RESUMEN
Conventional thyroid-disrupting chemicals (TDCs) such as polybrominated diphenyl ethers, polychlorinated biphenyls, and bisphenols perturb animal's thyroid endocrine system by mimicking the action of endogenous thyroid hormones (THs), since they share a similar backbone structure of coupled benzene rings with THs. 1-methyl-3-octylimidazolium bromide ([C8mim]Br), a commonly used ionic liquid (IL), has no structural similarity to THs. Whether it interferes with thyroid function and how its mode of action differs from conventional TDCs is largely unknown. Herein, zebrafish embryo-larvae experiments (in vivo), GH3 cell line studies (in vitro), and molecular simulation analyses (in silico) were carried out to explore the effect of [C8mim]Br on thyroid homeostasis and its underlying mechanism. Molecular docking results suggested that [C8mim]+ likely bound to retinoid X receptors (RXRs), which may compromise the formation of TH receptor/RXR heterodimers. This then perturbed the negative regulation of thyroid-stimulating hormone ß (tshß) transcription by T3 in GH3 cell line. The resulting enhancement of tshß expression further caused hyperthyroidism and developmental toxicity in larval zebrafish. These findings provided a crucial aspect of the ecological risks of ILs, and presented a new insight into the thyroid-disrupting mechanisms for emerging pollutants that do not have structural similarity to THs.
Asunto(s)
Glándula Tiroides , Contaminantes Químicos del Agua , Animales , Pez Cebra/metabolismo , Simulación del Acoplamiento Molecular , Contaminantes Químicos del Agua/toxicidad , Sistema Endocrino , Hormonas Tiroideas/metabolismo , LarvaRESUMEN
MC-LR can interfere with thyroid function in ï¬sh, but the underlying mechanism is still unclear. Current study focuses to study the intergenerational inheritance of MC-LR-induced thyroid toxicity in zebrafish and in rat thyroid cells. In vivo experiments, adult female zebrafish (F0) were exposed to MC-LR (0, 5, and 25 µg/L) for 90 days and mated with male zebrafish without MC-LR exposure to generate F1 generation. F1 embryos were allowed to develop normally to 7 days post-fertilization (dpf) in clear water. In the F0 generation, MC-LR induced disturbance of the hypothalamic-pituitary-thyroid (HPT) axis, leading to a decrease in the production of thyroid hormones. Maternal MC-LR exposure also induced growth inhibition by altering thyroid hormones (THs) homeostasis and interfering with thyroid metabolism and development in F1 offspring. Mechanistically, MC-LR caused excessive accumulation of ROS and induced ER stress that further lead to activation of UPR in the F0 and F1 offspring of zebrafish. Interestingly, our ï¬ndings suggested that MC-LR exposure hampered thyroglobulin turnover by triggering IRE1 and PERK pathway in zebrafish and FRTL-5 thyroid cells, thus disturbing the thyroid endocrine system and contributing to the thyroid toxicity from maternal to its F1 offspring of zebrafish. Particularly, inhibition of the IRE1 pathway by siRNA could alleviate thyroid development injury induced by MC-LR in FRTL-5 cells. In addition, MC-LR induced thyroid cell apoptosis by triggering ER stress. Taken together, our results demonstrated that maternal MC-LR exposure causes thyroid endocrine disruption by ER stress contributing to transgenerational effects in zebraï¬sh offspring.
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Estrés del Retículo Endoplásmico , Microcistinas , Glándula Tiroides , Animales , Femenino , Masculino , Apoptosis , Microcistinas/toxicidad , Microcistinas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/farmacología , Tiroglobulina/metabolismo , Tiroglobulina/farmacología , Glándula Tiroides/metabolismo , Glándula Tiroides/patología , Hormonas Tiroideas/metabolismo , Contaminantes Químicos del Agua/metabolismo , Pez Cebra/metabolismoRESUMEN
Benzisothiazolinone (BIT), one of the most widely used antimicrobial agents in consumer products, has frequently been detected in the water environment. The present study was conducted to determine the adverse effects of BIT on the thyroid neuroendocrine system of zebrafish embryos/larvae. Rat pituitary (GH3) cell line was employed to support the underlying mechanism of thyroid hormone disrupting effects. Significant coagulation and hatching delay were observed in embryos exposed to 30 µg/L of BIT, which in turn remarkably decreased hatchability and larval survival. In BIT-exposed larvae, tshß, tshr, and trh genes were significantly upregulated along with a decrease in thyroxine and triiodothyronine content, indicating that BIT decreased thyroid hormones and increased thyrotropin-releasing hormone and thyroid stimulating hormone secretion through a feedback circuit. The downregulation of trα and deio2 genes in the zebrafish larvae suggests the inhibition of thyroid hormone receptors and deiodination. Similar to the results in zebrafish, upregulation of tshß and downregulation of trα, trß, deio1, and deio2 genes were observed in GH3 cells. Our observations suggest that BIT can decrease the level of thyroid hormones by influencing central regulation, receptor binding, and deiodination.
Asunto(s)
Desinfectantes , Disruptores Endocrinos , Hormonas Tiroideas , Animales , Ratas , Línea Celular , Larva , Hormonas Tiroideas/metabolismo , Pez Cebra/metabolismo , Disruptores Endocrinos/toxicidad , Desinfectantes/toxicidadRESUMEN
The frequent detection of progestins in various aquatic environments and their potential endocrine disruptive effects in fish have attracted increasing attention worldwide. However, data on their effects on thyroid function and neurotoxicity in fish are limited, and the underlying mechanisms remain unclear. Here, the effects of gestodene (GES, a common progestin) on the thyroid endocrine and nervous systems of mosquitofish (Gambusia affinis) were studied. Adult female fish were exposed to GES at environmentally relevant concentrations (4.4-378.7 ng/L) for 60 days. The results showed that exposure to 378.7 ng/L GES caused a significant decrease in fish growth compared with the control and a marked reduction in the total distance traveled (50.6%) and swimming velocity (40.1-61.9%). The triiodothyronine (T3) levels were significantly increased by GES in a dose-dependent manner, whereas those of tetraiodothyronine (T4) were significantly decreased only at the G500 concentration. The acetylcholinesterase (AChE) activity was decreased significantly in the 4.42 ng/L GES treatments, but increased significantly at 378.67 ng/L. In the brain, a strong increase in the transcriptional levels of bdnf, trh, and dio2 was observed in fish after the 378.7 ng/L treatment. In addition, chronic exposure to GES caused colloid depletion with a concentration-dependent manner in the thyroid, and angiectasis, congestion, and vacuolar necrosis in the brain. These findings provide a better understanding of the effects of GES and associated underlying mechanisms in G. affinis.
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Ciprinodontiformes , Contaminantes Químicos del Agua , Animales , Femenino , Glándula Tiroides , Acetilcolinesterasa , Sistema Endocrino , Progestinas , Ciprinodontiformes/fisiología , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/análisisRESUMEN
Many environmental contaminants could be transmitted from parents and generate impairments to their progeny. The 2,4,6-tribromophenol (TBP), a novel brominated flame retardant which has been frequently detected in various organisms, was supposed to be bioaccumulated and intergenerational transmitted in human beings. Previous studies revealed that TBP could disrupt thyroid endocrine system in zebrafish larvae. However, there is no available data regarding the parental and transgenerational toxicity of this contaminant. Thus, in this study adult zebrafish were exposed to environmental contaminated levels of TBP for 60 days to investigate the parental and transgenerational impairments on thyroid endocrine system. Chemical analysis verified the bioaccumulation of TBP in tested organs of parents (concentration: liver>gonads>brain) and its transmission into eggs. For adults, increased thyroid hormones, disturbed transcriptions of related genes and histopathological changes in thyroid follicles indicate obvious thyroid endocrine disruptions. Transgenerational effects are indicated by the increased thyroid hormones both in eggs (maternal source) and in developed larvae (newly synthesized), as well as disrupted transcriptional profiles of key genes in HPT axis. The overall results suggest that the accumulated TBP could be transmitted from parent to offspring and generate thyroid endocrine disruptions in both generations.
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Disruptores Endocrinos , Retardadores de Llama , Contaminantes Químicos del Agua , Animales , Disruptores Endocrinos/toxicidad , Retardadores de Llama/toxicidad , Humanos , Larva , Fenoles , Glándula Tiroides , Hormonas Tiroideas , Contaminantes Químicos del Agua/toxicidad , Pez CebraRESUMEN
Dichlorooctylisothiazolinone (DCOIT), which is one of the isothiazolinone preservatives, is applied to water-based adhesives in food packaging. This study investigated the effects of DCOIT on the embryonic growth and thyroid endocrine system using zebrafish. Organism-level (hatchability, survival, and growth), hormone-level (triiodothyronine (T3) and thyroxine (T4)), gene-level (genes associated with the hypothalamus-pituitary-thyroid axis), and microRNA-level (microRNAs related to thyroid endocrine disruption) endpoints were measured. Significant rise in embryonic coagulation and delayed hatching (≥0.3 µg/L), and decreased larval length (30 µg/L) were observed in fish exposed to DCOIT. Lower contents of T3 and T4 were observed after exposure to DCOIT, which was accompanied by the upregulation of genes associated with the thyrotropin releasing hormone and thyroid stimulating hormone and the downregulation of genes associated with the thyroid hormone receptors and deiodination. Strong influence of DCOIT on dre-miR-193b and -499 may be a critical mechanism to inhibit transcription of trαa and trß, which in turn may affect thyroid hormones and development of the organism. Our findings suggest that hypothyroidism induced by the exposure to DCOIT is potentially associated with genetic and microRNA-level changes, which eventually affects development.
Asunto(s)
Disruptores Endocrinos , Contaminantes Químicos del Agua , Animales , Disruptores Endocrinos/toxicidad , Sistema Endocrino , Larva/efectos de los fármacos , Glándula Tiroides , Hormonas Tiroideas , Contaminantes Químicos del Agua/toxicidad , Pez Cebra/fisiologíaRESUMEN
Tris (2-chloroethyl) phosphate (TCEP), an emerging environmental pollutant, has been frequently detected in natural waters. The objective of this study was to investigate possible parental transfer of TCEP and transgenerational effects on the early development and thyroid hormone homeostasis in F1 larvae following parental whole life-cycle exposure to TCEP. To this end, zebrafish (Danio rerio) embryos were exposed to environmentally relevant concentrations (0.8, 4, 20 and 100 µg/L) of TCEP for 120 days until sexual maturation. Parental exposure to TCEP resulted in significant levels of TCEP, developmental toxicity including decreased survival and final hatching rates, accelerated heart rate and elevated malformation rate, as well as induction of oxidative stress and cell apoptosis in F1 offspring. In F1 eggs, declined thyroxin (T4) levels were observed, consistent with those in plasma of F0 adult females, indicating the maternal transfer of thyroid endocrine disruption to the offspring. In addition, mRNA levels of several genes along the hypothalamic-pituitary-thyroid (HPT) axis were significantly modified in F1 larvae, which could be linked to transgenerational developmental toxicity and thyroid hormone disruption. For the first time, we revealed that the parental exposure to environmentally relevant levels of TCEP could cause developmental toxicity and thyroid endocrine disruption in subsequent unexposed generation.
Asunto(s)
Glándula Tiroides , Pez Cebra , Femenino , Animales , Desarrollo Embrionario , Estadios del Ciclo de Vida , Larva , FosfatosRESUMEN
Organophosphate esters (OPEs) are widespread in various environmental media, and can disrupt thyroid endocrine signaling pathways. Mechanisms by which OPEs disrupt thyroid hormone (TH) signal transduction are not fully understood. Here, we present in vivo-in vitro-in silico evidence establishing OPEs as environmental THs competitively entering the brain to inhibit growth of zebrafish via multiple signaling pathways. OPEs can bind to transthyretin (TTR) and thyroxine-binding globulin, thereby affecting the transport of TH in the blood, and to the brain by TTR through the blood-brain barrier. When GH3 cells were exposed to OPEs, cell proliferation was significantly inhibited given that OPEs are competitive inhibitors of TH. Cresyl diphenyl phosphate was shown to be an effective antagonist of TH. Chronic exposure to OPEs significantly inhibited the growth of zebrafish by interfering with thyroperoxidase and thyroglobulin to inhibit TH synthesis. Based on comparisons of modulations of gene expression with the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases, signaling pathways related to thyroid endocrine functions, such as receptor-ligand binding and regulation of hormone levels, were identified as being affected by exposure to OPEs. Effects were also associated with the biosynthesis and metabolism of lipids, and neuroactive ligand-receptor interactions. These findings provide a comprehensive understanding of the mechanisms by which OPEs disrupt thyroid pathways in zebrafish.
RESUMEN
Chiral triazole pesticides may cause enantioselectively adverse effects to non-target organisms. In this work, we employed zebrafish as an aquatic organism model to explore stereoselective acute toxicity, bioaccumulation, oxidative stress, and thyroid disruption of cis-metconazole enantiomers. The median lethal concentration values of (1S, 5R)-metconazole, (1R, 5S)-metconazole, and the mixture of them against zebrafish were 4.01, 2.61 and 3.17 mgâ L-1, respectively. (1R, 5S)-Metconazole was preferentially bioaccumulated in zebrafish than (1S, 5R)-metconazole, and the bioconcentration factor of (1R, 5S)-metconazole was 1.28-fold larger than that of (1S, 5R)-metconazole. Then, the activity order of catalase, superoxide dismutase, and glutathione-S transferase enzymes in zebrafish was expressed as (1S, 5R)-metconazole > the mixture > (1R, 5S)-metconazole, while the order of malondialdehyde content in zebrafish was (1R, 5S)-metconazole > the mixture > (1S, 5R)-metconazole. Moreover, cis-metconazole exhibited enantioselective regulation effects on the levels of triiodothyronine and thyroxine in zebrafish, and (1R, 5S)-metconazole possessed stronger thyroid disruption ability to zebrafish than the others. By virtue of molecular docking methodology, the binding affair and docking energy results supported that interactions between (1R, 5S)-metconazole and thyroid hormone receptors were much stronger than those between (1S, 5R)-metconazole and same receptors. This study of enantioselective evaluation of cis-metconazole in zebrafish can provide favorable information for risk assessments of chiral pesticides toward environment and health of aquatic organisms.
Asunto(s)
Plaguicidas , Contaminantes Químicos del Agua , Animales , Bioacumulación , Simulación del Acoplamiento Molecular , Estrés Oxidativo , Plaguicidas/metabolismo , Plaguicidas/toxicidad , Estereoisomerismo , Glándula Tiroides , Triazoles/metabolismo , Contaminantes Químicos del Agua/toxicidad , Pez Cebra/metabolismoRESUMEN
Avobenzone and octinoxate are frequently used as organic ultraviolet filters, and these chemicals are widely detected in water. This study evaluated the potential of avobenzone and octinoxate to disrupt thyroid endocrine system in wild-type and thyroid hormone receptor alpha a knockout (thrαa-/-) zebrafish embryo/larvae. Following a 120 h exposure to various concentrations of avobenzone and octinoxate, larvae mortality and developmental toxicity in wild-type and thrαa-/- fish were assessed. Triiodothyronine (T3) and thyroxine (T4) levels as well as transcriptional levels of ten genes associated with the hypothalamus-pituitary-thyroid (HPT) axis were measured in wild-type fish. Significantly lower larvae survival rate in thrαa-/- fish exposed to ≥3 µM avobenzone and octinoxate suggests that the thyroid hormone receptor plays a crucial role in the toxic effects of avobenzone and octinoxate. A significant increase in the deio2 gene level in avobenzone-exposed zebrafish supports the result of an increased ratio of T3 to T4. Significant decrease of T4 level with upregulation of trh, tshß, and tshr genes indicates feedback in the hypothalamus and pituitary gland to maintain hormonal homeostasis. Our observation indicates that exposure to avobenzone and octinoxate affects the thyroid hormone receptor and the feedback mechanisms of the HPT axis. CLINICAL TRIALS REGISTRATION: Not applicable.
Asunto(s)
Disruptores Endocrinos , Contaminantes Químicos del Agua , Animales , Cinamatos , Disruptores Endocrinos/toxicidad , Sistema Endocrino , Larva , Propiofenonas , Receptores de Hormona Tiroidea/genética , Glándula Tiroides , Contaminantes Químicos del Agua/toxicidad , Pez Cebra/fisiologíaRESUMEN
The present study investigated the effects of paclobutrazol and uniconazole on thyroid endocrine system in rats. Lipidomic analysis was performed to obtain the biomarkers of thyroid endocrine disruption induced by paclobutrazol and uniconazole. Network pharmacology was further used to discover potential targets of biomarkers related to drugs and diseases. After paclobutrazol and uniconazole administration, seven and four common biomarkers related to thyroid endocrine disruption for female and male rats were obtained, respectively. Paclobutrazol and uniconazole significantly increased the biomarker levels of PG (12:0/15:0), PS (14:0/16:0), PA (20:1/15:0) and PG (13:0/17:0) in both sexes of rats. Exposure to paclobutrazol additionally caused a significant decrease of PG (22:6/20:2), PE (24:1/18:1) and PE (24:0/18:0) in female rats, while an increase in male rats. Changes of the common biomarkers for paclobutrazol and uniconazole revealed similar endocrine disruption effect, which was higher in the females. Network pharmacology and KEGG pathway analysis indicated that the thyroid endocrine disrupting effects of paclobutrazol and uniconazole may be related to V-akt murine thymoma viral oncogene homolog (Akts), mitogen-activated protein kinase (MAPKs), epidermal growth factor receptor (EGFR), Insulin-like growth factor (IGF-1), IGF-IR and V-Raf murine sarcoma viral oncogene homolog B1 (BRAF). The results demonstrated that paclobutrazol and uniconazole could cause thyroid endocrine disorders in male and female rats, which were sex-specific, thus highlighting the importance of safe and effective application of these plant growth regulators.
RESUMEN
The extensive applications of parabens in foods, drugs, and cosmetics cause inevitable exposure to humans. Revealing the developmental toxicity of parabens is of utmost importance regarding their safety evaluation. In this study, the effects of four commonly used parabens, including methyl paraben (20 â¼ 200 µM), ethyl paraben (20 â¼ 100 µM), propyl paraben (5 â¼ 20 µM), and butyl paraben (BuP, 2 â¼ 10 µM), were investigated on the early development of zebrafish embryos and larvae. The underlying mechanisms were explored from the aspect of their disturbance in the thyroid endocrine system using in vivo, in vitro, and in silico assays. Paraben exposure caused deleterious effects on the early development of zebrafish, with BuP displaying the highest toxicity among all, resulting in the exposure concentration-related mortality, decreased hatching rate, reduced body length, lowered heart rate, and the incidence of malformation. Further investigation showed that paraben exposure reduced thyroid hormone levels and disturbed the transcriptional expressions of the target genes in the hypothalamic-pituitary-thyroid axis. Molecular docking analysis combined with in vitro GH3 cell proliferation assay testified that all test parabens exhibited thyroid receptor agonistic activities. The findings confirmed the developmental toxicity of the test parabens and their thyroid endocrine disruption effects, providing substantial evidence on the safety control of paraben-based preservatives.
Asunto(s)
Parabenos , Glándula Tiroides , Animales , Simulación del Acoplamiento Molecular , Parabenos/análisis , Conservadores Farmacéuticos/toxicidad , Glándula Tiroides/metabolismo , Pez Cebra/metabolismoRESUMEN
Tris (2-chloroethyl) phosphate (TCEP) has been received great concerns because of its increasing presence in various environmental compartments and toxicity. In the present study, zebrafish embryos were exposed to environmentally relevant concentrations of TCEP (0.2, 2, 20, 200 µg/L) from 3 to 120 h post-fertilization (hpf). The results showed that TCEP exposure (20, 200 µg/L) led to developmental toxicity including decreased body length and delay of hatching. Treatment with TCEP significantly decreased whole-body thyroxine (T4) levels and mRNA level of thyroglobulin (tg), and enhanced transcriptions of genes sodium/iodide symporter (nis), thyroid hormone receptor α (trα) and ugt1ab involved in thyroid synthesis and metabolism, respectively. Additionally, TCEP altered the transcription of α1-tubulin, gap43 and mbp related to nervous system development, even at relatively low concentrations. Overall, our results revealed that TCEP exposure can lead to developmental toxicity, thyroid endocrine disruption and neurotoxicity on early developmental stages of zebrafish.
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Disruptores Endocrinos/toxicidad , Retardadores de Llama/toxicidad , Organofosfatos/toxicidad , Teratógenos/toxicidad , Animales , Embrión no Mamífero , Larva , Proteínas del Tejido Nervioso/genética , ARN Mensajero/metabolismo , Tiroxina/metabolismo , Triyodotironina/metabolismo , Pez Cebra , Proteínas de Pez Cebra/genéticaRESUMEN
Tralopyril, an antifouling biocide, widely used in antifouling systems to prevent underwater equipment from biological contamination, which can pose a potential risk to aquatic organisms and human health. However, there is little information available on the toxicity of tralopyril to aquatic organisms. Herein, zebrafish (Danio rerio) were used to investigate the toxicity mechanisms of tralopyril and a series of developmental indicators, thyroid hormones, gene expression and metabolomics were measured. Results showed that tralopyril significantly decreased the heart-beat and body length of zebrafish embryos-larvae exposed to 4.20 µg/L or higher concentrations of tralopyril and also induced developmental defects including pericardial hemorrhage, spine deformation, pericardial edema, tail malformation and uninflated gas bladder. Tralopyril decreased the thyroid hormone concentrations in embryos and changed the transcriptions of the related genes (TRHR, TSHß, TSHR, Nkx2.1, Dio1, TRα, TRß, TTR and UGT1ab). Additionally, metabolomics analysis showed that tralopyril affected the metabolism of amino acids, energy and lipids, which was associated with regulation of thyroid system. Furthermore, this study demonstrated that alterations of endogenous metabolites induced the thyroid endocrine disruption in zebrafish following the tralopyril treatment. Therefore, the results showed that tralopyril can induce adverse developmental effects on zebrafish embryos by disrupting the thyroid system and metabolism.
Asunto(s)
Glándula Tiroides , Pez Cebra , Animales , Pirroles , Hormonas TiroideasRESUMEN
2,4,6-tribromophenol (TBP) is generally used as a brominated flame retardant but is produced in the degradation of tetrabromobisphenol-A. Although TBP is frequently detected in the environment and in various biota, including fish species, we still know little about its toxicity and environmental health risk. Here we investigated the bioconcentration and effects of TBP on the thyroid endocrine system by using zebrafish as a model. Zebrafish embryos (2 h post-fertilization, hpf) were exposed to five concentrations of TBP (0, 0.3, 1, 10, and 100 µg/L) until 144 hpf. According to our chemical analysis, TBP underwent bioconcentration in zebrafish larvae. However, acute exposure to TBP did not affect the hatching of embryos or their risk of malformation, nor the growth and survival of larvae, indicating low developmental toxicity of TBP. The whole-body thyroxine (T4) contents were significantly increased in zebrafish larvae after exposure to TBP, indicating thyroid endocrine disruption occurred. Gene transcription levels in the hypothalamic-pituitary-thyroid (HPT) axis were also examined in larvae; these results revealed that the transcription of corticotrophin-releasing hormone (crh), thyrotropin-releasing hormone (trh), and thyroid-stimulating hormone (tshß) were all significantly downregulated by exposure to TBP. Likewise, genes encoding thyronine deiodinases (dio1, dio2, and dio3a/b) and thyroid hormone receptors (trα and trß) also had their transcription downregulated in zebrafish. Further, the gene transcription and protein expression of binding and transport protein transthyretin (TTR) were significantly increased after TBP exposure. Taken together, our results suggest the bioavailability of and potential thyroid endocrine disruption by TBP in fish.
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Bioacumulación/efectos de los fármacos , Embrión no Mamífero/efectos de los fármacos , Disruptores Endocrinos/toxicidad , Larva/efectos de los fármacos , Fenoles/toxicidad , Glándula Tiroides/efectos de los fármacos , Pez Cebra/metabolismo , Animales , Embrión no Mamífero/metabolismo , Disruptores Endocrinos/metabolismo , Larva/metabolismo , Fenoles/metabolismo , Glándula Tiroides/metabolismo , Tirotropina/metabolismo , Tiroxina/metabolismo , Pez Cebra/crecimiento & desarrollo , Proteínas de Pez Cebra/metabolismoRESUMEN
Cadmium is a common heavy metal pollutant. Previous studies have found that long-term cadmium exposure can cause damage to multiple organs/systems in humans and experimental animals; however, there are few studies that elucidate its effects on offspring development, discuss whether it can be transmitted to offspring from the parent, and debate whether it affects the functional development of the thyroid hormone system in offsprings. In this study, sexually mature zebrafish were exposed to different concentrations of cadmium chloride (0.01 µmol/L, 0.1 µmol/L, and 1 µmol/L) to study reproductive toxicity. It was found that parental zebrafish exposed to 1 µmol/L of cadmium chloride produced offsprings with different degrees of malformation. At 5 days post-fertilization (dpf), the levels of 3,5,3'-triiododenosine (T3) and thyroxine (T4) in the zebrafish were decreased. At 10 dpf, the T4 and T3 levels in the zebrafish of the offspring were significantly reduced. At the same time, the expression of thyroid receptor (trα and trß) genes in five dpf larvae was significantly up-regulated in the 1 µmol/L treatment group relative to the control group. The mRNAs of thyroid hormone synthesis and metabolism-related genes (tshß, dio1, dio2, ugt1ab, and ttr) were significantly up-regulated in the 0.1 µmol/L and 1 µmol/L treatment groups. This study demonstrates that parental cadmium chloride exposure produces reproductive toxicity in zebrafish and that the effects can be transferred from the parent to the offspring, resulting in developmental toxicity in the thyroid endocrine system.
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Cloruro de Cadmio/toxicidad , Disruptores Endocrinos/toxicidad , Exposición Materna/efectos adversos , Exposición Paterna/efectos adversos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Glándula Tiroides/efectos de los fármacos , Pez Cebra/crecimiento & desarrollo , Animales , Animales Recién Nacidos , Femenino , Fertilidad/efectos de los fármacos , Larva/efectos de los fármacos , Larva/crecimiento & desarrollo , Larva/metabolismo , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/patología , Tasa de Supervivencia , Glándula Tiroides/patología , Hormonas Tiroideas/metabolismo , Contaminantes Químicos del Agua/toxicidad , Pez Cebra/embriología , Pez Cebra/metabolismoRESUMEN
This study investigated the influences of titanium dioxide nanoparticles (n-TiO2) on the thyroid endocrine disruption and neurobehavioral defects induced by pentachlorophenol (PCP) in zebrafish (Danio rerio). Embryos (2 h post-fertilization) were exposed to PCP (0, 3, 10, and 30 µg/L) or in combination with n-TiO2 (0.1 mg/L) until 6 days post-fertilization. The results showed that n-TiO2 alone did not affect thyroid hormones levels or transcriptions of related genes. Exposure to PCP significantly decreased thyroid hormone thyroxine (T4) content, thyroid stimulating hormone (TSH) level and transcription of thyroglobulin (tg), but significantly increased 3,5,3'-triiodothyronine (T3) level and upregulation of deiodinase 2 (dio2). In comparison, the co-exposure with n-TiO2 significantly reduced the content of T3 by depressing the potential targets, tg and dio2. For neurotoxicity, the single and co-exposure resulted in similar effects with significant downregulation of neurodevelopment-related genes (ELAV like RNA Binding Protein 3, elavl3; Growth associated protein-43, gap43; α-tubulin) and inhibited locomotor activity. The results indicated that the presence of n-TiO2 significantly enhanced the PCP-induced thyroid endocrine disruption but not the neurobehavioral defects in zebrafish larvae.
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Disruptores Endocrinos/toxicidad , Pentaclorofenol/toxicidad , Pez Cebra/fisiología , Animales , Sistema Endocrino/efectos de los fármacos , Larva/efectos de los fármacos , Nanopartículas/toxicidad , Pentaclorofenol/metabolismo , Glándula Tiroides/efectos de los fármacos , Hormonas Tiroideas/metabolismo , Titanio/toxicidad , Triyodotironina/metabolismo , Pez Cebra/metabolismoRESUMEN
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 (0.18-0.36â¯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 0.24â¯ng/mL groups except decreased body weight (30 dpf, 0.24â¯ng/mL). However, exposed to 0.36â¯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 0.36â¯ng/mL ACT treatment. Moreover, RNA-Seq analysis implied that exposed to 0.36â¯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.
Asunto(s)
Disruptores Endocrinos/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Yoduro Peroxidasa/metabolismo , Compuestos Orgánicos de Estaño/toxicidad , Glándula Tiroides/metabolismo , Triyodotironina/biosíntesis , Animales , Línea Celular , Larva/metabolismo , Transducción de Señal/efectos de los fármacos , Hormonas Tiroideas/metabolismo , Pez Cebra/embriología , Yodotironina Deyodinasa Tipo IIRESUMEN
Graphene oxide (GO) has become a topic of increasing concern for its environmental and health risks. However, the potential toxic effects of GO on wildlife remain limited. The present study chose the Xenopus laevis tadpole as a model to assess the thyroid endocrine disruption as well as the lipid metabolic disturbance of GO. Tadpoles at the 51 stage were exposed to GO (0, 0.01, 0.1, and 1â¯mg/L) for 21 days, when tadpoles were undergoing an extremely complicated phase of morphological changes and growth. GO treatment showed obvious developmental toxicity, such as shortened snout-to-vent length (SVL) and hind limb length (HLL), decreased body weight, and delayed developmental stage. Exposure to GO also induced obvious decreases in whole-body triiodothyronine (T3) and thyroxin (T4) concentrations. The mRNA expression of genes related to the hypothalamic-pituitary-thyroid (HPT) axis also changed significantly. Furthermore, we observed significant decline in the fatty acids and triglycerides (TGs) concomitantly with changes in the expression of genes involved in the synthesis and metabolism of lipids in GO exposure groups. In contrast, high-density lipoprotein (HDL) and total bile acid levels increased remarkably, but cholesterol and low-density lipoprotein (LDH) levels showed no obvious changes. Taken together, the results revealed for the first time that GO could induce thyroid endocrine disruption and produce obvious disturbance effect on lipid synthesis and metabolism.
Asunto(s)
Disruptores Endocrinos/toxicidad , Grafito/toxicidad , Metabolismo de los Lípidos/efectos de los fármacos , Xenopus laevis/metabolismo , Animales , Grafito/farmacología , Larva/efectos de los fármacos , Metamorfosis Biológica/efectos de los fármacos , Óxidos/farmacología , Glándula Tiroides/efectos de los fármacos , Hormonas Tiroideas/metabolismo , Tiroxina/metabolismo , Triyodotironina/metabolismo , Xenopus laevis/crecimiento & desarrolloRESUMEN
Organotin compounds are the ubiquitous environmental pollutants due to their wide industrial and agricultural applications and unexpected releasing into the environment, which show characteristic of endocrine disruptors to interfere with the synthesis, receptor binding or action of endogenous-hormones. Organotin pesticides (OTPs) are used in agriculture and may impact endocrine functions on organisms. Thyroid hormones (THs) play fundamental roles in regulating the basal metabolism and energy balance, while thyroid function can be impaired by environmental contaminants. Therefore, it is crucial to clarify the effects and mechanisms of OTPs on hypothalamus-pituitary-thyroid (HPT) axis. In this study, Xenopus laevis tadpoles at stage 51 were exposed to fentin hydroxide and fenbutatin oxide (0.04, 0.20 and 1.00⯵g·L-1) for 21â¯days. It was found that both compounds caused inhibitory effects on metamorphic development of tadpoles (e.g., significant decrease in hindlimb length and retarding development). Triiodothyronine (T3) significantly decreased in tadpoles exposed to 0.20⯵g/L and 1.00⯵g/L of the two OTPs for 14â¯days or 21â¯days. The expressions of TH responsive genes trß, bteb and dio2 were down-regulated, while tshß and slc5a5 were up-regulated. Surface plasmon resonance (SPR) binding assays showed that fentin hydroxide had a moderate affinity to recombinant human thyroid hormone receptor ß but fenbutatin oxide did not have. Result of the SPR assay was highly consistent with the luciferase reporter gene assays that fentin hydroxide suppressed the relative luciferase activity in the presence of T3 while fenbutatin oxide did not, demonstrating fentin hydroxide but not fenbutatin oxide displayed an antagonistic activity against T3-TR complex mediated transcriptional activation. Overall, the findings elucidated the mechanisms induced by OTPs along HPT axis. These results highlighted the adverse influences of organotin pesticides on thyroid hormone- dependent development in vertebrates and the need for more comprehensive investigations of their potential ecological risks.