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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Reverse triiodothyronine (rT3) attenuates ischemia-reperfusion injury

Highlights: • rT3 mitigates IR injury in vivo. • rT3 mitigates IR injury in vitro. • rT3 reduced IR induced oxidative stress. Hypothyroidism has been associated with better recovery from cerebral ischemia-reperfusion (IR) injury in humans. However, any therapeutic advantage of inducing hypothyroidism for mitigating IR injury without invoking the adverse effect of whole body hypothyroidism remains a challenge. We hypothesize that a deiodinase II (D2) inhibitor reverse triiodothyronine (rT3) may render brain specific hypometabolic state to ensue reduced damage during an acute phase of cerebral ischemia without affecting circulating thyroid hormone levels. Preclinical efficacy of rT3 as a neuroprotective agent was determined in rat model of middle cerebral artery occlusion (MCAO) induced cerebral IR and in oxygen glucose deprivation/reoxygenation (OGD/R) model in vitro. rT3 administration in rats significantly reduced neuronal injury markers, infarct size and neurological deficit upon ischemic insult. Similarly, rT3 increased cellular survival in primary cerebral neurons under OGD/R stress. Based on our results from both in vivo as well as in vitro models of ischemia reperfusion injury we propose rT3 as a novel therapeutic agent in reducing neuronal damage and improving stroke outcome.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Triiodothyronine promotes the proliferation of epicardial progenitor cells through the MAPK/ERK pathway

Thyroid hormone has important functions in the development and physiological function of the heart. The aim of this study was to determine whether 3,5,3′-Triiodothyronine (T3) can promote the proliferation of epicardial progenitor cells (EPCs) and to investigate the potential underlying mechanism. Our results showed that T3 significantly promoted the proliferation of EPCs in a concentration- and time-dependent manner. The thyroid hormone nuclear receptor inhibitor bisphenol A (100 μmol/L) did not affect T3's ability to induce proliferation. Further studies showed that the mRNA expression levels of mitogen-activated protein kinase 1 (MAPK1), MAPK3, and Ki67 in EPCs in the T3 group (10 nmol/L) increased 2.9-, 3-, and 4.1-fold, respectively, compared with those in the control group (P < 0.05). In addition, the mRNA expression of the cell cycle protein cyclin D1 in the T3 group increased approximately 2-fold compared with the control group (P < 0.05), and there were more EPCs in the S phase of the cell cycle (20.6% vs. 12.0%, P < 0.05). The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway inhibitor U0126 (10 μmol/L) significantly inhibited the ability of T3 to promote the proliferation of EPCs and to alter cell cycle progression. This study suggested that T3 significantly promotes the proliferation of EPCs, and this effect may be achieved through activation of the MAPK/ERK signaling pathway. - Highlights: • Epicardial progenitor cells were successfully cultured from E12.5 mice. • Thyroid hormone T3 significantly promoted the proliferation of EPCs. • This biological effect may be mediated via activation of the MAPK/ERK pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Effects of Continuous Triiodothyronine Infusion on Citric Acid Cycle in the Normal Immature Swine Heart under Extracorporeal Membrane Oxygenation in vivo

Extracorporeal membrane oxygenation (ECMO) is frequently used in infants with postoperative cardiopulmonary failure. ECMO also suppresses circulating triiodothyronine (T 3 ) levels and modifies myocardial metabolism. We assessed the hypothesis that T 3 supplementation reverses ECMO induced metabolic abnormalities in the immature heart. Twenty-two male Yorkshire pigs (age 25-38 days) with ECMO were received [2- 13 C]lactate, [2,4,6,8- 13 C]octanoate (medium chain fatty acid) and [U- 13 C]long-chain fatty acids as metabolic tracers either systemically (totally physiological intracoronary concentration) or directly into the coronary artery (high substrate concentration) for the last 60 minutes of each protocol. Nuclear magnetic resonance (NMR) analysis of left ventricular tissue determined the fractional contribution (Fc) of these substrates to the citric acid cycle (CAC). Fifty percent of the pigs in each group received intravenous T 3 supplement (bolus at 0.6 μg/kg and then continuous infusion at 0.2 μg/kg/hour) during ECMO. Under both substrate loading conditions T 3 significantly increased lactate-Fc with a marginal increase in octanoate-Fc. Both T 3 and high substrate provision increased myocardial energy status indexed by [Phosphocreatine]/[ATP]. In conclusion, T 3 supplementation promoted lactate metabolism to the CAC during ECMO suggesting that T 3 releases inhibition of pyruvate dehydrogenase. Manipulation of substrate utilization by T 3 may be used therapeutically during ECMO to improve resting energy state and facilitate weaning.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2014

Triiodothyronine activates lactate oxidation without impairing fatty acid oxidation and improves weaning from extracorporeal membrane oxygenation

Background: Extracorporeal membrane oxygenation (ECMO) provides a rescue for children with severe cardiac failure. We previously showed that triiodothyronine (T3) improves cardiac function by modulating pyruvate oxidation during weaning. This study was focused on fatty acid (FA) metabolism modulated by T3 for weaning from ECMO after cardiac injury. Methods: Nineteen immature piglets (9.1-15.3 kg) were separated into 3 groups with ECMO (6.5 hours) and wean: normal circulation (Group-C);transient coronary occlusion (10 minutes) followed by ECMO (Group-IR); and IR with T3 supplementation (Group-IR-T3). 13-Carbon labeled lactate, medium-chain and long-chain FAs were infused as oxidative substrates. Substrate fractional contribution to the citric acid cycle (FC) was analyzed by 13-Carbon nuclear magnetic resonance. Results: ECMO depressed circulating T3 levels to 40% baseline at 4 hours and were restored in Group-IR-T3. Group-IR decreased cardiac power, which was not fully restorable and 2 pigs were lost because of weaning failure. Group-IR also depressed FC-lactate, while the excellent contractile function and energy efficiency in Group-IR-T3 occurred along with a marked FC-lactate increase and [ATP]/[ADP] without either decreasing FC-FAs or elevating myocardial oxygen consumption over Group-C or -IR. Conclusions: T3 releases inhibition of lactate oxidation following ischemia-reperfusion injury without impairing FA oxidation. These findings indicate that T3 depression during ECMO is maladaptive, and that restoring levels improves metabolic flux and enhances contractile function during weaning.

ECMO↗
DOE OSTI2014

Triiodothyronine facilitates weaning from extracorporeal membrane oxygenation by improved mitochondrial substrate utilization

Extracorporeal membrane oxygenation (ECMO) provides a bridge to recovery after myocardial injury in infants and children, yet morbidity and mortality remain high. Weaning from the circuit requires adequate cardiac contractile function, which can be impaired by metabolic disturbances induced either by ischemia-reperfusion and / or by ECMO.

Environmental Molecular Sciences Laboratory↗
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

Persistent organic pollutants and organophosphate esters in feathers and blood plasma of adult kittiwakes (Rissa tridactyla) from Svalbard – associations with body condition and thyroid hormones

Highlights: • PCBs, OCPs, PBDEs, and OPEs were detected and quantified in kittiwake feathers. • Pollutant levels in feathers and blood plasma did not correlate in adult kittiwakes. • Adult kittiwake feathers are not useful to monitor local contamination at Svalbard. • Pollutant levels differed between kittiwake colonies according to breeding stage. • Significant negative correlations were found for PCBs and ΣPBDEs with TT{sub 3}:fT{sub 3}. Polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), organochlorine pesticides (OCPs) and organophosphate esters (OPEs) were assessed in blood plasma and feathers of 19 adult black-legged kittiwakes (Rissa tridactyla) breeding in two colonies (Blomstrandhalvøya and Krykkjefjellet) at the Arctic archipelago, Svalbard. Potential associations with body condition index (BCI) and thyroid hormones were investigated. All compound classes were detected in both blood plasma and feathers, but due to low sample size and volumes, OPEs could only be quantified in four individuals, warranting larger follow-up studies. Kittiwakes breeding at Blomstrandhalvøya had significantly higher concentrations of organic pollutants in blood plasma than kittiwakes breeding at Krykkjefjellet (p < 0.001). Concentrations in blood plasma and feathers did not significantly correlate for any of the investigated compounds, and feather concentrations did not differ significantly between the colonies. This suggests that pollutant levels in adult kittiwake feathers do not reflect local contamination at breeding sites and are as such not useful to monitor local contamination at Svalbard. Significant negative associations between BCI and most pollutants were found in both populations, whereas significant correlations between the BCI, the ratio of total triiodothyronine to free triiodothyronine (TT3:fT3), and several pollutants were only found for kittiwakes from Blomstrandhalvøya (all r ≥ −0.60 and p ≤ 0.05). This indicates that higher levels of circulating pollutants during the breeding period covary with the TT3: fT3 ratio, and may act as an additional stressor during this period.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2013

Thyroid hormone receptor inhibits hepatoma cell migration through transcriptional activation of Dickkopf 4

Highlights: •T{sub 3} affects DKK4 mRNA and protein expression in HepG2-TR cells. •Regulation of DKK4 by T{sub 3} is at transcriptional level. •DKK4 overexpression suppresses hepatoma cell metastasis. -- Abstract: Triiodothyronine (T{sub 3}) is a potent form of thyroid hormone mediates several physiological processes including cellular growth, development, and differentiation via binding to the nuclear thyroid hormone receptor (TR). Recent studies have demonstrated critical roles of T{sub 3}/TR in tumor progression. Moreover, long-term hypothyroidism appears to be associated with the incidence of human hepatocellular carcinoma (HCC), independent of other major HCC risk factors. Dickkopf (DKK) 4, a secreted protein that antagonizes the canonical Wnt signaling pathway, is induced by T{sub 3} at both mRNA and protein levels in HCC cell lines. However, the mechanism underlying T{sub 3}-mediated regulation of DKK4 remains unknown. In the present study, the 5′ promoter region of DKK4 was serially deleted, and the reporter assay performed to localize the T{sub 3} response element (TRE). Consequently, we identified an atypical direct repeat TRE between nucleotides −1645 and −1629 conferring T{sub 3} responsiveness to the DKK4 gene. This region was further validated using chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA). Stable DKK4 overexpression in SK-Hep-1 cells suppressed cell invasion and metastatic potential, both in vivo andin vitro, via reduction of matrix metalloproteinase-2 (MMP-2) expression. Our findings collectively suggest that DKK4 upregulated by T{sub 3}/TR antagonizes the Wnt signal pathway to suppress tumor cell progression, thus providing new insights into the molecular mechanism underlying thyroid hormone activity in HCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Mediator subunit MED1 is a T3-dependent and T3-independent coactivator on the thyrotropin β gene promoter

Highlights: •MED1 is a bona fide T3-dependent coactivator on TSHB promoter. •Mice with LxxLL-mutant MED1 have attenuated TSHβ mRNA and thyroid hormone levels. •MED1 activates TSHB promoter T3-dependently in cultured cells. •T3-dependent MED1 action is enhanced when SRC1/SRC2 or HDAC2 is downregulated. •MED1 is also a T3-independent GATA2/Pit1 coactivator on TSHB promoter. -- Abstract: The MED1 subunit of the Mediator transcriptional coregulator complex is a nuclear receptor-specific coactivator. A negative feedback mechanism of thyroid-stimulating hormone (TSH, or thyrotropin) expression in the thyrotroph in the presence of triiodothyronine (T3) is employed by liganded thyroid hormone receptor β (TRβ) on the TSHβ gene promoter, where conventional histone-modifying coactivators act as corepressors. We now provide evidence that MED1 is a ligand-dependent positive cofactor on this promoter. TSHβ gene transcription was attenuated in MED1 mutant mice in which the nuclear receptor-binding ability of MED1 was specifically disrupted. MED1 stimulated GATA2- and Pit1-mediated TSHβ gene promoter activity in a ligand-independent manner in cultured cells. MED1 also stimulated transcription from the TSHβ gene promoter in a T3-dependent manner. The transcription was further enhanced when the T3-dependent corepressors SRC1, SRC2, and HDAC2 were downregulated. Hence, MED1 is a T3-dependent and -independent coactivator on the TSHβ gene promoter.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Thyroid hormones upregulate apolipoprotein E gene expression in astrocytes

Apolipoprotein E (apoE), a protein mainly involved in lipid metabolism, is associated with several neurodegenerative disorders including Alzheimer's disease. Despite numerous attempts to elucidate apoE gene regulation in the brain, the exact mechanism is still uncovered. The mechanism of apoE gene regulation in the brain involves the proximal promoter and multienhancers ME.1 and ME.2, which evolved by gene duplication. Herein we questioned whether thyroid hormones and their nuclear receptors have a role in apoE gene regulation in astrocytes. Our data showed that thyroid hormones increase apoE gene expression in HTB14 astrocytes in a dose-dependent manner. This effect can be intermediated by the thyroid receptor β (TRβ) which is expressed in these cells. In the presence of triiodothyronine (T3) and 9-cis retinoic acid, in astrocytes transfected to overexpress TRβ and retinoid X receptor α (RXRα), apoE promoter was indirectly activated through the interaction with ME.2. To determine the location of TRβ/RXRα binding site on ME.2, we performed DNA pull down assays and found that TRβ/RXRα complex bound to the region 341–488 of ME.2. This result was confirmed by transient transfection experiments in which a series of 5′- and 3′-deletion mutants of ME.2 were used. These data support the existence of a biologically active TRβ binding site starting at 409 in ME.2. In conclusion, our data revealed that ligand-activated TRβ/RXRα heterodimers bind with high efficiency on tissue-specific distal regulatory element ME.2 and thus modulate apoE gene expression in the brain. - Highlights: • T3 induce a dose-dependent increase of apoE expression in astrocytes. • Thyroid hormones activate apoE promoter in a cell specific manner. • Ligand activated TRβ/RXRα bind on the distal regulatory element ME.2 to modulate apoE. • The binding site of TRβ/RXRα heterodimer is located at 409 bp on ME.2.

60 APPLIED LIFE 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 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 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 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↗
DOE OSTI2013

Treating chronic arsenic toxicity with high selenium lentil diets

Arsenic (As) toxicity causes serious health problems in humans, especially in the Indo-Gangetic plains and mountainous areas of China. Selenium (Se), an essential micronutrient is a potential mitigator of As toxicity due to its antioxidant and antagonistic properties. Selenium is seriously deficient in soils world-wide but is present at high, yet non-toxic levels in the great plains of North America. We evaluate the potential of dietary Se in counteracting chronic As toxicity in rats through serum biochemistry, blood glutathione levels, immunotoxicity (antibody response), liver peroxidative stress, thyroid response and As levels in tissues and excreta. To achieve this, we compare diets based on high-Se Saskatchewan (SK) lentils versus low-Se lentils from United States. Rats drank control (0 ppm As) or As (40 ppm As) water while consuming SK lentils (0.3 ppm Se) or northwestern USA lentils (< 0.01 ppm Se) diets for 14 weeks. Rats on high Se diets had higher glutathione levels regardless of As exposure, recovered antibody responses in As-exposed group, higher fecal and urinary As excretion and lower renal As residues. Selenium deficiency caused greater hepatic peroxidative damage in the As exposed animals. Thyroid hormones, triiodothyronine (T3) and thyroxine (T4), were not different. After 14 weeks of As exposure, health indicators in rats improved in response to the high Se lentil diets. Our results indicate that high Se lentils have a potential to mitigate As toxicity in laboratory mammals, which we hope will translate into benefits for As exposed humans. - Highlights: • We reduce chronic arsenic toxicity in rats with a whole food solution. • High selenium lentils decrease liver damage and increase blood glutathione levels. • High selenium lentil diets increase urinary and fecal arsenic excretion. • High selenium lentil diets decrease arsenic levels in kidney, the storage organ. • High selenium lentil diets reverse arsenic suppression of the B cell response.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Effects of currently used pesticides and their mixtures on the function of thyroid hormone and aryl hydrocarbon receptor in cell culture

Evidence suggest that exposure to pesticides can interfere with the endocrine system by multiple mechanisms. The endocrine disrupting potential of currently used pesticides in Denmark was analyzed as single compounds and in an equimolar mixture of 5 selected pesticides. The pesticides were previously analyzed for effects on the function of estrogen and androgen receptors, the aromatase enzyme and steroidogenesis in vitro. In this study, the effect on thyroid hormone (TH) function and aryl hydrocarbon receptor (AhR) transactivity was assessed using GH3 cell proliferation assay (T-screen) and AhR responsive luciferase reporter gene bioassay, respectively. Thirteen pesticides were analyzed as follows: 2-methyl-4-chlorophenoxyacetic acid, terbuthylazine, iodosulfuron-methyl-sodium, mesosulfuron-methyl, metsulfuron-methyl, chlormequat chloride, bitertanol, propiconazole, prothioconazole, mancozeb and its metabolite ethylene thiourea, cypermethrin, tau-fluvalinate, and malathion (currently banned in DK). In the T-screen, prothioconazole, malathion, tau-fluvalinate, cypermethrin, terbuthylazine and mancozeb significantly stimulated and bitertanol and propiconazole slightly reduced the GH3 cell proliferation. In the presence of triiodothyronine (T3), prothioconazole, tau-fluvalinate, propiconazole, cypermethrin and bitertanol significantly antagonized the T3-induced GH3 cell proliferation. Eleven of the tested pesticides agonized the AhR function, and bitertanol and prothioconazole inhibited the basal AhR activity. Bitertanol, propiconazole, prothioconazole and cypermethrin antagonized the TCDD-induced AhR transactivation at the highest tested concentration. The 5-component mixture had inducing effect but the combined effect could not be predicted due to the presence of bitertanol eliciting inhibitory effect. Upon removal of bitertanol from the mixture, the remaining four pesticides acted additively. In conclusion, our data suggest that pesticides currently used in Denmark can interfere with TH signaling and AhR function in vitro and might have the potential to cause endocrine disruption. - Highlights: • Endocrine disrupting (ED) potential of currently used pesticides were evaluated in cell culture. • Pesticides were analyzed for disruption of TH and aryl hydrocarbon receptor function. • 6 pesticides increased the GH3 cell proliferation, whereasfour antagonized the T3-induced cell growth. • 11 pesticides had agonistic effect on AhR and 4 antagonized the TCDD-induced AhR transactivation. • The five component mixture had inducing effect in both assays.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2003

Hormonal changes associated with the transition between nursing and natural fasting in northern elephant seals (Mirounga angustirostris)

To better interpret previously described hormonal changes observed during the natural postweaning fast (2-3 months) endured by pups of the northern elephant seal (Mirounga angustirostris), we compared plasma cortisol, thyroid hormones, and leptin in pups (n=5) measured during nursing and fasting periods. Blood samples were taken at four times; early (9 days postpartum) and late (18-22 days postpartum) nursing, and early (second week postweaning) and late (eighth week postweaning) fasting. Plasma cortisol increased 39% between early and late nursing and almost 4-fold by late fasting. After the early nursing period, cortisol and body mass were negatively correlated (y=28.3-0.19 x; R=0.569; p=0.027). Total thyroxine (tT(4)), free T(4) (fT(4)), total triiodothyronine (tT3) and reverse T(3) (rT(3)) were greatest at early nursing and reduced by late nursing and remained so throughout the fast, with the exception of tT(4), which increased between late nursing (17.7+/-2.1 ng mL(-1)) and late fasting (30.1+/-2.8 ng mL(-1)) periods. Leptin remained unaltered among the four sampling periods and was not correlated with body mass. Pups appear to exhibit a shift in the relationship between cortisol and body mass suggesting a potential role for cortisol in the regulation of body fat. The higher concentrations of tT(3) and tT(4) during early nursing may reflect enhanced growth and development during this period, however the increase late in fasting is likely physiologically insignificant and an artifact of reduced metabolic clearance of these hormones. Transition of the pups from nursing to fasting states is characterized by a striking lack of change in cortisol, thyroid hormones, and leptin suggesting that any metabolic alterations associated with this transition may occur independent of these hormones.

NASA Discipline Regulatory Physiology↗