Photolysis of highly brominated flame retardants leads to time-dependent dioxin-responsive mRNA expression in chicken embryonic hepatocytes

Tetradecabromo-1,4-diphenoxybenzene (TeDB-DiPhOBz) and 2,2′,3,3′,4,4′,5,5′,6,6′-decabromodiphenyl ether (BDE-209) are flame retardant chemicals that can undergo photolytic degradation. The present study compared the time-dependent photolyic degradation of TeDB-DiPhOBz and BDE-209, and dioxin-like product formation as a result of (UV) irradiation (I; irradiation time periods of 0, 1, 4, 15 and 40 days). Photo-degraded product fractions of UV-I-TeDB-DiPhOBz (nominal concentration: 1.9 μM) were administered to chicken embryonic hepatocytes (CEH), and significant induction of CYP1A4/5 mRNA expression was observed for fractions collected at the day 15 and 40 time points (fold change of 7.3/3.6 and 9.1/4.7, respectively). For the UV-I-BDE-209 fractions (nominal concentration: 10 μM), significant CYP1A4/5 up-regulation occurred at all time points, and the fraction collected on day 1 induced the greatest fold change of 510/86, followed by 410/68 (day 4) and 110/26 (day 15), respectively. For the UV-I-BDE-209 fraction collected at day 40, significant CEH cytotoxicity was observed. As a result, CYP1A4/5 expression was determined at a nominal concentration of 1 μM instead of 10 μM and CYP1A4/5 fold changes of 11/8.2 (day 40) were observed. Fractions eliciting the greatest CYP1A4/5 mRNA upregulation were further screened for transcriptomic effects using a PCR array comprising 27 dioxin-responsive genes. A total of 6 and 16 of the 27 target genes were up or down-regulated following UV-I-TeDB-DiPhOBz and UV-I-BDE-209 exposure, respectively. Overall, and regardless of the formation rate, these results raise concerns regarding the potential formation of dioxin-like compounds from flame retardant

Application of Toxicogenomic Analysis in Human Health Risk Assessment

Presented at a Health Canada Foru

AhR sensing of bacterial pigments regulates antibacterial defence

The aryl hydrocarbon receptor (AhR) is a highly conserved ligand-dependent transcription factor that senses environmental toxins and endogenous ligands, thereby inducing detoxifying enzymes and modulating immune cell differentiation and responses. We hypothesized that AhR evolved to sense not only environmental pollutants but also microbial insults. We characterized bacterial pigmented virulence factors, namely the phenazines from Pseudomonas aeruginosa and the naphthoquinone phthiocol from Mycobacterium tuberculosis, as ligands of AhR. Upon ligand binding, AhR activation leads to virulence factor degradation and regulated cytokine and chemokine production. The relevance of AhR to host defence is underlined by heightened susceptibility of AhR-deficient mice to both P. aeruginosa and M. tuberculosis. Thus, we demonstrate that AhR senses distinct bacterial virulence factors and controls antibacterial responses, supporting a previously unidentified role for AhR as an intracellular pattern recognition receptor, and identify bacterial pigments as a new class of pathogen-associated molecular patterns