PUBLICATION

Mechanistic Investigations Into the Developmental Toxicity of Nitrated and Heterocyclic PAHs

Authors
Chlebowski, A.C., Garcia, G.R., La Du, J.K., Bisson, W.H., Truong, L., Massey Simonich, S.L., Tanguay, R.L.
ID
ZDB-PUB-170508-8
Date
2017
Source
Toxicological sciences : an official journal of the Society of Toxicology   157: 246-259 (Journal)
Registered Authors
La Du, Jane K., Tanguay, Robyn L.
Keywords
aryl hydrocarbon receptor, heterocyclic polycyclic aromatic hydrocarbon, nitrated polycyclic aromatic hydrocarbon, zebrafish.
MeSH Terms
  • Stress, Physiological/drug effects
  • Cytochrome P-450 CYP1A1/genetics
  • Receptors, Aryl Hydrocarbon/drug effects
  • Receptors, Aryl Hydrocarbon/genetics
  • Teratogens/toxicity*
  • Animals
  • Gene Knockdown Techniques
  • Heterocyclic Compounds/toxicity*
  • Zebrafish
  • Animals, Genetically Modified
  • Hydrocarbons, Cyclic/chemistry
  • Hydrocarbons, Cyclic/toxicity*
  • Oxidative Stress/drug effects
  • Nitrates/chemistry*
(all 14)
PubMed
28186253 Full text @ Toxicol. Sci.
CTD
28186253
Abstract
Nitrated polycyclic aromatic hydrocarbons (NPAHs) and heterocyclic PAHs (HPAHs) are recognized environmental pollutants. However, the health risks of NPAHs and HPAHs to humans and environmental systems are not well-studied. The developmental zebrafish (Danio rerio) model was used to evaluate the toxicity of a structurally diverse set of 27 NPAHs and 10 HPAHs. The individual activity of each compound towards the aryl hydrocarbon receptor (AHR), including the role of the AHR in observed toxicity, and genetic markers of oxidative stress and cardiac toxicity were evaluated. Zebrafish embryos were exposed from 6 to 120?hours post fertilization (hpf), to a broad concentration range of individual compounds, and evaluated for 22 developmental endpoints. The potential role of AHR was determined using the transgenic Tg(cyp1a:nls-egfp) reporter zebrafish line. All compounds were screened computationally through molecular docking using a previously developed AHR models of zebrafish isoforms 1A, 1B, and 2. Some compounds did not induce observable developmental toxic responses, whereas others produced statistically significant concentration-dependent toxicity. The tested compounds also exhibited a range of predicted AHR binding and cyp1a/GFP induction patterns, including cyp1a expression in the liver, vasculature, skin, and yolk, which we determined to be due to distinct isoforms of the AHR, using morpholino oligonucleotide knockdown. Furthermore, we investigated mRNA expression of oxidative and cardiac stress genes at 48 and 120 hpf, which indicated several potential mechanisms-of-action for NPAHs. Overall, we observed a range of developmental toxicities, cyp1a/GFP expression patterns, and gene expression profiles, suggestive of several potential mechanisms of action.
Genes / Markers
Figures
Figure Gallery (2 images)
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
cms2TgTransgenic Insertion
    1 - 1 of 1
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    Human Disease / Model
    No data available
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    ahr1aMO1-ahr1aMRPHLNO
    ahr1bMO1-ahr1bMRPHLNO
    ahr2MO1-ahr2MRPHLNO
    1 - 3 of 3
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    Fish
    No data available
    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    Marker Marker Type Name
    EGFPEFGEGFP
    1 - 1 of 1
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    Mapping
    No data available
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    Citation
    Chlebowski, A.C., Garcia, G.R., La Du, J.K., Bisson, W.H., Truong, L., Massey Simonich, S.L., Tanguay, R.L. (2017) Mechanistic Investigations Into the Developmental Toxicity of Nitrated and Heterocyclic PAHs. Toxicological sciences : an official journal of the Society of Toxicology. 157:246-259.