title: Toward the Design of Less Hazardous Chemicals: Exploring Comparative Oxidative Stress in Two Common Animal Models.
abstract: 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.
authors.affiliation: Department of Environmental Science, Baylor University , Waco, Texas 76798, United States.
authors.forename: Jone
authors.initials: J
authors.lastname: Corrales
authors.affiliation: Department of Environmental Science, Baylor University , Waco, Texas 76798, United States.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Kristofco
authors.affiliation: Department of Environmental Science, Baylor University , Waco, Texas 76798, United States.
authors.forename: W Baylor
authors.initials: WB
authors.lastname: Steele
authors.affiliation: Department of Environmental Science, Baylor University , Waco, Texas 76798, United States.
authors.forename: Gavin N
authors.initials: GN
authors.lastname: Saari
authors.affiliation: Department of Chemistry, George Washington University , Washington, D.C. 20052, United States.
authors.forename: Jakub
authors.initials: J
authors.lastname: Kostal
authors.affiliation: Department of Environmental Science, Baylor University , Waco, Texas 76798, United States.
authors.forename: E Spencer
authors.initials: ES
authors.lastname: Williams
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Margaret
authors.initials: M
authors.lastname: Mills
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Evan P
authors.initials: EP
authors.lastname: Gallagher
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Terrance J
authors.initials: TJ
authors.lastname: Kavanagh
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Nancy
authors.initials: N
authors.lastname: Simcox
authors.affiliation: Center for Green Chemistry and Green Engineering, Yale University , New Haven, Connecticut 06520, United States.
authors.forename: Longzhu Q
authors.initials: LQ
authors.lastname: Shen
authors.affiliation: Center for Green Chemistry and Green Engineering, Yale University , New Haven, Connecticut 06520, United States.
authors.forename: Fjodor
authors.initials: F
authors.lastname: Melnikov
authors.affiliation: Center for Green Chemistry and Green Engineering, Yale University , New Haven, Connecticut 06520, United States.|Department of Chemical and Environmental Engineering, Yale University , New Haven, Connecticut 06520, United States.
authors.forename: Julie B
authors.initials: JB
authors.lastname: Zimmerman
authors.affiliation: Department of Chemistry, George Washington University , Washington, D.C. 20052, United States.
authors.forename: Adelina M
authors.initials: AM
authors.lastname: Voutchkova-Kostal
authors.affiliation: Center for Green Chemistry and Green Engineering, Yale University , New Haven, Connecticut 06520, United States.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Anastas
authors.affiliation: Department of Environmental Science, Baylor University , Waco, Texas 76798, United States.
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Brooks
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D003530:Cyprinidae / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D015386:Hazardous Substances / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D023421:Models, Animal; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011789:Quantum Theory; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000378:metabolism
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D015386:Hazardous Substances; D051267:NF-E2-Related Factor 2; D013482:Superoxide Dismutase; D005982:Glutathione Transferase; D005978:Glutathione