Hepatic Transcriptomic Patterns in the Neonatal Rat After Pentabromodiphenyl Ether Exposure

Abstract

Human exposure to pentabromodiphenyl ether (PBDE) mixture (DE-71) and its PBDE-47 congener can occur both in utero and during lactation. Here, we tested the hypothesis that PBDE-induced neonatal hepatic transcriptomic alterations in Wistar Han rat pups can inform on potential toxicity and carcinogenicity after longer term PBDE exposures. Wistar Han rat dams were exposed to either DE-71 or PBDE-47 daily from gestation day (GD 6) through postnatal day 4 (PND 4). Total plasma thyroxine (T4) was decreased in PND 4 pups. In liver, transcripts for CYPs and conjugation enzymes, Nrf2, and ABC transporters were upregulated. In general, the hepatic transcriptomic alterations after exposure to DE-71 or PBDE-47 were similar and provided early indicators of oxidative stress and metabolic alterations, key characteristics of toxicity processes. The transcriptional benchmark dose lower confidence limits of the most sensitive biological processes were lower for PBDE-47 than for the PBDE mixture. Neonatal rat liver transcriptomic data provide early indicators on molecular pathway alterations that may lead to toxicity and/or carcinogenicity if the exposures continue for longer durations. These early toxicogenomic indicators may be used to help prioritize chemicals for a more complete toxicity and cancer risk evaluation.

Gene expression profiling after exposure to a chemical carcinogen, Pentabrominated Diphenyl Ether, at different life stages

“…As described in previously reported studies ( Dunnick et al, 2018c ; Shockley et al, 2020a ; Dunnick et al, 2020 ), the chemical pentabromodiphenyl ether-47 (PBDE-47, 2,2′,4,4′-tetrabromodiphenyl ether; CAS# 5436-43-1) was obtained from Cerillant Corp (Round Rock, TX; Lot ER081208-02). Chemical identity was confirmed by mass spectrometry and nuclear magnetic resonance spectroscopy.…”

“…The animals used were either male Wistar Han rat or Harlan Sprague Dawley rats which induced transcripts encoding metabolic enzymes, members of the Nrf2 antioxidant pathway, and ABC transporters upon exposure to PBDE-47 and the PBDE-47 mixture as described in previous publications ( Dunnick et al, 2018c ; Shockley et al, 2020a ; Shockley et al, 2020b ; Dunnick et al, 2020 ). In this paper, the transcriptomic data from different life stages was analyzed by groups (Group 1–5, see Table 1 ).…”

“…This paper evaluates liver toxicogenomic changes after exposure to a model chemical carcinogen (pentabrominated diphenyl ether ( Dunnick et al, 2018a ; Dunnick et al, 2018b )) in male rats at PND 4 (after in utero exposure), PND 22 (after in utero /postnatal exposure), and in adult male rats (after 5-day exposures). The hypothesis for this study was that exposure to pentabrominated diphenyl ether at different life cycle stages would activate disease pathways that could be used to predict longer term toxic and carcinogenic effects, thereby reducing the number of animals needed to obtain toxic and cancer hazard identification information used in risk assessment evaluations ( Dunnick et al, 2018c ; Shockley et al, 2020a ; Dunnick et al, 2020 ).…”

“…Three recent toxicogenomics studies evaluated the gene expression response to PBDE exposure in male rats at PND 4, PND 22, and adult animal evaluations ( Dunnick et al, 2018c ; Shockley et al, 2020a ; Dunnick et al, 2020 ). Each of these studies had a separate research interest (i.e., the response of male rats to PBDE at either PND4, PND22, or adult).…”

Flame Retardants-Mediated Interferon Signaling in the Pathogenesis of Nonalcoholic Fatty Liver Disease

“…Moreover, in utero, exposures of rat dams to DE-71 and BDE-47 decreased T4 level and upregulated hepatic transcripts of CYPs and conjugation enzymes, Nrf2, and ATP-binding cassette (ABC) transporters in postnatal day four (PND 4) rat pups, indicating metabolic alterations and increased oxidative stress. Cytoplasmic vacuolization in the liver was also observed in DE-71 exposure groups [ 150 ]. Exposure to a human-relevant dose from the dust of a commercial mixture of FR Firemaster ® 550 has been reported to be a potential obesogen, endocrine disruptor, and contributed to metabolic syndrome and insulin resistance in rats [ 151 ].…”