Astaxanthin mitigates dibutyl phthalate-induced thyroid hormone disruption in zebrafish larvae via multi-target regulation.

Phthalates are extensively used as plasticizers in a variety of daily-life products, resulting in widespread distribution in aquatic environments. However, limited information is available on the endocrine disrupting effects of phthalates in aquatic organisms. The aim of the present study was to examine whether exposure to mono-(2-ethylhexyl) phthalate (MEHP), the hydrolytic metabolite of di-(2-ethylhexyl) phthalate (DEHP) disrupts thyroid endocrine system in fish. In this study, zebrafish (Danio rerio) embryos were exposed to different concentrations of MEHP (1.6, 8, 40, and 200 μg/L) from 2 h post-fertilization (hpf) to 168 hpf. The whole-body content of thyroid hormone and transcription of genes involved in the hypothalamic-pituitary-thyroid (HPT) axis were examined. Treatment with MEHP significantly decreased whole-body T4 contents and increased whole-body T3 contents, indicating thyroid endocrine disruption. The upregulation of genes related to thyroid hormone metabolism (Dio2 and UGT1ab) might be responsible for decreased T4 contents. Elevated gene transcription of Dio1 was also observed in this study, which might assist to degrade increased T3 contents. Exposure to MEHP also significantly induced transcription of genes involved in thyroid development (Nkx2.1 and Pax8) and thyroid hormone synthesis (TSHβ, NIS and TG). However, the genes encoding proteins involved in TH transport (transthyretin, TTR) was transcriptionally significantly down-regulated after exposure to MEHP. Overall, these results demonstrate that acute exposure to MEHP alters whole-body contents of thyroid hormones in zebrafish embryos/larvae and changes the transcription of genes involved in the HPT axis, thus exerting thyroid endocrine toxicity.

Developmental toxicity and mechanism of dibutyl phthalate and alternative diisobutyl phthalate in the early life stages of zebrafish (Danio rerio)

Microcystin-RR exposure results in growth impairment by disrupting thyroid endocrine in zebrafish larvae

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

Fluoxetine (FLX), a typical selective serotonin reuptake inhibitors, has been frequently detected in aquatic environment and wild fish. However, little is known about its effect on thyroid endocrine system. In the present study, zebrafish (Danio rerio) embryos were exposed to 1, 3, 10, and 30 μg/L of FLX for 6 days. Chemical analysis demonstrated that FLX and its metabolic product (nonfluoxetine, NFLX) were accumulated in zebrafish larvae. The exposure resulted in decreased thyroid hormones (THs) levels, indicating thyroid endocrine disruption. Moreover, thyroid-stimulating hormone (TSH) content was significantly inhibited in a concentration-dependent manner after exposure to FLX. Gene transcription in the hypothalamic-pituitary-thyroid (HPT) axis was further examined, and the results showed that the genes encoding corticotrophin-releasing hormone (crh) and thyrotropin-releasing hormone (trh) were significantly up-regulated as a compensatory mechanism for the decreased TH contents accompanied with decreased tshβ mRNA expression. In addition, genes involved in thyroid hormone synthesis (sodium/iodide symporter, nis, thyroglobulin, tg) and transport (transthyretin, ttr) were down-regulated after exposure to FLX in a concentration-dependent manner. The increased gene transcription of deiodinases (dio2) and uridinediphosphate-glucuronosyltransferase (ugt1ab) might be responsible for the decrease of TH contents. In addition, a significant inhibition in thyroid hormone receptors (trα and trβ) gene expression was observed upon treatment with FLX. All these results demonstrated that FLX could alter THs and TSH content as well as gene transcription in the HPT axis, exerting an endocrine disruption of the thyroid system in zebrafish larvae.

Disrupting effects of neonicotinoids and their interaction with metals on thyroid hormone, an evidence of children in a rural area, South China.

Comparison of thyroid hormone disruption potentials by bisphenols A, S, F, and Z in embryo-larval zebrafish

Waterborne exposure to triadimefon causes thyroid endocrine disruption and developmental delay in Xenopus laevis tadpoles

Stereoselective cardiovascular toxicity of difenoconazole stereoisomers in zebrafish larvae (Danio rerio) through thyroid hormone disruption.

Bisphenol S (BPS) is widely used as a raw material in industry, resulting in its ubiquitous distribution in natural environment, including the aqueous environment. However, the effect of BPS on the thyroid endocrine system is largely unknown. In this study, zebrafish (Danio rerio) embryos were exposed to BPS at 1, 3, 10, and 30 μg/L, from 2 h post-fertilization (hpf) to 168hpf. Bioconcentration of BPS and whole-body thyroid hormones (THs), thyroid-stimulating hormone (TSH) concentrations as well as transcriptional profiling of key genes related to the hypothalamic-pituitary-thyroid (HPT) axis were examined. Chemical analysis indicated that BPS was accumulated in zebrafish larvae. Thyroxine (T4) and triiodothyronine (T3) levels were significantly decreased at ≥ 10 and 30 μg/L of BPS, respectively. However, TSH concentration was significantly induced in the 10 and 30 μg/L BPS-treated groups. After exposure to BPS, the mRNA expression of corticotrophin releasing hormone (crh) and thyroglobulin (tg) genes were up-regulated at ≥10 μg/L of BPS, in a dose-response manner. The transcription of genes involved in thyroid development (pax8) and synthesis (sodium/iodide symporter, slc5a5) were also significantly increased in the 30 μg/L of BPS treatment group. Moreover, exposure to 10 μg/L or higher concentration of BPS significantly up-regulated genes related to thyroid hormone metabolism (deiodinases, dio1, dio2 and uridinediphosphate glucoronosyltransferases, ugt1ab), which might be responsible for the altered THs levels. However, the transcript of transthyretin (ttr) was significantly down-regulated at ≥ 3 μg/L of BPS, while the mRNA levels of thyroid hormone receptors (trα and trβ) and dio3 remained unchanged. All the results indicated that exposure to BPS altered the whole-body THs and TSH concentrations and changed the expression profiling of key genes related to HPT axis, thus triggering thyroid endocrine disruption.

Bioconcentration and metabolism of decabromodiphenyl ether (BDE-209) result in thyroid endocrine disruption in zebrafish larvae

The thyroid hormone (TH) system is involved in many important physiological processes, including regulation of energy metabolism, growth and differentiation, development and maintenance of brain function, thermo-regulation, osmo-regulation, and axis of regulation of other endocrine systems, sexual behaviour and fertility, cardiovascular function. Therefore, concern about TH disruption (THD) has resulted in strategies being developed to identify THD chemicals (THDC). Information on potential of chemicals causing THD is typically derived from animal studies. However, for most chemicals, this information is often limited or even unavailable. It is also unlikely that animal experiments will be performed for all THD relevant chemicals in the near future for ethical, financial and practical reasons. In addition, typical animal experiments often do not provide information on the mechanism of action of THDC, making it harder to extrapolate results across species. Relevant effects may not be identified in animal studies when the effects are delayed, life stage specific, not assessed by the experimental paradigm (e.g., behaviour) or only occur when an organism has to adapt to environmental factors by modulating TH levels. Therefore, in vitro and in silico alternatives to identify THDC and quantify their potency are needed. THDC have many potential mechanisms of action, including altered hormone production, transport, metabolism, receptor activation and disruption of several feed-back mechanisms. In vitro assays are available for many of these endpoints, and the application of modern ‘-omics’ technologies, applicable for in vivo studies can help to reveal relevant and possibly new endpoints for inclusion in a targeted THDC in vitro test battery. Within the framework of the ASAT initiative (Assuring Safety without Animal Testing), an international group consisting of experts in the areas of thyroid endocrinology, toxicology of endocrine disruption, neurotoxicology, high-throughput screening, computational biology, and regulatory affairs has reviewed the state of science [1] for (1) known mechanisms for THD plus examples of THDC; (2) in vitro THD tests currently available or under development related to these mechanisms; and (3) in silico methods for estimating the blood levels of THDC. Based on this scientific review, the panel recommends a battery of test methods to be able to classify chemicals as of less or high concern for further hazard and risk assessment for THD.

Exposure to difenoconazole causes changes of thyroid hormone and gene expression levels in zebrafish larvae.

Bioconcentration of 2,4,6-tribromophenol (TBP) and thyroid endocrine disruption in zebrafish larvae

Effects of perchlorate on BDE-47-induced alteration thyroid hormone and gene expression of in the hypothalamus–pituitary–thyroid axis in zebrafish larvae