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Archives of Toxicology

, Volume 92, Issue 11, pp 3415–3433 | Cite as

PBDE-47 and PBDE mixture (DE-71) toxicities and liver transcriptomic changes at PND 22 after in utero/postnatal exposure in the rat

  • J. K. DunnickEmail author
  • K. R. Shockley
  • A. R. Pandiri
  • G. E. Kissling
  • K. E. Gerrish
  • T. V. Ton
  • R. E. Wilson
  • S. S. Brar
  • A. E. Brix
  • S. Waidyanatha
  • E. Mutlu
  • D. L. Morgan
Reproductive Toxicology

Abstract

Pentabromodiphenyl ethers (PBDE) are found in human tissue, in household dust, and in the environment, and a particular concern is the potential for the induction of cancer pathways from these fat-soluble persistent organic pollutants. Only one PBDE cancer study has been conducted and that was for a PBDE mixture (DE-71). Because it is not feasible to test all PBDE congeners in the environment for cancer potential, it is important to develop a set of biological endpoints that can be used in short-term toxicity studies to predict disease outcome after long-term exposures. In this study, PBDE-47 was selected as the test PBDE congener to evaluate and compare toxicity to that of the carcinogenic PBDE mixture. The toxicities of PBDE-47 and the PBDE mixture were evaluated at PND 22 in Wistar Han rat (Crl: WI (Han)) pups after in utero/postnatal exposure (0, 0.1, 15, or 50 mg/kg; dams, GD6-21; pups, PND 12-PND 21; oral gavage daily dosing). By PND 22, PBDE-47 caused centrilobular hypertrophy and fatty change in liver, and reduced serum thyroxin (T4) levels; similar effects were also observed after PBDE mixture exposure. Transcriptomic changes in the liver included induction of cytochrome p450 transcripts and up-regulation of Nrf2 antioxidant pathway transcripts and ABC membrane transport transcripts. Decreases in other transport transcripts (ABCG5 & 8) provided a plausible mechanism for lipid accumulation, characterized by a treatment-related liver fatty change after PBDE-47 and PBDE mixture exposure. The benchmark dose calculation based on liver transcriptomic data was generally lower for PBDE-47 than for the PBDE mixture. The up-regulation of the Nrf2 antioxidant pathway and changes in metabolic transcripts after PBDE-47 and PBDE mixture exposure suggest that PBDE-47, like the PBDE mixture (NTP 2016, TR 589), could be a liver toxin/carcinogen after long-term exposure.

Keywords

Pentabrominated diphenyl ethers; PBDE-47 PBDE mixture (DE-71) Liver transcriptomic patterns Liver toxicity 

Notes

Acknowledgements

We thank Dr. G. Knudsen, NCI at NIEHS, and Dr. A. Merrick, NIEHS, for their review of the manuscript. All persons gave their informed consent prior to their inclusion in the study. This article does not contain clinical studies or patient data. The in-life phase of the study was conducted under Contract ES-75561 with Alion Science and Technology, Inc. PBDE tissue-level measurements under Contract HHSN273201000016C. Statistical support was provided under Contract HHSN273201600011C.

Funding

The intramural program of the National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, supported this work. However, the statements, opinions, or conclusions contained therein do not necessarily represent the statements, opinions, or conclusions of NIEHS or NIH.

Compliance with ethical standards

Conflict of interest

None of the authors have any conflict of interest to declare.

Supplementary material

204_2018_2292_MOESM1_ESM.docx (26 kb)
Supplement 1. Littering statistics (DOCX 26 KB)
204_2018_2292_MOESM2_ESM.xlsx (15.6 mb)
Supplement 2. Liver Transcriptomic Results (XLSX 15927 KB)
204_2018_2292_MOESM3_ESM.xlsx (2.2 mb)
Supplement 3. PBDE-47 Benchmark dose analysis (XLSX 2267 KB)
204_2018_2292_MOESM4_ESM.xlsx (3.1 mb)
Supplement 4. PBDE mixture (DE-71) Benchmark dose analysis (XLSX 3178 KB)

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Authors and Affiliations

  • J. K. Dunnick
    • 1
    Email author
  • K. R. Shockley
    • 2
  • A. R. Pandiri
    • 3
  • G. E. Kissling
    • 2
  • K. E. Gerrish
    • 4
  • T. V. Ton
    • 3
  • R. E. Wilson
    • 3
  • S. S. Brar
    • 3
  • A. E. Brix
    • 5
  • S. Waidyanatha
    • 6
  • E. Mutlu
    • 6
  • D. L. Morgan
    • 1
  1. 1.Toxicology BranchNational Institute of Environmental Health SciencesResearch Triangle ParkUSA
  2. 2.Biostatistics and Computational Biology BranchNational Institute of Environmental Health SciencesResearch Triangle ParkUSA
  3. 3.Cellular and Molecular Pathology BranchNational Institute of Environmental Health SciencesResearch Triangle ParkUSA
  4. 4.Molecular Genomics CoreNational Institute of Environmental Health SciencesResearch Triangle ParkUSA
  5. 5.EPL, Inc.Research Triangle ParkUSA
  6. 6.Toxicology Operations BranchNational Institute of Environmental Health SciencesResearch Triangle ParkUSA

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