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.

Experimental Protocol for Examining Behavioral Response Profiles in Larval Fish: Application to the Neuro-stimulant Caffeine

“…Caffeine treatment levels in the present study were selected based on upper centile values for predicted environmental exposure scenarios from wastewater effluent 16 . When possible, we routinely select treatment levels for aquatic toxicology studies using probabilistic exposure assessments of environmental observations 19 20 21 . A THV, which is calculable for medicines, was also included as a treatment level in the present study.…”

“…, increasing replication) can be modified within the current protocol for future studies. Fish culture conditions follow previously published literature 17 . All experimental procedures and fish culture protocols followed Institutional Animal Care and Use Committee protocols approved at Baylor University.…”

Towards Sustainable Environmental Quality: Priority Research Questions for the Australasian Region of Oceania

“…Guidelines derived for individual stressors may not be sufficiently protective when ecosystems are exposed to multiple stressors. However, metabolic transformation of contaminants and other basic scientific limitations remain when extrapolating in vitro to in vivo effects and even comparing responses among the 2 most common fish models (Corrales et al 2016;Steele et al 2018). Salinization is particularly relevant to regions in Australasia, yet influences of salinity gradients on contaminants with diverse modes of action are poorly understood among species (Canedo-Arguelles et al 2018).…”

“…Unprecedented opportunities are emerging with use of high-throughput in vitro, transgenic fish lines, and in situ toxicogenomic platforms when coupled with targeted and nontargeted chemical analyses (Bradley et al 2017) in the field Bradley et al 2017;Perkins et al 2017). However, metabolic transformation of contaminants and other basic scientific limitations remain when extrapolating in vitro to in vivo effects and even comparing responses among the 2 most common fish models (Corrales et al 2016;Steele et al 2018). Advancing AOP efforts for mixtures and predictive modeling of these complex lowlevel constituents will be important.…”

3D Visualization of Developmental Toxicity of 2,4,6-Trinitrotoluene in Zebrafish Embryogenesis Using Light-Sheet Microscopy

“…Zebrafish ( Danio rerio ) embryos are ideal model vertebrates for assessing the acute toxicity of environmental samples and newly developing compounds [15,16]. Their development has been extensively characterized and embryos remain transparent until late pharyngula stages, allowing unobstructed imaging of key morphological events.…”