ZFIN ID: ZDB-PUB-161018-1
Towards the design of less hazardous chemicals: Exploring comparative oxidative stress in two common animal models
Corrales, J., Kristofco, L.A., Steele, W.B., Saari, G.N., Kostal, J., Williams, E.S., Mills, M., Gallagher, E.P., Kavanagh, T.J., Simcox, N., Shen, L.Q., Melnikov, F., Zimmerman, J.B., Voutchkova-Kostal, A.M., Anastas, P.T., Brooks, B.W.
Date: 2017
Source: Chemical Research in Toxicology   30(4): 893-904 (Journal)
Registered Authors: Gallagher, Evan P.
Keywords: none
MeSH Terms:
  • Animals
  • Antioxidants/metabolism
  • Biomarkers/metabolism
  • Cyprinidae/metabolism
  • DNA Damage/drug effects
  • Glutathione/metabolism
  • Glutathione Transferase/genetics
  • Glutathione Transferase/metabolism
  • Hazardous Substances/chemistry
  • Hazardous Substances/metabolism
  • Hazardous Substances/toxicity*
  • Models, Animal
  • NF-E2-Related Factor 2/genetics
  • NF-E2-Related Factor 2/metabolism
  • Oxidative Stress/drug effects*
  • Quantum Theory
  • Superoxide Dismutase/genetics
  • Superoxide Dismutase/metabolism
  • Zebrafish/metabolism
PubMed: 27750016 Full text @ Chem. Res. Toxicol.
Sustainable molecular design of less hazardous chemicals presents a potentially transformative approach to protect public health and the environment. Relationships between molecular descriptors and toxicity thresholds previously identified the octanol-water distribution coefficient, log D, and the HOMO-LUMO energy gap, ∆E, as two useful properties in the identification of reduced aquatic toxicity. To determine whether these two property-based guidelines are applicable to sublethal oxidative stress (OS) responses, two common aquatic in vivo models, the fathead minnow (Pimephales promelas) and zebrafish (Danio rerio), were employed to examine traditional biochemical biomarkers (lipid peroxidation, DNA damage, total glutathione) and antioxidant gene activation following exposure to eight structurally diverse industrial chemicals (bisphenol A, cumene hydroperoxide, dinoseb, hydroquinone, indene, perfluorooctanoic acid, R-(-)-carvone, tert-butyl hydroperoxide). Bisphenol A, cumene hydroperoxide, dinoseb, and hydroquinone were consistent inducers of OS. Glutathione was the most consistently affected biomarker, suggesting its utility as a sensitivity response to support the design of less hazardous chemicals. Antioxidant gene expression (changes in nrf2, gclc, gst, and sod) was most significantly (p<0.05) altered by R-(-)-carvone, cumene hydroperoxide and bisphenol A. Results from the present study indicate that metabolism of parent chemicals and the role of their metabolites in molecular initiating events should be considered during the design of less hazardous chemicals. Current empirical and computational findings identify the need for future derivation of sustainable molecular design guidelines for electrophilic reactive chemicals (e.g., SN2 nucleophilic substitution, Michael addition reactivity) to reduce OS related adverse outcomes in vivo.