hormone Levels in Men

BackgroundPhthalates are used extensively in many personal-care and consumer products, resulting in widespread nonoccupational human exposure through multiple routes and media. A limited number of animal studies suggest that exposure to phthalates may be associated with altered thyroid function, but human data are lacking.MethodsConcurrent samples of urine and blood were collected from 408 men. We measured urinary concentrations of mono(2-ethylhexyl) phthalate (MEHP), the hydrolytic metabolite of di(2-ethylhexyl) phthalate (DEHP), and other phthalate monoester metabolites, along with serum levels of free thyroxine (T4), total triiodothyronine (T3), and thyroid-stimulating hormone (TSH). Oxidative metabolites of DEHP were measured in urine from only 208 of the men.ResultsWe found an inverse association between MEHP urinary concentrations and free T4 and T3 serum levels, although the relationships did not appear to be linear when MEHP concentrations were categorized by quintiles. There was evidence of a plateau at the fourth quintile, which was associated with a 0.11 ng/dL decrease in free T4 [95% confidence interval (CI), –0.18 to –0.03] and a 0.05 ng/mL decrease in T3 (95% CI, –0.10 to 0.01) compared with the first (lowest) MEHP quintile. The inverse relationship between MEHP and free T4 remained when we adjusted for oxidative metabolite concentrations; this simultaneously demonstrated a suggestive positive association with free T4.ConclusionsUrinary MEHP concentrations may be associated with altered free T4 and/or total T3 levels in adult men, but additional study is needed to confirm the observed findings. Future studies must also consider oxidative DEHP metabolites relative to MEHP as a potential marker of metabolic susceptibility to DEHP exposure.