Expression dynamics of genes in the hypothalamic-pituitary-thyroid (HPT) cascade and their responses to 3,3′,5-triiodo-l-thyronine (T3) highlights potential vulnerability to thyroid-disrupting chemicals in zebrafish (Danio rerio) embryo-larvae

Parsons, Aoife E.; Lange, Anke; Hutchinson, Thomas H.; Miyagawa, Shinichi; Iguchi, Taisen; Kudoh, Tetsuhiro; Tyler, Charles R.

doi:10.1016/j.aquatox.2020.105547

Cited by 23 publications

(8 citation statements)

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“…THs play an important role in the growth and development of fish and the thyroid endocrine system, while the HPT axis can regulate the thyroid system [46]. In the current study, the levels of T3 and T4 were markedly changed after exposure to AFB1 or DON, and their contents were also distinctly altered in the JOT exposure groups.…”

Section: Discussionsupporting

confidence: 46%

Mixture toxic impacts and the related mechanism of aflatoxin B1 and deoxynivalenol on embryonic zebrafish (Danio rerio)

Wang

Chun³

et al. 2021

Environ Sci Eur

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Background Although humans and animals are often simultaneously exposed to a variety of mycotoxins via feed and food consumption, in which aflatoxin B1 (AFB1) and deoxynivalenol (DON) is one of the most prevalent combination of mycotoxins. Many toxicological studies have merely focused on the impacts of single mycotoxins. In the present study, the combined toxicity and the related mechanism of AFB1 and DON to zebrafish (Danio rerio) were investigated. Results Results exhibited that DON had lower toxicity to embryonic zebrafish with a 7-day LC50 of 218.3 mg a.i. L−1 in comparison to AFB1 (0.031 mg a.i. L−1). The mixture of AFB1 and DON elicited an additive combined effect on zebrafish embryos. The levels of CAT, caspase-3, and T4 markedly varied in most single and mixture groups. The expressions of four genes (cas3, apaf-1, cc-chem, and cyp19a) associated with oxidative stress, cellular apoptosis, immune system, and endocrine system were markedly varied upon the mixture exposure in comparison to the corresponding single exposure of AFB1 or DON. Conclusions Our results revealed that the impacts of a mixture could not be estimated solely based on toxicities of the single mycotoxins. Taken together, our comprehensive investigation on the mycotoxin mixtures and their potential mechanisms could better reflect the reality of mycotoxin contamination in food and feed.

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Section: Discussionsupporting

confidence: 46%

Mixture toxic impacts and the related mechanism of aflatoxin B1 and deoxynivalenol on embryonic zebrafish (Danio rerio)

Wang

Chun³

et al. 2021

Environ Sci Eur

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“…The binding of the agonists like THs with TR isoforms, that is, TRα and TRβ, would trigger the downstream transactivation and biological responses . The molecular docking analysis showed that, similar to the positive control (T3, Figure S4), four test parabens could bind with both TR isoforms by fitting in the active pockets via forming hydrogen bonds at distinct amino acids (Figure ).…”

Section: Discussionsupporting

confidence: 92%

“…These results strongly suggested the high vulnerability of the HPT axis to exogenous chemical insult during the early development of zebrafish. Additionally, the regulation of the HPT axis-related genes, like tt, dio1 , ugt1ab , and tr α, could directly correlate with the alteration of TH levels, ,, which was also evidenced by the findings on paraben-decreased TH contents herein (Figure ).…”

Section: Discussionmentioning

confidence: 96%

“…Some other biomarkers are indirectly related with the process of chemical-regulated HPT axis. For example, UGT enzymes, including ugt1ab , regulate the inactivation and excretion process of exogenous and endogenous compounds, while the expressions of TRs ( tr α and tr β) may determine the regulatory function of THs on the HPT axis of organisms …”

Section: Discussionmentioning

confidence: 99%

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Assessment of Thyroid Endocrine Disruption Effects of Parabens Using In Vivo, In Vitro, and In Silico Approaches

Liang

Yang

Liu

et al. 2021

Environ. Sci. Technol.

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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 ∼ 200 μM), ethyl paraben (20 ∼ 100 μM), propyl paraben (5 ∼ 20 μM), and butyl paraben (BuP, 2 ∼ 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.

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“…Upregulation of the deio2 gene in larvae exposed to avobenzone may also contribute to the increase in T3/T4 ratio. T4 can be converted to T3 through outer ring deiodination of deiodinase type I (deio1) and II (deio2) (Walpita et al 2009) or the glucuronidation enzymes ugt1ab (Parsons et al 2020). Upregulated deio2 transcription due to avobenzone exposure may enhance secretion of T3 and consequently increase the T3/T4 ratio.…”

Section: Discussionmentioning

confidence: 99%

Waterborne Exposure to Avobenzone and Octinoxate Induces Thyroid Endocrine Disruption in Wild-Type and Thrαa-/- Zebrafish Larvae

2022

Preprint

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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 embryos/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, tshβ, 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 feedback mechanisms of the HPT axis.

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Expression dynamics of genes in the hypothalamic-pituitary-thyroid (HPT) cascade and their responses to 3,3′,5-triiodo-l-thyronine (T3) highlights potential vulnerability to thyroid-disrupting chemicals in zebrafish (Danio rerio) embryo-larvae

Cited by 23 publications

References 68 publications

Mixture toxic impacts and the related mechanism of aflatoxin B1 and deoxynivalenol on embryonic zebrafish (Danio rerio)

Mixture toxic impacts and the related mechanism of aflatoxin B1 and deoxynivalenol on embryonic zebrafish (Danio rerio)

Assessment of Thyroid Endocrine Disruption Effects of Parabens Using In Vivo, In Vitro, and In Silico Approaches

Waterborne Exposure to Avobenzone and Octinoxate Induces Thyroid Endocrine Disruption in Wild-Type and Thrαa-/- Zebrafish Larvae

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