Fluoride & Zebrafish

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Zebrafish (Danio rerio) are considered an ideal model organism for studying thyroid development, function, and the effects of various factors, including endocrine-disrupting chemicals, on thyroid hormone regulation.

The US National Toxicology Program (NTP) has been working on an endocrine disruptor model using Zebrafish since 2016 (SEAZIT - Systematic Evaluation of the Application of Zebrafish in Toxicology). Yet, it failed to look at any of the existing data in its Draft Monograph on fluoride.

Zebrafish have even been used to study "dental fluorosis" (Zhang et al., 2016).

Inorganic Fluoride

Cao J, Feng C, Xie L, Li L, Chen J, Yun S, Guo W, Wang T, Wu Y, Meng R, Wang G, He X, Luo Y - "Sesamin attenuates histological alterations, oxidative stress and expressions of immune-related genes in liver of zebrafish (Danio rerio) exposed to fluoride" Fish Shellfish Immunol 106:715-723 (2020) doi: 10.1016/j.fsi.2020.08.039
https://www.sciencedirect.com/science/a ... 4820306033

Chen J, Luo Y, Cao J, Xie L - "Fluoride exposure changed the expression of microRNAs in gills of male zebrafish (Danio rerio)" Aquat Toxicol 233:105789 (2021) doi: 10.1016/j.aquatox.2021.105789
https://www.sciencedirect.com/science/a ... 5X21000485

Dondossola ER, Pacheco SD, Visentin SC, Mendes NV, Baldin SL, Bernardo HT, Scussel R, Rico EP - "Prolonged fluoride exposure alters neurotransmission and oxidative stress in the zebrafish brain" Neurotoxicology 89:92-98 (2022)
https://pubmed.ncbi.nlm.nih.gov/35065950/

Guo Wenjing, Wang T, Xue W, et al. - "Interference effects of fluoride on thyroid endocrine function in Zebrafish" Acta Scientiae Circumstantiae 39(4):1340-1347 (2019)
also cited as: Guo Wenjing, Wang Tianyu, Xue Wenjuan, et al. 2019 - "Interfering effect of fluorine on thyroid endocrine function in zebrafish" Journal of Environmental Science, 39(4):1340-1347 (2019)
DOI: 10.13671/j.hjkxxb.2018.0464
(Note time and dose-dependent bi-phasic effects)

Jianjie C, Wenjuan X, Jinling C, Jie S, Ruhui J, Meiyan L - "Fluoride caused thyroid endocrine disruption in male zebrafish (Danio rerio)" Aquat Toxicol 171:48-58 (2016)
https://pubmed.ncbi.nlm.nih.gov/26748264/
"The transcriptional levels of ...iodothyronine I (DIO1), and thyroid hormone receptor alpha (TRα) were also elevated in all fluoride-exposed male fish after 90 days of exposure...The results indicated that the growth of the male zebrafish used in the experiments was significantly inhibited, the thyroid microtrastructure was changed, and the levels of T3 and T4 were disturbed in fluoride-exposed male fish."

Karaman M, Toraman E, Sulukan E, Baran A, Bolat İ, Yıldırım S, Kankaynar M, Ghosigharehagaji A, Budak H, Ceyhun SB - "Fluoride exposure causes behavioral, molecular and physiological changes in adult zebrafish (Danio rerio) and their offspring" Environ Toxicol Pharmacol 97:104044 (2023) doi: 10.1016/j.etap.2022.104044
https://www.sciencedirect.com/science/a ... 892200237X

Li Junjun, Zhao Qiaoyu, Li Yue, Bao Ying, Li Bingyang, Yan Huazhu, Huo Si Meng, Fan Yumei, Yang Yanmei, Gao Yanhui - "Effects of embryonic fluoride exposure on skeletal development in zebrafish" Chinese Journal of Endemic Diseases 37(1):24-29 (2018). DOI: 10.3760/cma.j.issn.2095-4255.2018.01.006
"Low-dose fluoride exposure made zebrafish embryos bone sclerotic, and high-dose fluoride exposure made zebrafish embryos osteoporotic."

Li M, Cao J, Chen J, Song J, Zhou B, Feng C, Wang J - "Waterborne fluoride exposure changed the structure and the expressions of steroidogenic-related genes in gonads of adult zebrafish (Danio rerio)" Chemosphere 145:365-75 (2016) doi: 10.1016/j.chemosphere.2015.11.041
https://pubmed.ncbi.nlm.nih.gov/26692514/

Li M, Cao J, Zhao Y, Wu P, Li X, Khodaei F, Han Y, Wang J - "Fluoride impairs ovary development by affecting oogenesis and inducing oxidative stress and apoptosis in female zebrafish (Danio rerio)" Chemosphere 256:127105 (2020) doi: 10.1016/j.chemosphere.2020.127105
https://pubmed.ncbi.nlm.nih.gov/32450357/

Lu Y, Zhang X, Chen J, Cao J, Feng C, Yun S, Cheng Y, Cheng F - "Sex-specific effects of fluoride and lead on thyroid endocrine function in zebrafish (Danio rerio)" Chem Biol Interact 110151 (2022). doi: 10.1016/j.cbi.2022.110151
https://www.sciencedirect.com/science/a ... 9722003568

Mondal P, Shaw P, Bandyopadhyay A, Dey Bhowmik A, Chakraborty A, Sudarshan M, Chattopadhyay A - "Mixture effect of arsenic and fluoride at environmentally relevant concentrations in zebrafish (Danio rerio) liver: Expression pattern of Nrf2 and related xenobiotic metabolizing enzymes" Aquat Toxicol 213:105219 (2019) doi: 10.1016/j.aquatox.2019.06.002
https://pubmed.ncbi.nlm.nih.gov/31195325/

Mukhopadhyay D, Priya P, Chattopadhyay A - "Sodium fluoride affects zebrafish behaviour and alters mRNA expressions of biomarker genes in the brain: Role of Nrf2/Keap1" Environ Toxicol Pharmacol 40(2):352-9 (2015) doi: 10.1016/j.etap.2015.07.003
https://pubmed.ncbi.nlm.nih.gov/26245810/

Mukhopadhyay D, Srivastava R, Chattopadhyay A - "Sodium fluoride generates ROS and alters transcription of genes for xenobiotic metabolizing enzymes in adult zebrafish (Danio rerio) liver: expression pattern of Nrf2/Keap1 (INrf2)" Toxicol Mech Methods 25(5):364-73 (2015) doi: 10.3109/15376516.2015.1025348
https://www.tandfonline.com/doi/abs/10. ... 15.1025348

Mukhopadhyay D, Chattopadhyay A - "Induction of oxidative stress and related transcriptional effects of sodium fluoride in female zebrafish liver" Bull Environ Contam Toxicol 93(1):64-70 (2014) doi: 10.1007/s00128-014-1271-0
https://pubmed.ncbi.nlm.nih.gov/24705702/

Singh R, Khatri P, Srivastava N, Jain S, Brahmachari V, Mukhopadhyay A, Mazumder S - "Fluoride exposure abates pro-inflammatory response and induces in vivo apoptosis rendering zebrafish (Danio rerio) susceptible to bacterial infections" Fish Shellfish Immunol 63:314-321 (2017) doi: 10.1016/j.fsi.2017.02.022. Epub 2017 Feb 20. PMID: 28223109.
https://pubmed.ncbi.nlm.nih.gov/28223109/

Wang G, Wang T, Zhang X, Chen J, Feng C, Yun S, Cheng Y, Cheng F, Cao J - "Sex-specific effects of fluoride and lead exposures on histology, antioxidant physiology, and immune system in the liver of zebrafish (Danio rerio)" Ecotoxicology 31(3):396-414 (2022) doi: 10.1007/s10646-022-02519-5
https://link.springer.com/article/10.10 ... 22-02519-5

Wang T, Wu S, Chen J, Li L, Cao J - "Sesamin alleviated fluoride-induced thyroid endocrine disruption in zebrafish (Danio rerio)" Aquat Toxicol 261:106625 (2023) doi: 10.1016/j.aquatox.2023.106625
https://www.sciencedirect.com/science/a ... 5X2300228X
viewtopic.php?f=7&t=5483

Wu Y, Zhang X, Chen J, Cao J, Feng C, Luo Y, Lin Y - "Self-recovery study of fluoride-induced ferroptosis in the liver of zebrafish (Danio rerio)" Aquat Toxicol 251:106275 (2022) doi: 10.1016/j.aquatox.2022.106275
https://www.sciencedirect.com/science/a ... 5X22002016

Xue Wenjuan - "Study on the interference effect of fluoride on the hypothalamic-pituitary-thyroid axis in zebrafish" Dissertation (2015)
http://cdmd.cnki.com.cn/Article/CDMD-10 ... 623693.htm
viewtopic.php?f=21&t=2193

Zhang Y, Zhang Y, Zheng X, Xu R, He H, Duan X - "Grading and quantification of dental fluorosis in zebrafish larva" Arch Oral Biol 70:16-23 (2016) doi: 10.1016/j.archoralbio.2016.05.021
https://pubmed.ncbi.nlm.nih.gov/27300491/


Organic Fluoride [PFAS]

Kim J, Lee G, Lee YM, Zoh KD, Choi K - "Thyroid disrupting effects of perfluoroundecanoic acid and perfluorotridecanoic acid in zebrafish (Danio rerio) and rat pituitary (GH3) cell line" Chemosphere 262:128012 (2021) doi: 10.1016/j.chemosphere.2020.128012
https://www.sciencedirect.com/science/a ... 3520322074
"In GH3 cells, exposure to PFUnDA and PFTrDA upregulated Tshβ gene, suggesting that these PFCAs increase thyroid hormone synthesis through stimulation by Tsh."

Kim S, Stroski KM, Killeen G, Smitherman C, Simcik MF, Brooks BW - "8:8 Perfluoroalkyl phosphinic acid affects neurobehavioral development, thyroid disruption, and DNA methylation in developing zebrafish" Sci Total Environ 736:139600 (2020) doi: 10.1016/j.scitotenv.2020.139600
https://www.sciencedirect.com/science/a ... 972033120X
"At 144 h, several genes related to thyroid hormones that are essential for neurodevelopment, including corticotropin releasing hormone b (crhb), iodothyronine deiodinase 3a (dio3a), thyroid-stimulating hormone receptor (tshr) and nkx2 homeobox1 (nkx 2.1), were up-regulated by 8:8 PFPiA at 5.79 μM."

Mahoney H, Cantin J, Rybchuk J, Xie Y, Giesy JP, Brinkmann M - "Acute Exposure of Zebrafish (Danio rerio) to the Next-Generation Perfluoroalkyl Substance, Perfluoroethylcyclohexanesulfonate, Shows Similar Effects as Legacy Substances" Environ Sci Technol 57(10):4199-4207 (2023) doi: 10.1021/acs.est.2c08463
https://pubs.acs.org/doi/10.1021/acs.est.2c08463

Rericha Y, Simonich M, Truong L, Tanguay RL - "Review of the Zebrafish as a Model to Investigate per- and Polyfluoroalkyl Substance Toxicity" Toxicol Sci kfad051 (2023) doi: 10.1093/toxsci/kfad051
https://academic.oup.com/toxsci/advance ... 51/7176390

Shi X, Liu C, Wu G, Zhou B - "Waterborne exposure to PFOS causes disruption of the hypothalamus-pituitary-thyroid axis in zebrafish larvae" Chemosphere 77(7):1010-8 (2009) doi: 10.1016/j.chemosphere.2009.07.074
https://www.sciencedirect.com/science/a ... 3509009126
"A significant increase in NIS and Dio1 gene expression was observed at 200 microg L(-1) PFOS exposure, while TG gene expression was down-regulated at 200 and 400 microg L(-1) PFOS exposure."

Shi G, Cui Q, Zhang H, Cui R, Guo Y, Dai J - "Accumulation, Biotransformation, and Endocrine Disruption Effects of Fluorotelomer Surfactant Mixtures on Zebrafish" Chem Res Toxicol (2019) 32(7):1432-1440
https://pubmed.ncbi.nlm.nih.gov/31251046/
(T3 and T4 levels decreased in the 50 and 500 μg/L females and increased T4 level in 500 μg/L exposed males.)

Ulhaq ZS, Tse WKF - "Perfluorohexanesulfonic acid (PFHxS) induces oxidative stress and causes developmental toxicities in zebrafish embryos" J Hazard Mater 457:131722 (2023). doi: 10.1016/j.jhazmat.2023.131722
https://www.sciencedirect.com/science/a ... 9423010051

Wang J, Shi G, Yao J, Sheng N, Cui R, Su Z, Guo Y, Dai J - "Perfluoropolyether carboxylic acids (novel alternatives to PFOA) impair zebrafish posterior swim bladder development via thyroid hormone disruption" Environ Int 134:105317 (2020) doi: 10.1016/j.envint.2019.105317
https://pubmed.ncbi.nlm.nih.gov/31733528/
"For genes related to TH synthesis, the transcription levels of dio2 increased in the PFOA, PFO3OA, and PFO5DoDA-treated groups."

Wang G, Wang T, Zhang X, Chen J, Feng C, Yun S, Cheng Y, Cheng F, Cao J - "Sex-specific effects of fluoride and lead exposures on histology, antioxidant physiology, and immune system in the liver of zebrafish (Danio rerio)" Ecotoxicology 31(3):396-414 (2022)
https://pubmed.ncbi.nlm.nih.gov/35088223/
NOTE: Biphasic and sex-specific effects.

Wang Q, Liu Y, Zhang M, Liu S, Wan N, Li M, Tu W - "Novel PFOS alternative OBS inhibits body growth of developing zebrafish by triggering thyroid function disorder and osteoclast differentiation" Chemosphere 341:140068 (2023) doi: 10.1016/j.chemosphere.2023.140068
https://linkinghub.elsevier.com/retriev ... 23)02338-X
"This study systematically explored the inhibitory effects of PFOS and OBS exposure on body development and tightly linked the toxic effects to thyroid function disorder and osteoclast differentiation."

Wasel O, Thompson KM, Freeman JL - "Assessment of unique behavioral, morphological, and molecular alterations in the comparative developmental toxicity profiles of PFOA, PFHxA, and PFBA using the zebrafish model system" Environ Int 170:107642 (2022). doi: 10.1016/j.envint.2022.107642.
https://www.sciencedirect.com/science/a ... 2022005694

Xu M, Legradi J, Leonards P - "A comprehensive untargeted metabolomics study in zebrafish embryos exposed to perfluorohexane sulfonate (PFHxS)" Sci Total Environ 887:163770 (2023) doi: 10.1016/j.scitotenv.2023.163770
https://www.sciencedirect.com/science/a ... 9723023914

Xiu Ruiqin, Gao Shirong, Xu Yongxiang, et al. - "Study on joint toxicity of fluoride and selenium to fish" China Environmental Science 15(5):348-350 (1995)
https://europepmc.org/article/cba/285541

Yi S, Wang J, Wang R, Liu M, Zhong W, Zhu L, Jiang G - "Structure-Related Thyroid Disrupting Effect of Perfluorooctanesulfonate-like Substances in Zebrafish Larvae" Environ Sci Technol (2024) 58(1):182-193. doi: 10.1021/acs.est.3c07003 3.
https://pubs.acs.org/doi/10.1021/acs.est.3c07003
"PFOS-like substances could competitively replace THs to bind with TH plasma and membrane transporters, thereby disrupting TH transport and action, respectively. Moreover, they are also potent to disrupt TH synthesis and activation through Na+/K+-dependent transport of I- or competitive binding to the sites of deiodinases."

Zhang S, Guo X, Lu S, He J, Wu Q, Liu X, Han Z, Xie P - "Perfluorohexanoic acid caused disruption of the hypothalamus-pituitary-thyroid axis in zebrafish larvae" Ecotoxicol Environ Saf 232:113283 (2022) doi: 10.1016/j.ecoenv.2022.113283
https://www.sciencedirect.com/science/a ... 1322001233
"Treatment with PFHxA significantly downregulated dio2 gene transcription (0.79- and 0.79-fold) in the 2.4 and 12 mg/L exposure groups. The level of the dio1 gene was also decreased when exposed to 12 mg/L PFHxA."

Zhang S, Guo X, Lu S, Sang N, Li G, Xie P, Liu C, Zhang L, Xing Y - "Exposure to PFDoA causes disruption of the hypothalamus-pituitary-thyroid axis in zebrafish larvae" Environ Pollut 235:974-982 (2018) doi: 10.1016/j.envpol.2018.01.015
https://www.sciencedirect.com/science/a ... 9117326453
BI-PHASIC: "Upregulation and downregulation of iodothyronine deiodinases (dio1) gene expression were observed upon the treatment of 1.2 mg/L and 6 mg/L PFDoA, respectively."

see also:

Castro TFD, Paiva IM, Carvalho AFS, Assis IL, Palmieri MJ, Andrade-Vieira LF, Marcussi S, Solis-Murgas LD - "Genotoxicity of spent pot liner as determined with the zebrafish (Danio rerio) experimental model" Environ Sci Pollut Res Int 25(12):11527-11535 (2018) doi: 10.1007/s11356-018-1404-9
https://link.springer.com/article/10.10 ... 018-1404-9

Duan M, Zhang J, Liu J, Qian L, Chen X, Zhao F, Zhao W, Zhong Z, Yang Y, Wang C - "Toxic effects of broflanilide exposure on development of zebrafish (Danio rerio) embryos and its potential cardiotoxicity mechanism" Environ Pollut 286:117481 (2021)
https://pubmed.ncbi.nlm.nih.gov/34126520/

Wang Dongmei et al. - "Toxic effect of norfloxacin on zebrafish embryo development and its effect on TGF-β1" Biotechnology Bulletin No. 1 (2016)
http://www.cqvip.com/qk/90799x/2016001/667729303.html