Toxicity profiling of flame retardants in zebrafish embryos using a battery of assays for developmental toxicity, neurotoxicity, cardiotoxicity and hepatotoxicity toward human relevance

Alzualde, Ainhoa; Behl, Mamta; Sipes, Nisha S.; Hsieh, Jui-Hua; Alday, Aintzane; Tice, Raymond R.; Paules, Richard S.; Muriana, Arantza; Quevedo, Celia

doi:10.1016/j.ntt.2018.10.002

Cited by 128 publications

(63 citation statements)

References 58 publications

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“…Several recent streams of data are converging on the conclusion that OPFRs show equivalent (or in some cases greater) toxicity compared to some of the phased-out PBDEs in several human-derived cell-based models (Behl et al 2015). These compounds have also been shown to produce neurobehavioral deficits in complementary animal models (Alzualde et al 2018;Bailey and Levin 2015;Glazer et al 2018;Oliveri et al 2015;Yan et al 2017;Zhang et al 2019) and might be a regretful substitution (Zimmerman and Anastas 2015).…”

Section: Discussionmentioning

confidence: 99%

Organophosphorus flame retardants are developmental neurotoxicants in a rat primary brainsphere in vitro model

et al. 2020

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Due to regulatory bans and voluntary substitutions, halogenated polybrominated diphenyl ether (PBDE) flame retardants (FR) are increasingly substituted by mainly organophosphorus FR (OPFR). Leveraging a 3D rat primary neural organotypic in vitro model (rat brainsphere), we compare developmental neurotoxic effects of BDE-47—the most abundant PBDE congener—with four OPFR (isopropylated phenyl phosphate—IPP, triphenyl phosphate—TPHP, isodecyl diphenyl phosphate—IDDP, and tricresyl phosphate (also known as trimethyl phenyl phosphate)—TMPP). Employing mass spectroscopy-based metabolomics and transcriptomics, we observe at similar human-relevant non-cytotoxic concentrations (0.1–5 µM) stronger developmental neurotoxic effects by OPFR. This includes toxicity to neurons in the low µM range; all FR decrease the neurotransmitters glutamate and GABA (except BDE-47 and TPHP). Furthermore, n-acetyl aspartate (NAA), considered a neurologic diagnostic molecule, was decreased by all OPFR. At similar concentrations, the FR currently in use decreased plasma membrane dopamine active transporter expression, while BDE-47 did not. Several findings suggest astrogliosis induced by the OPFR, but not BDE-47. At the 5 µM concentrations, the OPFR more than BDE-47 interfered with myelination. An increase of cytokine gene and receptor expressions suggests that exposure to OPFR may induce an inflammatory response. Pathway/category overrepresentation shows disruption in 1) transmission of action potentials, cell–cell signaling, synaptic transmission, receptor signaling, (2) immune response, inflammation, defense response, (3) cell cycle and (4) lipids metabolism and transportation. Taken together, this appears to be a case of regretful substitution with substances not less developmentally neurotoxic in a primary rat 3D model.

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Section: Discussionmentioning

confidence: 99%

Organophosphorus flame retardants are developmental neurotoxicants in a rat primary brainsphere in vitro model

et al. 2020

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“…It has been reported that TBBPA affects thyroid hormone levels in zebrafish with consequent alterations in behavior suggesting that this organism may be utilized as a novel model to identify neurotoxic compounds (Fraser et al 2017;Zhu et al 2018;DeWit et al 2008). Alzualde et al (2018) reported no marked change in behavior and neurotoxic effects in larval zebrafish exposed to 1-100 µM TBBPA. Godfrey et al (2017) found no significant alterations in locomotor activity in zebrafish larva exposed to 13 µL TBBPA.…”

Section: Zebrafishmentioning

confidence: 94%

Absence of neurotoxicity and lack of neurobehavioral consequences due to exposure to tetrabromobisphenol A (TBBPA) exposure in humans, animals and zebrafish

Kacew

Hayes

2019

Arch Toxicol

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Tetrabromobisphenol A (2,2′,6,6′-tetrabromo-4,4′-isopropylidenediphenol, CAS no. 79-94-7) (TBBPA) is an effective brominated flame retardant present in many consumer products whose effectiveness is attributable to its ability to retard flames and consequently save human lives. Toxicokinetic studies revealed that TBBPA when absorbed via the gastrointestinal tract is rapidly metabolized to glucuronide or sulfate metabolites which are rapidly eliminated by the kidney. TBBPA does not accumulate in the body and there is no evidence that the parent compound is present in the brain. Although this brominated flame retardant was detected in human breast milk and serum, there was no evidence that TBBPA reached the brain in in vivo animal studies as reflected by the absence of neuropathological, neurotoxic, or behavioral alterations indicating that the central nervous system is not a target tissue. These animal investigations were further supported by use of the larval/embryo observations that TBBPA did not produce behavioral changes in a larval/embryo zebrafish a model of chemical-induced neurotoxicity. Although some protein expressions were increased, deceased or not affected in the blood-brain barrier indicating no evidence that TBBPA entered the brain, the changes were contradictory, or gender related, and behavior was not affected supporting that this compound was not neurotoxic. Taken together, TBBPA does not appear to target the brain and is not considered as a neurotoxicant.

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“…Kaiser et al [6] observed that B-MDM, EHMC, and OCR were three main pollutants in sediments from the Rhine main area near Frankfurt (Hesse, Germany), with their highest levels of 62.2, 6.8, and 642 µg kg −1 , respectively. Jurado et al [8] reported the detection of a variety of benzophenones in groundwater of Barcelona and the maximum concentrations were measured as 36.6 ng L −1 (BP-4), 19.4 ng L −1 (BP-3), and 19.2 ng L −1 (BP-1). Balmer et al [9] reported that the concentration of 4-MBC in fish from Swiss midland lakes can reach 166 ng g −1 on a lipid basis.…”

Section: Introductionmentioning

confidence: 99%

“…Zebrafish (Danio rerio) have been widely used as indicator organism in toxicological studies of environmental pollutants [18,19]. The aim of this work was to (1) measure the levels of four oxidative stress indicators (i.e., SOD, GST, GSH, and MDA) in zebrafish liver exposed to these three pollutants, and (2) evaluate their toxicity order using the integrated biomarker response (IBR) index.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Oxidative Stress Status in Zebrafish (Danio rerio) Liver Induced by Three Typical Organic UV Filters (BP-4, PABA and PBSA)

Huang

Wang

et al. 2020

IJERPH

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Organic UV filters are a kind of emerging pollutants, which have been widely used in personal care products (PCPs). This study evaluated the effects of benzophenone-4 (BP-4), 4-aminobenzoic acid (PABA), and 2-phenylbenzimidazole-5-sulfonic acid (PBSA) on the selected indices of antioxidative responses in zebrafish (Danio rerio) liver. Zebrafish were exposed to two different doses (i.e., 0.5 and 5 mg L−1) of semi-static water with three individual compounds. Liver samples were collected on 7 and 14 days to analyze biochemical indicators, including superoxide dismutase (SOD), glutathione S-transferase (GST), reduced glutathione (GSH), and malondialdehyde (MDA). Oxidative stress occurred in zebrafish liver with significantly changed indicators during the whole exposure period. Different experimental groups could induce or inhibit the activity of antioxidant enzymes with varying degrees. With a prolonged exposure time and increased exposure dose, the hepatic lipid peroxidation was also obviously observed. Moreover, the toxicity order of three organic UV filters was analyzed using the integrated biomarker response (IBR) index and the results indicate that exposure to PABA for 7 days at 0.5 mg L−1 and PBSA for 7 days at 5 mg L−1 induced the most severe oxidative stress in the liver of zebrafish.

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Toxicity profiling of flame retardants in zebrafish embryos using a battery of assays for developmental toxicity, neurotoxicity, cardiotoxicity and hepatotoxicity toward human relevance

Cited by 128 publications

References 58 publications

Organophosphorus flame retardants are developmental neurotoxicants in a rat primary brainsphere in vitro model

Organophosphorus flame retardants are developmental neurotoxicants in a rat primary brainsphere in vitro model

Absence of neurotoxicity and lack of neurobehavioral consequences due to exposure to tetrabromobisphenol A (TBBPA) exposure in humans, animals and zebrafish

Evaluation of the Oxidative Stress Status in Zebrafish (Danio rerio) Liver Induced by Three Typical Organic UV Filters (BP-4, PABA and PBSA)

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