Toward the Design of Less Hazardous Chemicals: Exploring Comparative Oxidative Stress in Two Common Animal Models

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, ΔE, 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, and 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,
and 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 and Michael
addition reactivity) to reduce OS related adverse outcomes in vivo.