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PFOS-induced thyroid hormone system disrupted rats display organ-specific changes in their transcriptomes
2022
Davidsen, Nichlas | Ramhøj, Louise | Lykkebo, Claus Asger | Kugathas, Indusha | Poulsen, Rikke | Rosenmai, Anna Kjerstine | Evrard, Bertrand | Darde, Thomas A. | Axelstad, Marta | Bahl, Martin Iain | Hansen, Martin | Chalmel, Frederic | Licht, Tine Rask | Svingen, Terje
Perfluorooctanesulfonic acid (PFOS) is a persistent anthropogenic chemical that can affect the thyroid hormone system in humans and animals. In adults, thyroid hormones (THs) are regulated by the hypothalamic-pituitary-thyroid (HPT) axis, but also by organs such as the liver and potentially the gut microbiota. PFOS and other xenobiotics can therefore disrupt the TH system at various locations and through different mechanisms. To start addressing this, we exposed adult male rats to 3 mg PFOS/kg/day for 7 days and analysed effects on multiple organs and pathways simultaneously by transcriptomics. This included four primary organs involved in TH regulation, namely hypothalamus, pituitary, thyroid, and liver. To investigate a potential role of the gut microbiota in thyroid hormone regulation, two additional groups of animals were dosed with the antibiotic vancomycin (8 mg/kg/day), either with or without PFOS. PFOS exposure decreased thyroxine (T4) and triiodothyronine (T3) without affecting thyroid stimulating hormone (TSH), resembling a state of hypothyroxinemia. PFOS exposure resulted in 50 differentially expressed genes (DEGs) in the hypothalamus, 68 DEGs in the pituitary, 71 DEGs in the thyroid, and 181 DEGs in the liver. A concomitant compromised gut microbiota did not significantly change effects of PFOS exposure. Organ-specific DEGs did not align with TH regulating genes; however, genes associated with vesicle transport and neuronal signaling were affected in the hypothalamus, and phase I and phase II metabolism in the liver. This suggests that a decrease in systemic TH levels may activate the expression of factors altering trafficking, metabolism and excretion of TH. At the transcriptional level, little evidence suggests that the pituitary or thyroid gland is involved in PFOS-induced TH system disruption.
اظهر المزيد [+] اقل [-]Developmental assays using invasive cane toads, Rhinella marina, reveal safety concerns of a common formulation of the rice herbicide, butachlor
2021
Shuman-Goodier, Molly E. | Singleton, Grant R. | Forsman, Anna M. | Hines, Shyann | Christodoulides, Nicholas | Daniels, Kevin D. | Propper, Catherine R.
Identifying the adverse impacts of pesticide exposure is essential to guide regulations that are protective of wildlife and human health. Within rice ecosystems, amphibians are valuable indicators because pesticide applications coincide with sensitive reproductive and developmental life stages. We conducted two experiments using wild cane toads (Rhinella marina) to test 1) whether environmentally relevant exposure to a commercial formulation of butachlor, an acetanilide herbicide used extensively in rice, affects amphibian development and 2) whether cane toad tadpoles are capable of acclimatizing to sub-lethal exposure. First, we exposed wild cane toads to 0.002, 0.02, or 0.2 mg/L of butachlor (Machete EC), during distinct development stages (as eggs and hatchlings, as tadpoles, or continuously) for 12 days. Next, we exposed a subset of animals from the first experiment to a second, lethal concentration and examined survivorship. We found that cane toads exposed to butachlor developed slower and weighed less than controls, and that development of the thyroid gland was affected: exposed individuals had smaller thyroid glands and thyrocyte cells, and more individual follicles. Analyses of the transcriptome revealed that butachlor exposure resulted in downregulation of transcripts related to metabolic processes, anatomic structure development, immune system function, and response to stress. Last, we observed evidence of acclimatization, where animals exposed to butachlor early in life performed better than naïve animals during a second exposure. Our findings indicate that the commercial formulation of butachlor, Machete EC, causes thyroid endocrine disruption in vertebrates, and suggest that exposure in lowland irrigated rice fields presents a concern for wildlife and human health. Furthermore, we establish that developmental assays with cane toads can be used to screen for adverse effects of pesticides in rice fields.
اظهر المزيد [+] اقل [-]Integrated thyroid endocrine disrupting effect on zebrafish (Danio rario) larvae via simultaneously repressing type II iodothyronine deiodinase and activating thyroid receptor-mediated signaling following waterborne exposure to trace azocyclotin
2019
Jiao, Fang | Qiao, Kun | Jiang, Yao | Li, Shuying | Zhao, Jinghao | Gui, Wenjun
As a widely used organotin acaricide nowadays, azocyclotin (ACT) could induce thyroidal endocrine disruption in fishes and amphibians, but its dominant disrupting mode remains unknown. In this study, zebrafish were firstly exposed to ACT (0.18–0.36 ng/mL) from 2 hpf (hours post fertilization) to 30 dpf (days post fertilization), and a series of developmental toxicological endpoints and thyroid hormones were measured. Result showed that no developmental toxicity to zebrafish was found in 0.18 and 0.24 ng/mL groups except decreased body weight (30 dpf, 0.24 ng/mL). However, exposed to 0.36 ng/mL ACT led to reductions in heartbeat (48 hpf), hatching rate (72 hpf) and bodyweight (30 dpf). General tendencies of decreases in free T3 but increases in free T4 and reductions in ratio of free T3/T4 were also found, inferring that type II deiodinase (Dio2) was repressed. This inference was confirmed by Western analysis that Dio2 expression reduced by 42.7% after 0.36 ng/mL ACT treatment. Moreover, RNA-Seq analysis implied that exposed to 0.36 ng/mL ACT altered the genome-wide gene expression profiles of zebrafish. Totally 5660 genes (involving 3154 down-regulated and 2596 up-regulated genes) were differentially expressed, and 13 deferentially expressed genes including down-regulated dio2 were significantly enriched in thyroid hormone signaling pathway. Subsequently, an in vitro thyroid receptor-reporter gene assay using GH3 cells was performed to further explore the potential disrupting mechanism. Result showed that luciferase activity slightly increased after exposure to ACT alone or ACT combined with low level T3, but was suppressed when combined with high level T3. It indicted there probably existed a competitive relationship in some extent between ACT and T3 in vivo. Overall, the present study provided preliminary evidences that long-term exposure to trace ACT repressed Dio2 expression, declined T3 and then activated thyroid receptor-mediated signaling, thereby leading to integrated thyroid endocrine disruption in zebrafish larvae.
اظهر المزيد [+] اقل [-]Early life exposure to triphenyl phosphate: Effects on thyroid function, growth, and resting metabolic rate of Japanese quail (Coturnix japonica) chicks
2019
Guigueno, M.F. | Head, J.A. | Letcher, R.J. | Karouna-Renier, N. | Peters, L. | Hanas, A.M. | Fernie, K.J.
Triphenyl phosphate (TPHP; CAS # 115-86-6), a commonly used plasticizer and flame retardant, has been reported in wild birds and identified as a potential high-risk chemical. We exposed Japanese quail (Coturnix japonica) by in ovo injection, and once hatched, orally each day for 5 days to safflower oil (controls) or TPHP dissolved in vehicle at low (5 ng TPHP/g), mid (50 ng TPHP/g), or high (100 ng TPHP/g) nominal TPHP doses. The low TPHP dose reflected concentrations in wild bird eggs, with mid and high doses 10x and 20x greater to reflect potential increases in environmental TPHP concentrations in the future. Despite no effects on mRNA expression in thyroid-related genes, TPHP exposure enhanced thyroid gland structure in high TPHP males, but in females, suppressed thyroid gland structure and activity (all TPHP females), and circulating free triiodothyronine (high TPHP females only). Consistent with thyroidal changes, and compared to controls, mid and high TPHP chicks experienced significantly reduced resting metabolic rate (≤13%) and growth (≤53%); mid TPHP males and high TPHP females were significantly smaller. The observed thyroidal effects and suppressed growth and metabolic rate of the quail chicks suggest that TPHP may adversely affect the health of wild birds.
اظهر المزيد [+] اقل [-]Stereoselective degradation and thyroid endocrine disruption of lambda-cyhalothrin in lizards (Eremias argus) following oral exposure
2018
Chang, Jing | Hao, Weiyu | Xu, Yuanyuan | Xu, Peng | Li, Wei | Li, Jianzhong | Wang, Huili
The disturbance of the thyroid system and elimination of chiral pyrethroid pesticides with respect to enantioselectivity in reptiles have so far received limited attention by research. In this study, bioaccumulation, thyroid gland lesions, thyroid hormone levels, and hypothalamus-pituitary-thyroid axis-related gene expression in male Eremias argus were investigated after three weeks oral administration of lambda-cyhalothrin (LCT) enantiomers. In the lizard liver, the concentration of LCT was negatively correlated with the metabolite-3-phenoxybenzoic acid (PBA) level during 21 days of exposure. (+)-LCT exposure induced a higher thyroid follicular epithelium height than (−)-LCT exposure. The thyroxine levels were increased in both treated groups while only (+)-LCT exposure induced a significant change in the triiodothyronine (T3) level. In addition, the expressions of hypothalamus-pituitary-thyroid axis-related genes including thyroid hormone receptors (trs), deiodinases (dios), uridinediphosphate glucuronosyltransferase (udp), and sulfotransferase (sult) were up-regulated after exposure to the two enantiomers. (+)-LCT treatment resulted in higher expression of trs and (−)-LCT exposure led to greater stimulation of dios in the liver, which indicated PBA-induced antagonism on thyroid hormone receptors and LCT-induced disruption of thyroxine (T4) deiodination. The results suggest the (−)-LCT exposure causes higher residual level in lizard liver while induces less disruption on lizard thyroid activity than (+)-LCT.
اظهر المزيد [+] اقل [-]Synthesis and applications of bismuth-impregnated biochars originated from spent coffee grounds for efficient adsorption of radioactive iodine: A mechanism study
2022
Kwak, Jinwoo | Lee, Sang-Ho | Shin, Jaegwan | Lee, Yong-Gu | Kim, Sangwon | Son, Changgil | Ren, Xianghao | Shin, Jae-Ki | Park, Yongeun | Chon, Kangmin
The adsorption of radioactive iodine, which is capable of presenting high mobility in aquatic ecosystems and generating undesirable health effects in humans (e.g., thyroid gland dysfunction), was comprehensively examined using pristine spent coffee ground biochar (SCGB) and bismuth-impregnated spent coffee ground biochar (Bi@SCGB) to provide valuable insights into the variations in the adsorption capacity and mechanisms after pretreatment with Bi(NO₃)₃. The greater adsorption of radioactive iodine toward Bi@SCGB (adsorption capacity (Qₑ) = 253.71 μg/g) compared to that for SCGB (Qₑ = 23.32 μg/g) and its reduced adsorption capability at higher pH values provide evidence that the adsorption of radioactive iodine with SCGB and Bi@SCGB is strongly influenced by the presence of bismuth materials and the electrostatic repulsion between their negatively charged surfaces and negatively charged radioactive iodine (IO₃⁻). The calculated R² values for the adsorption kinetics and isotherms support that chemisorption plays a crucial role in the adsorption of radioactive iodine by SCGB and Bi@SCGB in aqueous phases. The adsorption of radioactive iodine onto SCGB was linearly correlated with the contact time (h¹/²), and the diffusion of intra-particle predominantly determined the adsorption rate of radioactive iodine onto Bi@SCGB (Cₛₜₐgₑ II (129.20) > Cₛₜₐgₑ I (42.33)). Thermodynamic studies revealed that the adsorption of radioactive iodine toward SCGB (ΔG° = −8.47 to −7.83 kJ/mol; ΔH° = −13.93 kJ/mol) occurred exothermically and that for Bi@SCGB (ΔG° = −15.90 to −13.89 kJ/mol; ΔH° = 5.88 kJ/mol) proceeded endothermically and spontaneously. The X-ray photoelectron spectroscopy (XPS) analysis of SCGB and Bi@SCGB before and after the adsorption of radioactive iodine suggest the conclusion that the change in the primary adsorption mechanism from electrostatic attraction to surface precipitation upon the impregnation of bismuth materials on the surfaces of spent coffee ground biochars is beneficial for the adsorption of radioactive iodine in aqueous phases.
اظهر المزيد [+] اقل [-]Subacute exposure to lead promotes disruption in the thyroid gland function in male and female rats
2021
de Lima Junior, Niedson Correia | Camilo, Juliana Franco | do Carmo, Pâmella Rodrigues | de Andrade, Marcelle Novaes | Braz, Bernardo Ferreira | Santelli, Ricardo Erthal | de Brito Gitirana, Lycia | Ferreira, Andrea Claudia Freitas | de Carvalho, Denise Pires | Miranda-Alves, Leandro | Dias, Glaecir Roseni Mundstock
Exposure to heavy metals, such as lead, is a global public health problem. Lead has a long historic relation to several adverse health conditions and was recently classified as an endocrine disruptor. The aim of this study was to investigate the effects of subacute exposure to lead on the thyroid gland function. Adult male and female Wistar rats received a lead acetate solution containing 10 or 25 mg/kg, by gavage, three times a week, for 14 days. One week later, behavioral testing showed no alterations in anxiety and motor-exploratory parameters, as evaluated by Open-Field and Plus-Maze Tests, but impairment in learning and memory was found in the male 25 mg/kg lead-treated group and in both female lead-treated groups, as evaluated by the Inhibitory Avoidance Test. After one week, serum levels of tT3 were reduced in the 25 mg/kg female group and in the 10 mg∕ kg male group. However, tT4 levels were increased in the 25 mg/kg male group and in both female treated groups. TSH levels did not change and lead serum levels were undetectable. Morphologic alterations were observed in the thyroid gland, including abnormal thyroid parenchyma follicles of different sizes, epithelial stratification and vacuolization of follicular cells, decrease in colloid eosinophilia and vascular congestion, accompanied by morphometric alterations. An increase in collagen deposition was also observed. No differences were observed in TPO activity or protein expression, H₂O₂ generation by NADPH oxidases or hepatic D1 mRNA expression. However, thyroid NIS protein expression was considerably decreased in the male and female lead-treated groups, while TSHr expression was decreased in the 25 mg/kg female lead-treated group. These findings demonstrated that subacute exposure to lead acetate disrupts thyroid gland function in both sexes, leading to morphophysiological impairment and to changes in learning and memory abilities.
اظهر المزيد [+] اقل [-]The environmental contaminant tributyltin leads to abnormalities in different levels of the hypothalamus-pituitary-thyroid axis in female rats
2018
Andrade, Marcelle Novaes | Santos-Silva, Ana Paula | Rodrigues-Pereira, Paula | Paiva-Melo, Francisca Diana | de Lima Junior, Niedson Correa | Teixeira, Mariana Pires | Soares, Paula | Dias, Glaecir Roseni Munstock | Graceli, Jones Bernardes | de Carvalho, Denise Pires | Ferreira, Andrea Claudia Freitas | Miranda-Alves, Leandro
Tributyltin is a biocide used in nautical paints, aiming to reduce fouling of barnacles in ships. Despite the fact that many effects of TBT on marine species are known, studies in mammals have been limited, especially those evaluating its effect on the function of the hypothalamus-pituitary-thyroid (HPT) axis. The aim of this study was to investigate the effects of subchronic exposure to TBT on the HPT axis in female rats. Female Wistar rats received vehicle, TBT 200 ng kg−1 BW d−1 or 1000 ng kg−1 BW d−1 orally by gavage for 40 d. Hypothalamus, pituitary, thyroid, liver and blood samples were collected. TBT200 and TBT1000 thyroids showed vacuolated follicular cells, with follicular hypertrophy and hyperplasia. An increase in epithelial height and a decrease in the thyroid follicle and colloid area were observed in TBT1000 rats. Moreover, an increase in the epithelium/colloid area ratio was observed in both TBT groups. Lower TRH mRNA expression was observed in the hypothalami of TBT200 and TBT1000 rats. An increase in Dio1 mRNA levels was observed in the hypothalamus and thyroid in TBT1000 rats only. TSH serum levels were increased in TBT200 rats. In TBT1000 rats, there was a decrease in total T4 serum levels compared to control rats, whereas T3 serum levels did not show significant alterations. We conclude that TBT exposure can promote critical abnormalities in the HPT axis, including changes in TRH mRNA expression and serum TSH and T4 levels, in addition to affecting thyroid morphology. These findings demonstrate that TBT disrupts the HPT axis. Additionally, the changes found in thyroid hormones suggest that TBT may interfere with the peripheral metabolism of these hormones, an idea corroborated by the observed changes in Dio1 mRNA levels. Therefore, TBT exposition might interfere not only with the thyroid axis but also with thyroid hormone metabolism.
اظهر المزيد [+] اقل [-]Plasticizers: negative impacts on the thyroid hormone system
2022
Bereketoglu, Ceyhun | Pradhan, Ajay
This review aims to understand the impacts of plasticizers on the thyroid system of animals and humans. The thyroid gland is one of the earliest endocrine glands that appear during embryogenesis. The thyroid gland synthesizes thyroid hormones (TH), triiodothyronine (T3), and thyroxine (T4) that are important in the regulation of body homeostasis. TH plays critical roles in regulating different physiological functions, including metabolism, cell growth, circadian rhythm, and nervous system development. Alteration in thyroid function can lead to different medical problems. In recent years, thyroid-related medical problems have increased and this could be due to rising environmental pollutants. Plasticizers are one such group of a pollutant that impacts thyroid function. Plasticizers are man-made chemicals used in a wide range of products, such as children’s toys, food packaging items, building materials, medical devices, cosmetics, and ink. The increased use of plasticizers has resulted in their detection in the environment, animals, and humans. Studies indicated that plasticizers could alter thyroid function in both animals and humans at different levels. Several studies demonstrated a positive and/or negative correlation between plasticizers and serum T4 and T3 levels. Plasticizers could also change the expression of various TH-related genes and proteins, including thyroid-stimulating hormone (TSH), thyrotropin-releasing hormone (TRH), and transporters. Histological analyses demonstrated thyroid follicular cell hypertrophy and hyperplasia in response to several plasticizers. In conclusion, plasticizers could disrupt TH homeostasis and the mechanisms of toxicity could be diverse.
اظهر المزيد [+] اقل [-]Toxicological effects of toxic metals (cadmium and mercury) on blood and the thyroid gland and pharmacological intervention by vitamin C in rabbits
2019
Khan, Rida | Tareen, Shaukat | Mumtaz, Shumaila | Andleeb, Saiqa | Ulhaq, Mazhar | T̤āhir, Ḥāfiz̤ Muḥammad | Khan, Muhammad Khalil Ahmad | Khan, Muhammad Adeeb | Shakir, Hafiz Abdullah
Cadmium and mercury are non-biodegradable toxic metals that may cause many detrimental effects to the thyroid gland and blood. Vitamin C has been found to be a significant chain-breaking antioxidant and enzyme co-factor against metal toxicity and thus make them less available for animals. The current study was performed to find the effect of individual metals (cadmium and mercury), their co-administration, and the ameliorative effects of vitamin C on some of the parameters that indicate oxidative stress and thyroid dysfunction. Cadmium chloride (1.5 mg/kg), mercuric chloride (1.2 mg/kg), and vitamin C (150 mg/kg of body weight) were orally administered to eight treatment groups of the rabbits (1. control; 2. Vit C; 3. CdCl₂; 4. HgCl₂; 5. Vit C + CdCl₂; 6. Vit C + HgCl₂; 7. CdCl₂ + HgCl₂, and 8. Vit C + CdCl₂ + HgCl₂). After the biometric measurements of all experimental rabbits, biochemical parameters viz. triidothyronine (T₃), thyroxine (T₄), thyroid-stimulating hormone (TSH), and triglycerides were measured using commercially available kits. The results exhibited significant decline (p < 0.05) in mean hemoglobin, corpuscular hemoglobin, packed cell volume, T₃ (0.4 ± 0.0 ng/ml), and T₄ (26.3 ± 1.6 ng/ml) concentration. While, TSH (0.23 ± 0.01 nmol/l) and triglyceride (4.42 ± 0.18 nmol/l) were significantly (p < 0.05) increased but chemo-treatment with Vit C reduces the effects of Cd, Hg, and their co-administration but not regained the values similar to those of controls. This indicates that Vit C had a shielding effect on the possible metal toxicity. The Cd and Hg also found to accumulate in vital organs when measured by atomic absorption spectrophotometer. The metal concentration trend was observed as follows: kidney > liver > heart > lungs. It was concluded that Cd and Hg are toxic and tended to bioaccumulate in different organs and their toxic action can be subdued by vitamin C in biological systems.
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