scholarly journals Neurodevelopmental toxicity assessment of flame retardants using a human DNT in vitro testing battery

2021 ◽  
Author(s):  
Jördis Klose ◽  
Melanie Pahl ◽  
Kristina Bartmann ◽  
Farina Bendt ◽  
Jonathan Blum ◽  
...  
Keyword(s):  
Human Cell ◽  
Polybrominated Diphenyl Ethers ◽  
Flame Retardants ◽  
Real Life ◽  
Toxicity Assessment ◽  
Oligodendrocyte Differentiation ◽  
Neurodevelopmental Toxicity ◽  
Diphenyl Phosphate

AbstractDue to their neurodevelopmental toxicity, flame retardants (FRs) like polybrominated diphenyl ethers are banned from the market and replaced by alternative FRs, like organophosphorus FRs, that have mostly unknown toxicological profiles. To study their neurodevelopmental toxicity, we evaluated the hazard of several FRs including phased-out polybrominated FRs and organophosphorus FRs: 2,2′,4,4′-tetrabromodiphenylether (BDE-47), 2,2′,4,4′,5-pentabromodiphenylether (BDE-99), tetrabromobisphenol A, triphenyl phosphate, tris(2-butoxyethyl) phosphate and its metabolite bis-(2-butoxyethyl) phosphate, isodecyl diphenyl phosphate, triphenyl isopropylated phosphate, tricresyl phosphate, tris(1,3-dichloro-2-propyl) phosphate, tert-butylphenyl diphenyl phosphate, 2-ethylhexyl diphenyl phosphate, tris(1-chloroisopropyl) phosphate, and tris(2-chloroethyl) phosphate. Therefore, we used a human cell–based developmental neurotoxicity (DNT) in vitro battery covering a large variety of neurodevelopmental endpoints. Potency according to the respective most sensitive benchmark concentration (BMC) across the battery ranked from <1 μM (5 FRs), 1<10 μM (7 FRs) to the >10 μM range (3 FRs). Evaluation of the data with the ToxPi tool revealed a distinct ranking (a) than with the BMC and (b) compared to the ToxCast data, suggesting that DNT hazard of these FRs is not well predicted by ToxCast assays. Extrapolating the DNT in vitro battery BMCs to human FR exposure via breast milk suggests low risk for individual compounds. However, it raises a potential concern for real-life mixture exposure, especially when different compounds converge through diverse modes-of-action on common endpoints, like oligodendrocyte differentiation in this study. This case study using FRs suggests that human cell–based DNT in vitro battery is a promising approach for neurodevelopmental hazard assessment and compound prioritization in risk assessment. Graphical abstract

scholarly journals Using a Multi-Stage hESC Model to Characterize BDE-47 Toxicity During Neurogenesis

2019 ◽  
Vol 171 (1) ◽  
pp. 221-234 ◽  
Author(s):  
Hao Chen ◽  
Helia Seifikar ◽  
Nicholas Larocque ◽  
Yvonne Kim ◽  
Ibrahim Khatib ◽  
...  
Keyword(s):  
Neural Development ◽  
Polybrominated Diphenyl Ethers ◽  
Neuronal Development ◽  
Embryonic Stem ◽  
Cellular Level ◽  
Environmental Chemicals ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Neurodevelopmental Toxicity

Abstract Although the ramifications associated with polybrominated diphenyl ethers (PBDEs) exposures during human pregnancy have yet to be determined, increasing evidence in humans and animal models suggests that these compounds cause neurodevelopmental toxicity. Human embryonic stem cells (hESCs) models can be used to study the effects of environmental chemicals throughout the successive stages of neuronal development. Here, using a hESC differentiation model, we investigated the effects of common PBDE congeners (BDE-47 or -99) on the successive stages of early neuronal development. First, we determined the points of vulnerability to PBDEs across 4 stages of in vitro neural development by using assays to assess for cytotoxicity. Differentiated neural progenitors were identified to be more sensitive to PBDEs than their less differentiated counterparts. In follow-up investigations, we observed BDE-47 to inhibit functional processes critical for neurogenesis (eg, proliferation, expansion) in hESC-derived neural precursor cells (NPCs) at sub-lethal concentrations. Finally, to determine the mechanism(s) underlying PBDE-toxicity, we conducted global transcriptomic and methylomic analyses of BDE-47. We identified 589 genes to be differentially expressed due to BDE-47 exposure, including molecules involved in oxidative stress mediation, cell cycle, hormone signaling, steroid metabolism, and neurodevelopmental pathways. In parallel analyses, we identified a broad significant increase in CpG methylation. In summary our results suggest, on a cellular level, PBDEs induce human neurodevelopmental toxicity in a concentration-dependent manner and sensitivity to these compounds is dependent on the developmental stage of exposure. Proposed mRNA and methylomic perturbations may underlie toxicity in early embryonic neuronal populations.

Some milestones in in vitro organ Toxicity Assessment. The Kidney as a Case Study

1995 ◽  
Vol 9 (6) ◽  
pp. 795-814 ◽  
Author(s):  
J.-P. Morin ◽  
C. Leclere ◽  
S. Marouillat ◽  
C. Monteil
Keyword(s):  
Toxicity Assessment ◽  
Organ Toxicity

scholarly journals Brominated Flame Retardants in the Environment: their Sources and Effects (A Review)

2006 ◽  
Vol 75 (4) ◽  
pp. 587-599 ◽  
Author(s):  
P. Mikula ◽  
Z. Svobodová
Keyword(s):  
Polybrominated Diphenyl Ethers ◽  
Hormonal Regulation ◽  
Flame Retardants ◽  
Brominated Flame Retardants ◽  
Toxic Effects ◽  
Potential Health ◽  
Diphenyl Ethers ◽  
Industrial Use ◽  
Living Organisms

Brominated flame retardants (BFRs) are organic substances frequently used in many industries. The most important group within BFRs are polybrominated diphenyl ethers (PBDEs). Because they persist in the environment, accumulate in food chains and have toxic effects, they are a potential health risk both for animals and humans. Polybrominated diphenyl ethers may disrupt processes of hormonal regulation in living organisms by reducing thyroxine concentrations in the plasma of the exposed individuals. In vitro studies have demonstrated the ability of these substances to bind to estrogen and androgen receptors. Tests on rodents have also demonstrated neurotoxicity of some of the PBDEs. Although industrial use of PBDEs is now regulated to a large extent, PBDEs have already been detected in areas with no apparent industrial load, e.g. in Greenland. This article presents an overview of BFRs-related issues with a particular emphasis on PBDEs, describes toxic effects of those substances and their metabolism in living organisms, and discusses issues related to the incidence of PBDEs in the environment.

scholarly journals Inhibition of Human Liver Carboxylesterase (hCE1) by Organophosphate Ester Flame Retardants and Plasticizers: Implications for Pharmacotherapy

2019 ◽  
Vol 171 (2) ◽  
pp. 396-405 ◽  
Author(s):  
Allison L Phillips ◽  
Heather M Stapleton
Keyword(s):  
Angiotensin Converting Enzyme ◽  
House Dust ◽  
Human Liver ◽  
Human Exposure ◽  
Flame Retardants ◽  
Enzyme Inhibitor ◽  
Converting Enzyme ◽  
Ic50 Values ◽  
Diphenyl Phosphate

Abstract Organophosphate ester (OPE) flame retardants and plasticizers, consumer product additives with widespread human exposure, were evaluated for their effect on the activity of purified human liver carboxylesterase (hCE1). Four of the 15 OPEs tested had IC50 values lower than 100 nM, including triphenyl phosphate (TPHP), 2-ethylhexyl diphenyl phosphate (EHDPHP), 4-isopropylphenyl diphenyl phosphate (4IPPDPP), and 4-tert-butylphenyl diphenyl phosphate (4tBPDPP), as did 4 of the commercial flame retardant mixtures tested. Because hCE1 is critical for the activation of imidapril, an angiotensin-converting enzyme-inhibitor prodrug prescribed to treat hypertension, the most potent inhibitors, TPHP and 4tBPDPP, and an environmentally relevant mixture (house dust) were further evaluated for their effect on imidapril bioactivation in vitro. TPHP and 4tBPDPP were potent inhibitors of hCE1-mediated imidapril activation (Ki = 49.0 and 17.9 nM, respectively). House dust extracts (100 µg/ml) also caused significant reductions (up to 33%) in imidapril activation. Combined, these data suggest that exposure to OPEs may affect pharmacotherapy.

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

2020 ◽  
Author(s):  
Helena T. Hogberg ◽  
Rita de Cássia da Silveira E Sá ◽  
Andre Kleensang ◽  
Mounir Bouhifd ◽  
Ozge Cemiloglu Ulker ◽  
...  
Keyword(s):  
Flame Retardants ◽  
In Vitro Model ◽  
Diphenyl Ether ◽  
Phenyl Phosphate ◽  
Neurotoxic Effects ◽  
Organophosphorus Flame Retardants ◽  
Diphenyl Phosphate ◽  
Vitro Model ◽  
Lipids Metabolism

Abstract 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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