Dataset Information

Using a Multi-Stage hESC Model to Characterize BDE-47 Toxicity during Neurogenesis.

ABSTRACT: While the ramifications associated with polybrominated diphenyl ethers (PBDE) 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 cell models (hESCs) 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 four 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 (e.g., 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 (DE) 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.

SUBMITTER: Chen H

PROVIDER: S-EPMC6736394 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Chen Hao H Seifikar Helia H Larocque Nicholas N Kim Yvonne Y Khatib Ibrahim I Fernandez Charles J CJ Abello Nicomedes N Robinson Joshua F JF

Toxicological sciences : an official journal of the Society of Toxicology 20190901 1

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 ...[more]

PMID: 31173147

Similar Datasets

Project description:BACKGROUND:Polybrominated diphenyl ethers (PBDEs) were widely used as flame retardants until the early 2000s, mainly in home furnishings and electronics. The persistence of PBDEs in the environment leads to continued ubiquitous exposure to low levels, with infants and children experiencing higher exposures than adults. Accumulating evidence suggest that low-level exposures during early life stages can affect brain development and lead to long-term behavioral impairments. We investigated the effects of zebrafish exposure to low doses of the two prominent PBDEs; 2,2',4,4',5,-Pentabromodiphenyl ether (BDE-99) and 2,2',4,4',-Tetrabromodiphenyl ether (BDE-47), during embryo-development on short- and long-term behavioral endpoints. We included the organophosphate pesticide chlorpyrifos (CPF) due to its well documented neurotoxicity across species from zebrafish to humans. METHODS:Zebrafish embryos were exposed to the following individual treatments; 0.1% DMSO (vehicle control); 0.3?M CPF; 0.01, 0.03, 0.1, 0.3?M BDE-47; 0.003, 0.03, 0.3, 1, 3, 10, 20?M BDE-99 from 5 until 120h post fertilization (hpf). Low exposure levels were determined as those not causing immediate overt toxicity, and behavior assays were conducted in the low-level range. At 144 hpf the larvae were tested for locomotor activity. At approximately 6 months of age adult zebrafish were tested in a behavioral battery including assays for anxiety-related behavior, sensorimotor response and habituation, social interaction, and predator avoidance. RESULTS:In the short-term, larval locomotor activity was reduced in larvae treated with 0.3?M CPF and 0.1?M BDE-47. BDE-99 treatment caused non-monotonic dose effects, with 0.3?M causing hyperactivity and 1?M or higher causing hypoactivity. In the long-term, adult anxiety-related behavior was reduced in all treatments as measured in both the novel tank dive test and tap test. DISCUSSION:We show that exposure of zebrafish embryos to low concentrations of the brominated flame retardants BDE-47 and BDE-99, and the organophosphate pesticide CPF, caused both short- and long-term behavioral impairments. Interestingly, we also found that at very low exposure concentrations, where there were no visible effects on larval activity, adult behavior was still strongly affected.

Dataset Information

Using a Multi-Stage hESC Model to Characterize BDE-47 Toxicity during Neurogenesis.

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets