Comparative toxicity and liver transcriptomics of legacy and emerging brominated flame retardants following 5-day exposure in the rat

Shockley, Keith R.; Cora, Michelle; Malarkey, David E.; Jackson-Humbles, Daven; Vallant, Molly; Collins, Brad; Mutlu, Esra; Robinson, Victor A.; Waidyanatha, Surayma; Zmarowski, Amy; Machesky, Nicholas; Richey, Jamie; Harbo, Sam J.; Cheng, Emily H.; Patton, Kristen K.; Sparrow, Barney; Dunnick, June K.

doi:10.1016/j.toxlet.2020.07.016

Cited by 19 publications

(31 citation statements)

References 69 publications

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“…The emerging flame retardants included 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB, CAS RN: 183658–27–7), bis(2-ethylhexyl) tetrabromophthalate (TBPH, CAS RN: 26040–51–7), tetrabromobisphenol A-bis(2,3-dibromopropyl ether (TBBPA-DBPE, CAS RN: 21850–44–2), 1,2-bis(tribromophenoxy)ethane (BTBPE, CAS RN: 37853–59–1), decabromodiphenylethane (DBDPE, CAS RN: 84852–53–9), and hexachlorocyclopentadienyl-dibromocyclooctane (HCDBCO, CAS RN: 51936–55–1). Chemical identities were confirmed, and chemical purities were determined prior to use in the studies [1] . The oral dose formulations were prepared in corn oil vehicle (Spectrum, New Brunswick, New Jersey) and were determined to be within 10% of the target concentration.…”

Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

“… Large-scale gene expression analysis of legacy* and emerging** brominated flame retardants were conducted in the male Harlan Sprague Dawley rat [1] . Each animal was dosed for 5 days with the chemical at concentrations of 0.1 – 1000 μmol/kg body weight per day.…”

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confidence: 99%

“…The transcriptomic data can be used to provide insights into the degree of toxicity, toxic mechanisms, disease pathways activated by exposure, and for benchmark dose analysis. The gene expression data for each of the nine flame retardants discussed here accompanies the research article entitled, “Comparative Toxicity and Liver Transcriptomics of Legacy and Emerging Brominated Flame Retardants following 5-Day Exposure in the Rat” [1] . * polybrominated diphenyl ether 47 (PBDE 47), decabromodiphenyl ether (decaBDE), hexabromocyclododecane (HBCD); ** 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB); bis(2-ethylhexyl) tetrabromophthalate (TBPH); tetrabromobisphenol A-bis(2,3-dibromopropyl ether (TBBPA-DBPE); 1,2-bis(tribromophenoxy)ethane (BTBPE); decabromodiphenylethane (DBDPE); hexachlorocyclopentadienyl-dibromocyclooctane (HCDBCO).…”

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confidence: 99%

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Transcriptomic data from the rat liver after five days of exposure to legacy or emerging brominated flame retardants

et al. 2020

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Large-scale gene expression analysis of legacy* and emerging** brominated flame retardants were conducted in the male Harlan Sprague Dawley rat [1] . Each animal was dosed for 5 days with the chemical at concentrations of 0.1 – 1000 μmol/kg body weight per day. Following the last dose, a specimen of the left liver was removed for RNA extraction. The amplified RNA (aRNA) was fragmented and then hybridized to Affymetrix Rat Genome 230 2.0 Arrays. Each GeneChip® array was scanned using an Affymetrix GeneChip® Scanner 3000 7 G to generate raw expression level data (.CEL files). Statistical contrasts were used to find pairwise gene expression differences between the control group and each dose group using the R/maanova package [2] . The transcriptomic data can be used to provide insights into the degree of toxicity, toxic mechanisms, disease pathways activated by exposure, and for benchmark dose analysis. The gene expression data for each of the nine flame retardants discussed here accompanies the research article entitled, “Comparative Toxicity and Liver Transcriptomics of Legacy and Emerging Brominated Flame Retardants following 5-Day Exposure in the Rat” [1] . * polybrominated diphenyl ether 47 (PBDE 47), decabromodiphenyl ether (decaBDE), hexabromocyclododecane (HBCD); ** 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB); bis(2-ethylhexyl) tetrabromophthalate (TBPH); tetrabromobisphenol A-bis(2,3-dibromopropyl ether (TBBPA-DBPE); 1,2-bis(tribromophenoxy)ethane (BTBPE); decabromodiphenylethane (DBDPE); hexachlorocyclopentadienyl-dibromocyclooctane (HCDBCO).

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Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Transcriptomic data from the rat liver after five days of exposure to legacy or emerging brominated flame retardants

et al. 2020

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“…An increase in liver weight is a robust response observed in many in vivo studies with HBCDDs (EFSA CONTAM Panel, 2011a; Maranghi et al., 2013; Yanagisawa et al., 2014; Gannon et al., 2019a; Shockley et al., 2020). Zou et al.…”

Section: Assessmentmentioning

confidence: 99%

Update of the risk assessment of hexabromocyclododecanes (HBCDDs) in food

Schrenk

Bignami

Bodin³

et al. 2021

EFS2

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The European Commission asked EFSA to update its 2011 risk assessment on hexabromocyclododecanes ( HBCDD s) in food. HBCDD s, predominantly mixtures of the stereoisomers α‐, β‐ and γ‐ HBCDD , were widely used additive flame retardants. Concern has been raised because of the occurrence of HBCDD s in the environment, food and in humans. Main targets for toxicity are neurodevelopment, the liver, thyroid hormone homeostasis and the reproductive and immune systems. The CONTAM Panel concluded that the neurodevelopmental effects on behaviour in mice can be considered the critical effects. Based on effects on spontaneous behaviour in mice, the Panel identified a lowest observed adverse effect level ( LOAEL ) of 0.9 mg/kg body weight (bw) as the Reference Point, corresponding to a body burden of 0.75 mg/kg bw. The chronic intake that would lead to the same body burden in humans was calculated to be 2.35 μg/kg bw per day. The derivation of a health‐based guidance value ( HBGV ) was not considered appropriate. Instead, the margin of exposure ( MOE ) approach was applied to assess possible health concerns. Over 6,000 analytical results for HBCDD s in food were used to estimate the exposure across dietary surveys and age groups of the European population. The most important contributors to the chronic dietary LB exposure to HBCDD s were fish meat, eggs, livestock meat and poultry. The CONTAM Panel concluded that the resulting MOE values support the conclusion that current dietary exposure to HBCDD s across European countries does not raise a health concern. An exception is breastfed infants with high milk consumption, for which the lowest MOE values may raise a health concern.

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Insight into Tetrabromobisphenol A‐Associated Liver Transcriptional Landscape via Single Cell RNA Sequencing

Bai,

Zhu,

et al. 2023

Advanced Biology

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In recent years, there has been growing concern over the rising incidence of liver diseases, with increasing exposure to environmental toxins as a significant contributing factor. However, the mechanisms of liver injury induced by environmental pollutants are largely unclear. Here, using tetrabromobisphenol A (TBBPA), a widely used brominated flame retardant, as an example, environmental toxin‐induced liver toxicity in mice is characterized via single‐cell sequencing technology. Heterogeneous gene expression profiles after exposure to TBBPA in major cell types of the liver are demonstrated. In hepatocytes, pathway analysis of differentially expressed genes reveals the enhanced interferon response and diminished metabolic processes. The disrupted endothelial functions in TBBPA‐treated cells are then shown. Moreover, the activation of M2‐polarization in Kupffer cells, as well as activated effector T and B cells are unveiled in TBBPA‐treated cells. Finally, ligand‐receptor pair analysis shows that TBBPA disrupts cell‐cell communication and induces an inflammatory microenvironment. Overall, the results reveal that TBBPA‐induced dysfunction of hepatocytes and endothelial cells may then activate and recruit other immune cells such as Kuffer cells, and T/NK cells into the liver, further increasing inflammatory response and liver injury. Thus, the results provide novel insight into undesiring environmental pollutant‐induced liver injury.

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Comparative toxicity and liver transcriptomics of legacy and emerging brominated flame retardants following 5-day exposure in the rat

Cited by 19 publications

References 69 publications

Transcriptomic data from the rat liver after five days of exposure to legacy or emerging brominated flame retardants

Transcriptomic data from the rat liver after five days of exposure to legacy or emerging brominated flame retardants

Update of the risk assessment of hexabromocyclododecanes (HBCDDs) in food

Insight into Tetrabromobisphenol A‐Associated Liver Transcriptional Landscape via Single Cell RNA Sequencing

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