Polybrominated diphenyl ether (PBDE) neurotoxicity: a systematic review and meta-analysis of animal evidence

Dorman, David C.; Chiu, Weihsueh A.; Hales, Barbara F.; Hauser, Russ; Johnson, Kamin J.; Mantus, Ellen; Martel, Susan; Robinson, Karen A.; Rooney, Andrew A.; Rudel, Ruthann A.; Sathyanarayana, Sheela; Schantz, Susan L.; Waters, Katrina M.

doi:10.1080/10937404.2018.1514829

Cited by 56 publications

(24 citation statements)

References 78 publications

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“…1B,C). These presynaptic defects and the pronounced effect of 6-OH on evoked activity under the Bic washout treatment paradigm, which has been previously Certain hydroxylated PBDEs impair neuronal MEK-ERK signaling 8 published as a model of in vitro plasticity (63), may partially explain the reported relationship between learning deficits and BDE-47/99 exposure in animal studies (9), as it is known that their hydroxylated metabolites can be produced endogenously, primarily via CYP2B6, which is dynamically expressed in the brain (31)(32)(33)(85)(86)(87).…”

Section: Discussionmentioning

confidence: 79%

“…Concerningly, a substantial amount of research has established the relationship of PBDE exposure levels with behavioral deficits in humans, as well as in animal models. Recently, several large-scale and systematic reviews have concluded that PBDE exposures impact externalizing behaviors and IQ in children and that BDE-47, -99, and -209 affect learning in animal studies (6)(7)(8)(9). There is also concern for the relationship between environmental toxins like PBDEs and autism spectrum disorders (ASD), though the evidence is less conclusive, especially in human studies (6,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

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Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes

Poston

Rejepova

Ghaninejad-Esfahani

et al. 2020

Journal of Biological Chemistry

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The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose neurodevelopmental toxicity mechanisms remain largely unclear. Using dissociated cortical neurons from embryonic Rattus norvegicus, we found here that chronic exposure to 6-OH–BDE-47, one of the most prevalent hydroxylated PBDE metabolites, suppresses both spontaneous and evoked neuronal electrical activity. On the basis of our previous work on mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) (MEK) biology and our observation that 6-OH–BDE-47 is structurally similar to kinase inhibitors, we hypothesized that certain hydroxylated PBDEs mediate neurotoxicity, at least in part, by impairing the MEK–ERK axis of MAPK signal transduction. We tested this hypothesis on three experimental platforms: 1) in silico, where modeling ligand–protein docking suggested that 6-OH–BDE-47 is a promiscuous ATP-competitive kinase inhibitor; 2) in vitro in dissociated neurons, where 6-OH–BDE-47 and another specific hydroxylated BDE metabolite similarly impaired phosphorylation of MEK/ERK1/2 and activity-induced transcription of a neuronal immediate early gene; and 3) in vivo in Drosophila melanogaster, where developmental exposures to 6-OH–BDE-47 and a MAPK inhibitor resulted in offspring displaying similarly increased frequency of mushroom-body β–lobe midline crossing, a metric of axonal guidance. Taken together, our results support that certain ortho-hydroxylated PBDE metabolites are promiscuous kinase inhibitors and can cause disruptions of critical neurodevelopmental processes, including neuronal electrical activity, pre-synaptic functions, MEK–ERK signaling, and axonal guidance.

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Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes

Poston

Rejepova

Ghaninejad-Esfahani

et al. 2020

Journal of Biological Chemistry

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“…Effects in humans and laboratory animals are generally similar. Independent, systematic reviews undertaken by the US National Academy of Medicine and the International Agency for Research on Cancer confirm and validate these findings [ 214 215 ].…”

Section: Impacts Of Ocean Pollution On Human Healthmentioning

confidence: 79%

Human Health and Ocean Pollution

Landrigan

Stegeman

Fleming

et al. 2020

Annals of Global Health

347

170

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Methods: Topic-focused reviews that examine the effects of ocean pollution on human health, identify gaps in knowledge, project future trends, and offer evidence-based guidance for effective intervention. Environmental Findings: Pollution of the oceans is widespread, worsening, and in most countries poorly controlled. It is a complex mixture of toxic metals, plastics, manufactured chemicals, petroleum, urban and industrial wastes, pesticides, fertilizers, pharmaceutical chemicals, agricultural runoff, and sewage. More than 80% arises from land-based sources. It reaches the oceans through rivers, runoff, atmospheric deposition and direct discharges. It is often heaviest near the coasts and most highly concentrated along the coasts of low-and middle-income countries. Plastic is a rapidly increasing and highly visible component of ocean pollution, and an estimated 10 million metric tons of plastic waste enter the seas each year. Mercury is the metal pollutant of greatest concern in the oceans; it is released from two main sources-coal combustion and small-scale gold mining. Global spread of industrialized agriculture with increasing use of chemical fertilizer leads to extension of Harmful Algal Blooms (HABs) to previously unaffected regions. Chemical pollutants are ubiquitous and contaminate seas and marine organisms from the high Arctic to the abyssal depths. Ecosystem Findings: Ocean pollution has multiple negative impacts on marine ecosystems, and these impacts are exacerbated by global climate change. Petroleum-based pollutants reduce photosynthesis in marine microorganisms that generate oxygen. Increasing absorption of carbon dioxide into the seas causes ocean acidification, which destroys coral reefs, impairs shellfish development, dissolves calcium-containing microorganisms at the base of the marine food web, and increases the toxicity of some pollutants. Plastic pollution threatens marine mammals, fish, and seabirds and accumulates in large mid-ocean gyres. It breaks down into microplastic and nanoplastic particles containing multiple manufactured chemicals that can enter the tissues of marine organisms, including species consumed by humans. Industrial releases, runoff, and sewage increase frequency and severity of HABs, bacterial pollution, and anti-microbial resistance. Pollution and sea surface warming are triggering poleward migration of dangerous pathogens such as the Vibrio species. Industrial discharges, pharmaceutical wastes, pesticides, and sewage contribute to global declines in fish stocks. Human Health Findings: Methylmercury and PCBs are the ocean pollutants whose human health effects are best understood. Exposures of infants in utero to these pollutants through maternal consumption of contaminated seafood can damage developing brains, reduce IQ and increase children's risks for autism, ADHD and learning disorders. Adult exposures to methylmercury increase risks for cardiovascular disease and dementia. Manufactured chemicals-phthalates, bisphenol A, flame retardants, and perfluorinated chemicals...

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“…Our results are congruent with a disrupted developmental trajectory of the Social Processing Domain as outlined in the 2010 NIMH Research Domain Criteria (RDoC) framework 1 ; a key characteristic of ASD pathology. Our work is further strengthened by the use of the litter as the unit of statistical analysis, thus overcoming risk of bias (RoB) of individual studies 99 and inter-individual variability. Further, DE-71 produced the common hormetic response, such that only 0.1 but not 0.4 mg/kg exhibited most of the behavior changes even though there was a dose-dependent increase in brain accumulation of ∑PBDE congeners.…”

Section: Discussionmentioning

confidence: 99%

Persistent autism-relevant phenotype produced by in utero and lactational exposure of female mice to the commercial PBDE mixture, DE-71

Kozlova

Valdez

Denys

et al. 2021

Preprint

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Polybrominated diphenyl ethers (PBDEs) are ubiquitous persistent organic pollutants (POPs) that are known neuroendocrine disrupting chemicals with adverse neurodevelopmental effects. PBDEs may act as risk factors for autism spectrum disorders (ASD), characterized by abnormal psychosocial functioning, although direct evidence is currently lacking. Using a translational exposure model, we tested the hypothesis that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in female offspring. C57Bl6/N mouse dams (F0) were exposed to DE-71 via oral administration of 0 (VEH/CON), 0.1 (L-DE-71) or 0.4 (H-DE-71) mg/kg bw/d from 3 wk prior to gestation through lactation. Mass spectrometry analysis indicated in utero and lactational transfer of PBDEs (ppb) to F1 female offspring brain tissue at postnatal day (PND) 15 which was reduced by PND 110. Neurobehavioral testing of social novelty preference (SNP) and social recognition memory (SRM) revealed that adult L-DE-71 F1 offspring display altered short- and long-term SRM, in the absence of reduced sociability, and increased repetitive behavior. These effects were concomitant with reduced olfactory discrimination of social odors. Additionally, L-DE-71 exposure also altered short-term novel object recognition memory but not anxiety or depressive-like behavior. Moreover, F1 L-DE-71 displayed downregulated mRNA transcripts for oxytocin (Oxt) in the bed nucleus of the stria terminalis (BNST) and supraoptic nucleus, vasopressin (Avp) in the BNST and upregulated Avp1ar in BNST, and Oxtr in the paraventricular nucleus. Our work demonstrates that developmental PBDE exposure produces ASD-relevant neurochemical, olfactory processing and behavioral phenotypes that may result from early neurodevelopmental reprogramming within central social and memory networks.

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Polybrominated diphenyl ether (PBDE) neurotoxicity: a systematic review and meta-analysis of animal evidence

Cited by 56 publications

References 78 publications

Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes

Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes

Human Health and Ocean Pollution

Persistent autism-relevant phenotype produced by in utero and lactational exposure of female mice to the commercial PBDE mixture, DE-71

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