Substituted Two- to Five-Ring Polycyclic Aromatic Compounds Are Potent Agonists of Atlantic Cod (Gadus morhua) Aryl Hydrocarbon Receptors Ahr1a and Ahr2a.

Roger Lille-Langøy,Anders Goksøyr,Magne O Sydnes,Daniela M Pampanin,Odd André Karlsen,Kåre Bredeli Jørgensen

doi:10.1021/acs.est.1c02946

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are among the most toxic and bioavailable components found in petroleum and represent a high risk to aquatic organisms. The aryl hydrocarbon receptor (Ahr) is a ligand-activated transcription factor that mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other planar aromatic hydrocarbons, including certain PAHs. Ahr acts as a xenosensor and modulates the transcription of biotransformation genes in vertebrates, such as cytochrome P450 1A (cyp1a). Atlantic cod (Gadus morhua) possesses two Ahr proteins, Ahr1a and Ahr2a, which diverge in their primary structure, tissue-specific expression, ligand affinities, and transactivation profiles. Here, a luciferase reporter gene assay was used to assess the sensitivity of the Atlantic cod Ahrs to 31 polycyclic aromatic compounds (PACs), including two- to five-ring native PAHs, a sulfur-containing heterocyclic PAC, as well as several methylated, methoxylated, and hydroxylated congeners. Notably, most parent compounds, including naphthalene, phenanthrene, and partly, chrysene, did not act as agonists for the Ahrs, while hydroxylated and/or alkylated versions of these PAHs were potent agonists. Importantly, the greater potencies of substituted PAH derivatives and their ubiquitous occurrence in nature emphasize that more knowledge on the toxicity of these environmentally and toxicologically relevant compounds is imperative.

Highlights

Polycyclic aromatic compounds (PACs) are a diverse group of chemicals that contain aromatic rings organized in linear, angular, or clustered structures
In vitro aryl hydrocarbon receptor (Ahr) activation not necessarily correlates to adverse outcomes in organisms, reporter gene assays as applied in this study may still expand our understanding of polycyclic aromatic compounds (PACs)-mediated toxicities
In several cases, including NAP and PHE, the unsubstituted congener did not act as an Ahr agonist, which is in agreement with previous data reporting that two- and three-ring unsubstituted Polycyclic aromatic hydrocarbons (PAHs) are generally inactive in fish, avian, and mammalian systems.[40,51]

Summary

■ INTRODUCTION

Polycyclic aromatic compounds (PACs) are a diverse group of chemicals that contain aromatic rings organized in linear, angular, or clustered structures. Transdiols of naphthalene and phenanthrene, which are considered the most prominent biotransformation products of these compounds commonly found in fish bile, are included in these analyses, and to our knowledge, this is the first time these metabolites have been evaluated as agonists for Ahr.[40] Importantly, in vitro Ahr activation not necessarily correlates to adverse outcomes in organisms, reporter gene assays as applied in this study may still expand our understanding of PAC-mediated toxicities Such data could prove important for future risk assessment and further reveal functional differences between receptors and receptor subtypes and potentially divergences in species susceptibility to PAC exposure.[5,39]. Welch′s t-test was used to compare the maximum Ahrmediated response and potency (Emax and EC50) between Ahr1a or Ahr2a produced by the same test compound (Prism v7)

■ RESULTS

■ DISCUSSION

■ ACKNOWLEDGMENTS

Findings

■ REFERENCES