Gene expression changes in immune response pathways following oral administration of tetrabromobisphenol A (TBBPA) in female Wistar Han rats

Abstract

Tetrabromobisphenol A (TBBPA) is a brominated flame retardant used globally at high volumes, primarily in the epoxy resin of circuit boards. It has been detected in the environment and in humans. The National Toxicology Program found that chronic oral TBBPA treatment of 250 mg/kg and higher caused an increased incidence of uterine lesions in female Wistar Han rats. The present laboratory has previously reported changes in gene expression associated with estrogen homeostasis in liver and uterine tissue of adult female Wistar Han rats after five days of gavage with 250 mg/kg of TBBPA. Microarray analysis of tissue from these same TBBPA-treated rats was performed to detect additional pathways perturbed by TBBPA. Microarray analysis of uterine tissue detected downregulation of genes in pathways of the immune response following TBBPA treatment. These results, along with validation of associated gene expression changes using droplet digital PCR, are reported here. Our findings suggest mechanisms that may be related to estrogen-mediated immunosuppression.

TBBPA disposition and kinetics in pregnant and nursing Wistar Han IGS rats

“…At very high doses, TBBPA causes hepatotoxicities and heme metabolism disturbances (13, 14) that are likely due to the formation of free radicals (15). Repeated and chronic exposures to orally administered TBBPA resulted in the downregulation of gene products implicated in several immunologic pathways in uterine tissues (11, 16, 17). TBBPA has also been shown to compete with estrogen for conjugation by the estrogen sulfotransferase (SULT1E1), potentially prolonging estrogen signaling in sensitive tissues (e.g., uterus) (18).…”

Microarrays and NGS for Drug Discovery

“…Moreover, using microarray and ddPCR, it is observed that epidermal growth factor receptor (EGFR) expression can be used as a prognostic biomarker in patients with oropharyngeal squamous cell carcinoma, as it is associated with smoking status [65]. In another study, microarray analysis of uterine tissue, along with validation using ddPCR has allowed for observing downregulation of genes in pathways of the immune response following tetrabromobisphenol A treatment [66]. Moreover, ddPCR analysis of miRNAs identified using a microarray assay has revealed that anti-apoptotic miRNA may be potentially involved in antagonistic effects between the Alternaria mycotoxins alternariol and altertoxin II in HepG2 cells [67].…”

Derivation of a no‐significant‐risk‐level for tetrabromobisphenol A based on a threshold non‐mutagenic cancer mode of action

“…The literature search identified a carcinogenicity study of TBBPA by the US NTP (NTP, 2014), and associated published studies that evaluated these NTP (2014) tumor findings and the TBBPA cancer MOA (Dunnick et al, 2015;Hall, Coulter, Knudsen, Sanders, & Birnbaum, 2017;Harvey et al, 2015;Lai, Kacew, & Dekant, 2015;Sanders et al, 2016;Wikoff et al, 2015;Wikoff et al, 2016). These data are pertinent because the lack of cancer data was identified as a data gap precluding the development of a cancer potency value by regulatory agencies (EFSA, 2011;Health Canada, 2013 However, we did not request this information.)…”

“…In the NTP 2-year TBBPA bioassay, and as evaluated by Wikoff et al (2015), uterine tumors in rats were identified as the most appropriate endpoint for use in derivation of a cancer toxicity value. Based on the considerable amount of evidence that TBBPA is not mutagenic, a non-linear MOA was postulated for TBBPA-induced uterine tumors based on interference with estrogen metabolism, as discussed by several authors (Borghoff, Wikoff, Harvey, & Haws, 2016;Dunnick et al, 2015;Hall et al, 2017;Harvey et al, 2015;Lai et al, 2015;Sanders et al, 2016;Wikoff et al, 2015), most comprehensively by Wikoff et al (2016). The interference with estrogen is not thought to involve TBBPA binding directly to the estrogen receptor (ER).…”