Disruption of Oxidative Phosphorylation (OXPHOS) by Hydroxylated Polybrominated Diphenyl Ethers (OH-PBDEs) Present in the Marine Environment

Legradi, Jessica; Dahlberg, Anna-Karin; Cenijn, P.H.; Marsh, Göran; Asplund, Lillemor; Bergman, Åke; Legler, Juliette

doi:10.1021/es5039744

Cited by 57 publications

(46 citation statements)

References 53 publications

(104 reference statements)

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“…However, when comparing the effects of the three substances in the a TMRM assay, which also gives a positive response for uncoupling and narcotic substances, 6OH-BDE90 and PCP both alter the membrane potential in a similar concentration range whereas FCCP proves to be highly more potent (Legradi et al, 2014). In line with our classification analysis based on the significantly regulated genes, where 6OH-BDE90 and PCP from a new sub cluster together next to the polar narcotics ( Figure 9B).…”

Section: Toxiogenomic-based Moa Assignment Of a Chemical With Unknownsupporting

confidence: 76%

“…It appears that 6OH-BDE90 and PCP have the potential for both uncoupling and polar narcosis, depending on test conditions (concentration, duration) or test species (Sixt et al, 1995;Schüürmann et al, 1997;Legradi et al, 2014). The findings presented in this study suggest that the toxicogenomic approach is able to elucidate differences in MoA.…”

Section: Toxiogenomic-based Moa Assignment Of a Chemical With Unknownmentioning

confidence: 66%

“…Tests conducted by Legradi et al (2014) including PCP, 6OH-BDE90, and FCCP show in regard to the TPP + assay which does not give a positive response for narcotic substances, PCP and FCCP exhibit a similar LOEC whereas 6OH-BDE90 has a much higher LOEC, presenting a similar potency of PCP and FCCP and a much lower potency for 6OH-BDE90. This finding is in line with our classification analysis based on the 5000 most varied genes ( Figure 9A).…”

Section: Toxiogenomic-based Moa Assignment Of a Chemical With Unknownmentioning

confidence: 97%

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Mode of Action Assignment of Chemicals Using Toxicogenomics: A Case Study with Oxidative Uncouplers

Hawliczek-Ignarski

Cenijn²,

Legler³

et al. 2017

Front. Environ. Sci.

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A criterion frequently used to group chemicals in risk assessment is "mode of toxic action" (MoA). Routinely, structure-based approaches are used for the MoA categorization of chemicals, but they can produce conflicting results or fail to classify compounds. Biological activity-based approaches such as toxicogenomics which provide an unbiased overview of the transcriptomic changes after exposure to a compound may complement structure-based approaches in MoA assignment. Here, we investigate whether toxicogenomic profiles as generated after in vitro exposure of an established cell line (C3A hepatoma cells) are able to group together chemicals with an uncoupling MoA, and to distinguish the uncouplers from chemicals with other MoAs. In a first step, we examined whether chemicals sharing the same uncoupling of oxidative phosphorylation (OXPHOS) MoA produce similar toxicogenomic profiles and can be grouped together. In a next step, we tested whether the toxicogenomic profiles discriminate between OXPHOS and chemicals displaying a (polar) narcotic MoA. Experimentally, cells were exposed in vitro to equipotent concentrations of the test compounds and gene expression profiles were measured. The resulting toxicogenomic profiles assigned OXPHOS to one cluster and discriminated between the OXPHOS and the (polar) narcotics. In addition, the toxicogenomics data revealed that one and the same chemical can display multiple MoAs, which may help to explain conflicting results of MoA classification from structure-based approaches. The results strongly suggest the feasibility of MoA grouping of chemicals by using in vitro cell assay-based toxicogenomic profiles.

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Section: Toxiogenomic-based Moa Assignment Of a Chemical With Unknownsupporting

confidence: 76%

Section: Toxiogenomic-based Moa Assignment Of a Chemical With Unknownmentioning

confidence: 66%

Section: Toxiogenomic-based Moa Assignment Of a Chemical With Unknownmentioning

confidence: 97%

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Mode of Action Assignment of Chemicals Using Toxicogenomics: A Case Study with Oxidative Uncouplers

Hawliczek-Ignarski

Cenijn²,

Legler³

et al. 2017

Front. Environ. Sci.

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“…6-OH-BDE-47 (~1.3 μM) has also been shown to cause oxidative stress in the tails of zebrafish larvae using TUNEL staining (Usenko et al, 2012). More recently, in vitro studies with mixtures of OH-BDEs found in the environment were found to disrupt oxidative phosphorylation (through protonophoric uncoupling or inhibition of the electron transport chain) and to have synergistic effects in zebrafish PAC2 cells (Legradi et al, 2014). Additionally 6-OH-BDE-47 has been shown to impact multiple aspects of adult neurogenesis (including cytotoxicity, proliferation, neuronal/oligodendrocyte differentiation) in primary adult neural stem progenitor cells of adult mice (Li et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…These effects were more severe than the effects caused by the parent compound, BDE-47 (Dingemans et al, 2010a, 2010b, 2008). Furthermore, 6-OH-BDE-47 exposure during zebrafish larval development has shown thyroid hormone disruption (~1.3 μM) and disrupted energy metabolism (oxidative phosphorylation) (~1 μM) (Legradi et al, 2014; Liu et al, 2015; Usenko et al, 2012; van Boxtel et al, 2008). Adult neurogenesis is also a target of 6-OH-BDE-47 exposure, including effects on neuronal/oligodendrocyte differentiation in primary adult neural stem progenitor cells of adult mice (Li et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Persisting effects of a PBDE metabolite, 6-OH-BDE-47, on larval and juvenile zebrafish swimming behavior

Macaulay

Bailey

Levin

et al. 2015

Neurotoxicology and Teratology

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Polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants that are widely detected in the environment, biota, and humans. In mammals, PBDEs can be oxidatively metabolized to form hydroxylated polybrominated diphenyl ethers (OH-BDEs). While studies have examined behavioral deficits or alterations induced by exposure to PBDEs in both rodents and fish, no study to date has explored behavioral effects from exposure to OH-BDEs, which have been shown to have greater endocrine disrupting potential compared to PBDEs. In the present study, zebrafish (Danio rerio) were exposed during embryonic and larval development (0-6 days post fertilization, dpf) to a PBDE metabolite, 6-hydroxy, 2,2’,4,4’ tetrabromodiphenyl ether (10-50 nM) and then examined for short and long-term behavioral effects. Exposed zebrafish tested as larvae (6 dpf) showed an altered swimming response to light-dark transitions, exhibiting hypoactivity in light periods compared to control fish. When fish exposed from 0-6 dpf were tested as juveniles (45 dpf), they showed an increased fear response and hyperactivity in response to tests of novel environment exploration and habituation learning. These results demonstrate that early life exposure to a PBDE metabolite can have immediate or later life (more than a month after exposure) effects on activity levels, habituation, and fear/anxiety.

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Exposure to a PBDE/OH‐BDE mixture alters juvenile zebrafish (Danio rerio) development

Macaulay

Chernick

Chen

et al. 2016

Enviro Toxic and Chemistry

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Polybrominated diphenyl ethers (PBDEs) and halogenated phenolic compounds (e.g., hydroxylated BDEs (OH-BDEs)) arecontaminants detected together frequently in human tissues, and are structurally similar to thyroid hormones (TH). THs partially mediate metamorphic transitions between life stages in zebrafish, making this a critical developmental window which may be uniquely vulnerable to chemicals disrupting thyroid signaling. In this study, zebrafish were exposed to 6-OH-BDE-47 (30 nM) alone or to a low (30 μg/L) or high dose (600 μg/L) mixture of PentaBDEs, 6-OH-BDE-47 (0.5–6 μg/L), & 2,4,6 tribromophenol (TBP) (5–100 μg/L) during juvenile development (9–23 days post fertilization; dpf) and evaluated for developmental endpoints mediated by TH signaling. Fish were sampled at three time points and examined for developmental and skeletal morphology, apical thyroid and skeletal gene markers, and modifications in swimming behavior (as adults). Exposure to the high mixture resulted in > 85% mortality within one week of exposure, despite being below reported acute toxicity thresholds for individual congeners. The low mixture and 6-OH-BDE-47 groups exhibited reductions in body length and delayed maturation, specifically relating to swim bladder,?, fin, and pigmentation development. Reduced skeletal ossification was also observed in 6-OH-BDE-47 treated fish. Assessment of thyroid and osteochondral gene regulatory networks demonstrated significantly increased expression of genes that regulate skeletal development and THs. Overall, these results indicate that exposures to PBDEs/OH-BDEs mixtures adversely impact zebrafish maturation during metamorphosis.

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Disruption of Oxidative Phosphorylation (OXPHOS) by Hydroxylated Polybrominated Diphenyl Ethers (OH-PBDEs) Present in the Marine Environment

Cited by 57 publications

References 53 publications

Mode of Action Assignment of Chemicals Using Toxicogenomics: A Case Study with Oxidative Uncouplers

Mode of Action Assignment of Chemicals Using Toxicogenomics: A Case Study with Oxidative Uncouplers

Persisting effects of a PBDE metabolite, 6-OH-BDE-47, on larval and juvenile zebrafish swimming behavior

Exposure to a PBDE/OH‐BDE mixture alters juvenile zebrafish (Danio rerio) development

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