Aryl hydrocarbon receptor-dependent toxicity by retene requires metabolic competence

Rude, Christian I.; Wilson, Lindsay B.; La Du, Jane; Lalli, Priscila M.; Colby, Sean M.; Schultz, Katherine J.; Smith, Jordan N.; Waters, Katrina M.; Tanguay, Robyn L.

doi:10.1093/toxsci/kfae098

Aryl hydrocarbon receptor-dependent toxicity by retene requires metabolic competence

Journal Article · Tue Aug 06 00:00:00 EDT 2024 · Toxicological Sciences

DOI:https://doi.org/10.1093/toxsci/kfae098· OSTI ID:2539753

Rude, Christian I. ^[1]; Wilson, Lindsay B. ^[1]; La Du, Jane ^[1]; Lalli, Priscila M. ^[2]; Colby, Sean M. ^[2]; ^[2]; Smith, Jordan N. ^[3]; ^[3]; ^[1]

Oregon State Univ., Corvallis, OR (United States)
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Oregon State Univ., Corvallis, OR (United States); Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Polycyclic aromatic hydrocarbons (PAHs) are a class of organic compounds frequently detected in the environment with widely varying toxicities. Many PAHs activate the aryl hydrocarbon receptor (AHR), inducing the expression of a battery of genes, including xenobiotic metabolizing enzymes like cytochrome P450s (CYPs); however, not all PAHs act via this mechanism. We screened several parent and substituted PAHs in in vitro AHR activation assays to classify their unique activity. Retene (1-methyl-7-isopropylphenanthrene) displays Ahr2-dependent teratogenicity in zebrafish, but did not activate human AHR or zebrafish Ahr2, suggesting a retene metabolite activates Ahr2 in zebrafish to induce developmental toxicity. To investigate the role of metabolism in retene toxicity, studies were performed to determine the functional role of cyp1a, cyp1b1, and the microbiome in retene toxicity, identify the zebrafish window of susceptibility, and measure retene uptake, loss, and metabolite formation in vivo. Cyp1a-null fish were generated using CRISPR-Cas9. Cyp1a-null fish showed increased sensitivity to retene toxicity, whereas Cyp1b1-null fish were less susceptible, and microbiome elimination had no significant effect. Zebrafish required exposure to retene between 24 and 48 hours post fertilization (hpf) to exhibit toxicity. After static exposure, retene concentrations in zebrafish embryos increased until 24 hpf, peaked between 24 and 36 hpf, and decreased rapidly thereafter. We detected retene metabolites at 36 and 48 hpf, indicating metabolic onset preceding toxicity. This study highlights the value of combining molecular and systems biology approaches with mechanistic and predictive toxicology to interrogate the role of biotransformation in AHR-dependent toxicity.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 2539753

Report Number(s):: PNNL-SA--196662

Journal Information:: Toxicological Sciences, Journal Name: Toxicological Sciences Journal Issue: 1 Vol. 202; ISSN 1096-6080

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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Development and Applications of a Zebrafish (Danio rerio) CYP1A-Targeted Monoclonal Antibody (CRC4) with Reactivity across Vertebrate Taxa: Evidence for a Conserved CYP1A Epitope Anderson, Amy L.; Dubanksy, Benjamin D.; Wilson, Lindsay B. Toxics, Vol. 10, Issue 7 https://doi.org/10.3390/toxics10070404	journal	July 2022
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59 BASIC BIOLOGICAL SCIENCES
AHR
PAHs
aryl hydrocarbon receptor
biotransformation
cytochrome p450
developmental toxicity
polycyclic aromatic hydrocarbons
retene
zebrafish

Aryl hydrocarbon receptor-dependent toxicity by retene requires metabolic competence

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