Hepatic transcriptional dose-response analysis of male and female Fischer rats exposed to hexabromocyclododecane
- DOI
- Language of the publication
- English
- Date
- 2018-12-27
- Type
- Article
- Author(s)
- Farmahin, Reza
- Gannon, Anne Marie
- Gagné, Rémi
- Rowan-Carroll, Andrea
- Kuo, Byron
- Williams, Andrew
- Curran, Ivan
- Yauk, Carole L.
- Publisher
- Elsevier
Abstract
Hexabromocyclododecane (HBCD) is a brominated flame retardant found in the environment and human tissues. The toxicological effects of HBCD exposure are not clearly understood. We employed whole-genome RNA-sequencing on liver samples from male and female Fischer rats exposed to 0, 250, 1250, and 5000 mg technical mixture of HBCD/kg diet for 28 days to gain further insight into HBCD toxicity. HBCD altered 428 and 250 gene transcripts in males and females, respectively, which were involved in metabolism of xenobiotics, oxidative stress, immune response, metabolism of glucose and lipids, circadian regulation, cell cycle, fibrotic activity, and hormonal balance. Signature analysis supported that HBCD operates through the constitutive androstane and pregnane X receptors. The median transcriptomic benchmark dose (BMD) for the lowest statistically significant pathway was within 1.5-fold of the BMD for increased liver weight, while the BMD for the lowest pathway with at least three modeled genes (minimum 5% of pathway) was similar to the lowest apical endpoint BMD. The results show how transcriptional analyses can inform mechanisms underlying chemical toxicity and the doses at which potentially adverse effects occur. This experiment is part of a larger study exploring the use of toxicogenomics and high-throughput screening for human health risk assessment.
Plain language summary
Health Canada is responsible for the assessment and management of health risks posed to Canadians by chemicals in their environment. Toxicogenomics investigates how genes respond to chemicals and provides useful information about the biological changes that lead to disease, which is an important consideration for human health risk assessment. In this study, toxicogenomics was used to investigate the chemical hexabromocyclododecane (HBCD). HBCD is a flame retardant that is widespread in the environment and human tissues. The toxicological effects of HBCD exposure are not clearly understood, and this paper is one in a series of experiments exploring its health effects. Clear effects of HBCD on the liver have been published previously. Thus, Health Canada undertook a study to understand the biological changes that occur in liver following short-term (28 day) exposure of male and female rats to HBCD. Rats were exposed to various concentrations of HBCD in their diets and liver samples were collected. Toxicogenomics was used to study how gene activity changes following the treatments. HBCD exposure led to sex-specific changes in gene activity, with 428 and 250 affected genes in males and females, respectively. Affected genes were involved in various physiological processes. Gene activity coincided with HBCD concentrations associated with liver weight changes. Overall, the study provides further understanding into the biological mechanisms underlying HBCD-induced toxicity. This work highlights the utility of toxicogenomics to identify important molecular pathways leading to disease, and serves as an example to demonstrate how it may be used in chemical assessments.
Subject
- Health,
- Health and safety