CRISPR-Generated Nrf2a Loss- and Gain-of-Function Mutants Facilitate Mechanistic Analysis of Chemical Oxidative Stress-Mediated Toxicity in Zebrafish.

The transcription factor Nrf2a induces a cellular antioxidant response and provides protection against chemical-induced oxidative stress, as well as playing a critical role in development and disease. Zebrafish are a powerful model to study the role of Nrf2a in these processes but have been limited by reliance on transient gene knockdown techniques or mutants with only partial functional alteration. We developed several lines of zebrafish carrying different null (loss of function, LOF) or hyperactive (gain of function, GOF) mutations to facilitate our understanding of the Nrf2a pathway in protecting against oxidative stress.

Toward Less Hazardous Industrial Compounds: Coupling Quantum Mechanical Computations, Biomarker Responses, and Behavioral Profiles To Identify Bioactivity of S2 Electrophiles in Alternative Vertebrate Models.

Sustainable molecular design of less hazardous chemicals promises to reduce risks to public health and the environment. Computational chemistry modeling coupled with alternative toxicology models (e.g.

Spatio-temporal bioaccumulation and trophic transfer of ionizable pharmaceuticals in a semi-arid urban river influenced by snowmelt.

Bioaccumulation of pharmaceuticals in aquatic organisms is increasingly reported in the peer-reviewed literature. However, seasonal instream dynamics including occurrence and bioaccumulation across trophic positions are rarely studied, particularly in semiarid streams with flows influenced by seasonal snowmelt and municipal effluent discharges. Thus, we selected East Canyon Creek in Park City, Utah, USA to examine spatio-temporal bioaccumulation of select ionizable pharmaceuticals across trophic positions using trophic magnification factors calculated at incremental distances (0.

Comparative behavioral toxicology with two common larval fish models: Exploring relationships among modes of action and locomotor responses.

Behavioral responses inform toxicology studies by rapidly and sensitively detecting molecular initiation events that propagate to physiological changes in individuals. These behavioral responses can be unique to chemical specific mechanisms and modes of action (MOA) and thus present diagnostic utility. In an initial effort to explore the use of larval fish behavioral response patterns in screening environmental contaminants for toxicity and to identify behavioral responses associated with common chemical specific MOAs, we employed the two most common fish models, the zebrafish and the fathead minnow, to define toxicant induced swimming activity alterations during interchanging photoperiods.

Global review and analysis of erythromycin in the environment: Occurrence, bioaccumulation and antibiotic resistance hazards.

Environmental observations of antibiotics and other pharmaceuticals have received attention as indicators of an urbanizing global water cycle. When connections between environment and development of antibiotic resistance (ABR) are considered, it is increasingly important to understand the life cycle of antibiotics. Here we examined the global occurrence of erythromycin (ERY) in: 1.

Differential uptake of and sensitivity to diphenhydramine in embryonic and larval zebrafish.

The zebrafish fish embryo toxicity (FET) test is increasingly employed for alternative toxicity studies, yet our previous research identified increased sensitivity of zebrafish slightly older than embryos employed in FET methods (0-4 d postfertilization [dpf]). We identified rapid steady-state accumulation of diphenhydramine across zebrafish embryo and larval stages. However, significantly (p < 0.

The Molecular Design Research Network.

Herein, we provide an overview of a research network that is aimed at fostering interdisciplinary collaboration between chemists and toxicologists with the goal of rationally designing safer commercial chemicals. The collaborative is the Molecular Design Research Network (MoDRN) that was created in 2013 with funding from the EPA-National Science Foundation Networks for Sustainable Molecular Design and Synthesis (NSMDS) program. MoDRN is led by 4 universities, Baylor University, University of Washington, The George Washington University, and Yale University.

Global scanning of antihistamines in the environment: Analysis of occurrence and hazards in aquatic systems.

Concentration of the global population is increasingly occurring in megacities and other developing regions, where access to medicines is increasing more rapidly than waste management systems are implemented. Because freshwater and coastal systems are influenced by wastewater effluent discharges of differential quality, exposures in aquatic systems must be considered. Here, we performed a global scanning assessment of antihistamines (AHs), a common class of medicines, in surface waters and effluents.

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).

Global Assessment of Bisphenol A in the Environment: Review and Analysis of Its Occurrence and Bioaccumulation.

Because bisphenol A (BPA) is a high production volume chemical, we examined over 500 peer-reviewed studies to understand its global distribution in effluent discharges, surface waters, sewage sludge, biosolids, sediments, soils, air, wildlife, and humans. Bisphenol A was largely reported from urban ecosystems in Asia, Europe, and North America; unfortunately, information was lacking from large geographic areas, megacities, and developing countries. When sufficient data were available, probabilistic hazard assessments were performed to understand global environmental quality concerns.

Age matters: Developmental stage of Danio rerio larvae influences photomotor response thresholds to diazinion or diphenhydramine.

Because basic toxicological data is unavailable for the majority of industrial compounds, High Throughput Screening (HTS) assays using the embryonic and larval zebrafish provide promising approaches to define bioactivity profiles and identify potential adverse outcome pathways for previously understudied chemicals. Unfortunately, standardized approaches, including HTS experimental designs, for examining fish behavioral responses to contaminants are rarely available. In the present study, we examined movement behavior of larval zebrafish over 7 days (4-10 days post fertilization or dpf) during typical daylight workday hours to determine whether intrinsic activity differed with age and time of day.

Comparative pharmacology and toxicology of pharmaceuticals in the environment: diphenhydramine protection of diazinon toxicity in Danio rerio but not Daphnia magna.

Pharmaceuticals and other contaminants of emerging concern present unique challenges to environmental risk assessment and management. Fortunately, mammalian pharmacology and toxicology safety data are more readily available for pharmaceuticals than other environmental contaminants. Identifying approaches to read-across such pharmaceutical safety information to non-target species represents a major research need to assess environmental hazards.

Bioaccumulation and trophic dilution of human pharmaceuticals across trophic positions of an effluent-dependent wadeable stream.

Though pharmaceuticals are increasingly observed in a variety of organisms from coastal and inland aquatic systems, trophic transfer of pharmaceuticals in aquatic food webs have not been reported. In this study, bioaccumulation of select pharmaceuticals was investigated in a lower order effluent-dependent stream in central Texas, USA, using isotope dilution liquid chromatography-tandem mass spectrometry (MS). A fish plasma model, initially developed from laboratory studies, was tested to examine observed versus predicted internal dose of select pharmaceuticals.

Comparison of contaminants of emerging concern removal, discharge, and water quality hazards among centralized and on-site wastewater treatment system effluents receiving common wastewater influent.

A comparative understanding of effluent quality of decentralized on-site wastewater treatment systems, particularly for contaminants of emerging concern (CECs), remains less understood than effluent quality from centralized municipal wastewater treatment plants. Using a novel experimental facility with common influent wastewater, effluent water quality from a decentralized advanced aerobic treatment system (ATS) and a typical septic treatment system (STS) coupled to a subsurface flow constructed wetland (WET) were compared to effluent from a centralized municipal treatment plant (MTP). The STS did not include soil treatment, which may represent a system not functioning properly.

Pharmaceuticals in the environment: lessons learned for reducing uncertainties in environmental risk assessment.

Pharmaceuticals in the environment are often present at trace levels (e.g., ng/L) in surface waters and effluents of developed countries, yet represent contaminants of emerging concern.