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Researchers investigated developmental neurotoxicity of a complex polycyclic aromatic hydrocarbon (PAH) mixture extracted from contaminated sediment using three model organisms: Atlantic killifish, zebrafish, and C. elegans worms. While the PAH mixture activated the expected Aryl hydrocarbon Receptor (AhR) pathway in fish, the neurotoxic effects occurred independently of this pathway, as demonstrated by persistent neurobehavioral damage in AhR-resistant killifish populations and dopaminergic neuronal damage in worms, which lack vertebrate-type AhR activation. The neurotoxicity appears to involve altered neuronal redox status and energy metabolism rather than canonical AhR signaling.
Why it matters
This research reveals that current risk assessments for PAH mixtures may be incomplete if they focus primarily on AhR-mediated toxicity. Understanding these alternative neurotoxic mechanisms is critical for protecting human and wildlife health in areas contaminated with complex PAH mixtures from sources like creosote sites and industrial pollution.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Typical environmental exposures to the toxic class of chemicals known as polycyclic aromatic hydrocarbons (PAHs) involve complex mixtures; however, relatively few mechanistic toxicity studies have evaluated them as environmental mixtures, instead focusing on individual compounds or simple mixtures. In this study, we first derived Republic Sediment Extract (REPSE), a complex PAH mixture extracted from sediment at the Republic Creosoting site of the Elizabeth River in Norfolk, Virginia. After characterizing the PAH contents of REPSE, we evaluated its mechanisms of developmental neurotoxicity in three evolutionarily distinct taxa, leveraging the unique strengths of Atlantic killifish, zebrafish, and Caenorhabditis elegans as model species, with a focus on the Aryl hydrocarbon Receptor (AhR) pathway. Embryonic REPSE exposure caused induction of CYP1A in both fish species at sub-teratogenic concentrations, consistent with activation of the canonical AhR pathway. These sub-teratogenic exposures nevertheless induced neurotoxicity across both fish species, altering neurobehavioral phenotypes in fish, and induced dopaminergic neuronal damage in worms, again at non-teratogenic concentrations. To determine whether these effects were linked to canonical AhR response pathways, we examined killifish offspring from the pollution-adapted Republic Creosoting population, which exhibited characteristic recalcitrance to CYP1A induction, but remained susceptible to the neurobehavioral effects of REPSE. The induction of neuronal damage in worms provides orthogonal evidence for a non-AhR mechanism, because C. elegans AhR is not transcriptionally activated by PAHs as in vertebrates. Further probing of potential mechanisms underlying REPSE-induced neurotoxicity in worms revealed altered neuronal redox status (roGFP) and energy availability (ATP:ADP ratio). Collectively, our multispecies approach reveals conserved mechanisms of PAH mixture neurotoxicity, including effects that extend beyond canonical AhR signaling.