Activation of Nrf2 at Critical Windows of Development Alters Tissue-Specific Protein -Glutathionylation in the Zebrafish () Embryo.

Activation of Nrf2-the master regulator of antioxidative response-at different stages of embryonic development has been shown to result in changes in gene expression, but the tissue-specific and downstream effects of Nrf2 activation during development remain unclear. This work seeks to elucidate the tissue-specific Nrf2 cellular localization and the downstream changes in protein -glutathionylation during critical windows of zebrafish () development. Wild-type and mutant zebrafish embryos with a loss-of-function mutation in Nrf2a were treated with two canonical activators, sulforaphane (SFN; 40 µM) or tert-butylhydroquinone (tBHQ; 1 µM), for 6 h at either pharyngula, hatching, or the protruding-mouth stage.

Maternal PFOS exposure affects offspring development in Nrf2-dependent and independent ways in zebrafish (Danio rerio).

Perfluorooctanesulfonic acid (PFOS) is a ubiquitous legacy environmental contaminant detected broadly in human samples and water supplies. PFOS can cross the placenta and has been detected in cord blood and breastmilk samples, underscoring the importance of understanding the impacts of maternal PFOS exposure during early development. This study aimed to investigate the effects of a preconception exposure to PFOS on developmental endpoints in offspring, as well as examine the role of the transcription factor Nuclear factor erythroid-2-related factor (Nrf2a) in mediating these effects.

Comparing the effects of developmental exposure to alpha lipoic acid (ALA) and perfluorooctanesulfonic acid (PFOS) in zebrafish (Danio rerio).

Alpha lipoic acid (ALA) is a dietary supplement that has been used to treat a wide range of diseases, including obesity and diabetes, and have lipid-lowering effects, making it a potential candidate for mitigating dyslipidemia resulting from exposures to the per- and polyfluoroalkyl substance (PFAS) family member perfluorooctanesulfonic acid (PFOS). ALA can be considered a non-fluorinated structural analog to PFOS due to their similar 8-carbon chain and amphipathic structure, but, unlike PFOS, is rapidly metabolized. PFOS has been shown to reduce pancreatic islet area and induce β-cell lipotoxicity, indicating that changes in β-cell lipid microenvironment is a mechanism contributing to hypomorphic islets.

Dietary exposure to the food preservative tert-Butylhydroquinone (tBHQ) impairs zebrafish (Danio rerio) survival, growth, organ development, and gene expression in Nrf2a-dependent and independent ways.

Tert-Butylhydroquinone (tBHQ), a preservative used to prevent oxidative deterioration of oil, fat, and meat products, has been linked to both chemoprotective and adverse effects. This study investigates the impact of dietary tBHQ consumption on survival, growth parameters, organ development, and gene expression in zebrafish (Danio rerio). As tBHQ activates the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2a), a zebrafish line with a mutation in the DNA-binding domain of Nrf2a was used to identify Nrf2a-dependent vs independent effects.

Developmental impacts of Nrf2 activation by dimethyl fumarate (DMF) in the developing zebrafish (Danio rerio) embryo.

Dimethyl fumarate (DMF) is pharmaceutical activator of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates of many cellular antioxidant response pathways, and has been used to treat inflammatory diseases such as multiple sclerosis. However, DMF has been shown to produce adverse effects on offspring in animal studies and as such is not recommended for use during pregnancy. The goal of this work is to better understand how these adverse effects are initiated and the role of DMF-induced Nrf2 activation during three critical windows of development in embryonic zebrafish (Danio rerio): pharyngula, hatching, and protruding-mouth stages.

The Zebrafish (Danio rerio) Embryo Model as a Tool to Assess Drinking Water Treatment Efficacy for Freshwater Impacted by Crude Oil Spill.

Traditional approaches toward evaluating oil spill mitigation effectiveness in drinking water supplies using analytical chemistry can overlook residual hydrocarbons and treatment byproducts of unknown toxicity. Zebrafish (Danio rerio) were used to address this limitation by evaluating the reduction in toxicity to fish exposed to laboratory solutions of dissolved crude oil constituents treated with 3 mg/L ozone (O ) with or without a peroxone-based advanced oxidation process using 0.5 M H O /M O or 1 M H O /M O .

Nrf2a dependent and independent effects of early life exposure to 3,3'-dichlorobiphenyl (PCB-11) in zebrafish (Danio rerio).

The environmental pollutant 3,3'-dichlorobiphenyl (PCB-11) is a lower-chlorinated polychlorinated biphenyl (PCB) congener present in air and water samples. Both PCB-11 and its metabolite, 4-PCB-11-Sulfate, are detected in humans, including in pregnant women. Previous research in zebrafish (Danio rerio) has shown that 0.

Relationships between type 2 diabetes, cell dysfunction, and redox signaling: A meta-analysis of single-cell gene expression of human pancreatic α- and β-cells.

Background: Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by insulin resistance and failure of β-cells to meet the metabolic demand for insulin. Recent advances in single-cell RNA sequencing (sc-RNA-Seq) have allowed for in-depth studies to further understand the underlying cellular mechanisms of T2DM. In β-cells, redox signaling is critical for insulin production.

The Nrf2a pathway impacts zebrafish offspring development with maternal preconception exposure to perfluorobutanesulfonic acid.

Since the voluntary phaseout of perfluorooctanesulfonic acid (PFOS), smaller congeners, such as perfluorobutanesulfonic acid (PFBS) have served as industrial replacements and been detected in contaminated aquifers. This study sought to examine the effects of a maternal preconception PFBS exposure on the development of eggs and healthy offspring. Adult female zebrafish received a one-week waterborne exposure of 0.

Modulation of PPAR signaling disrupts pancreas development in the zebrafish, Danio rerio.

Peroxisome Proliferator Activated Receptors (PPARs) are transcription factors that regulate processes such as lipid and glucose metabolism. Synthetic PPAR ligands, designed as therapeutics for metabolic disease, provide a tool to assess the relationship between PPAR activity and pancreas development in vivo, an area that remains poorly characterized. Here, we aim to assess the effects of PPAR agonists and antagonists on gene expression, embryonic morphology and pancreas development in transgenic zebrafish embryos.

Maternal preconception PFOS exposure of Drosophila melanogaster alters reproductive capacity, development, morphology and nutrient regulation.

Perfluorooctanesulfonic acid (PFOS) is a persistent synthetic surfactant widely detected in the environment. Developmental PFOS exposures are associated with low birth weight and chronic exposures increase risk for obesity and type 2 diabetes. As an obesogen, PFOS poses a major public health exposure risk and much remains to be understood about the critical windows of exposure and mechanisms impacted, especially during preconception.

Dibenzyl trisulfide binds to and competitively inhibits the cytochrome P450 1A1 active site without impacting the expression of the aryl hydrocarbon receptor.

The toxicological manifestation of many pollutants relies upon their binding to the aryl hydrocarbon receptor (AHR), and it follows a cascade of reactions culminating in an elevated expression of cytochrome P450 (CYP) 1 enzymes. CYP1A1 and CYP1B1 are associated with enhanced carcinogenesis when chronically exposed to certain polyaromatic hydrocarbons, and their inhibition may lead to chemoprevention. We evaluated dibenzyl trisulfide (DTS), expressed in the ethnomedical plant, Petiveria alliacea, for such potential chemoprevention.

Developmental exposures to perfluorooctanesulfonic acid (PFOS) impact embryonic nutrition, pancreatic morphology, and adiposity in the zebrafish, Danio rerio.

Perfluorooctanesulfonic acid (PFOS) is a persistent environmental contaminant previously found in consumer surfactants and industrial fire-fighting foams. PFOS has been widely implicated in metabolic dysfunction across the lifespan, including diabetes and obesity. However, the contributions of the embryonic environment to metabolic disease remain uncharacterized.

Using Monochlorobimane to Visualize Glutathione Utilization in the Developing Zebrafish (Danio rerio) Embryo.

Glutathione (GSH) plays fundamental roles in cellular redox buffering and is a common detoxification pathway for excretion of xenobiotics. This is especially crucial during vertebrate embryogenesis, when an organism is at one of its most vulnerable life stages. Importantly, GSH content and redox potential can dictate cell fate decisions, which can have profound consequences if altered by early life xenobiotic exposures.

Heavy Metal Exposure Leads to Rapid Changes in Cellular Biophysical Properties.

Biophysical properties of cells, such as cell mechanics, cell shape, and cell migration, are emerging hallmarks for characterizing various cell functions. Conversely, disruptions to these biophysical properties may be used as reliable indicators of disruptions to cell homeostasis, such as in the case of chemical-induced toxicity. In this study, we demonstrate that treatment of lead(II) nitrate and cadmium nitrate leads to dosage-dependent changes in a collection of biophysical properties, including cellular traction forces, focal adhesions, mechanical stiffness, cell shape, migration speed, permeability, and wound-healing efficacy in mammalian cells.

Modulating glutathione thiol status alters pancreatic β-cell morphogenesis in the developing zebrafish (Danio rerio) embryo.

Emerging evidence suggests that redox-active chemicals perturb pancreatic islet development. To better understand potential mechanisms for this, we used zebrafish (Danio rerio) embryos to investigate roles of glutathione (GSH; predominant cellular redox buffer) and the transcription factor Nrf2a (Nfe2l2a; zebrafish Nrf2 co-ortholog) in islet morphogenesis. We delineated critical windows of susceptibility to redox disruption of β-cell morphogenesis, interrogating embryos at 24, 48 and 72 h post fertilization (hpf) and visualized Nrf2a expression in the pancreas using whole-mount immunohistochemistry at 96 hpf.

Per- and Polyfluoroalkyl Substances and Obesity, Type 2 Diabetes and Non-alcoholic Fatty Liver Disease: A Review of Epidemiologic Findings.

Per- and polyfluoroalkyl substances, a group of fluoro-surfactants widely detected in the environment, wildlife and humans, have been linked to adverse health effects. A growing body of literature has addressed their effects on obesity, diabetes and non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis. This review summarizes the brief historical use and chemistry of per- and polyfluoroalkyl substances, routes of human exposure, as well as the epidemiologic evidence for associations between exposure to per- and polyfluoroalkyl substances and the development of obesity, diabetes and non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis.

Chemical Characterization of a Legacy Aqueous Film-Forming Foam Sample and Developmental Toxicity in Zebrafish ().

Background: Drinking water contamination related to the use of aqueous film-forming foam (AFFF) has been documented at hundreds of military bases, airports, and firefighter training facilities. AFFF has historically contained high levels of long-chain per- and polyfluoroalkyl substances (PFAS), which pose serious health concerns. However, the composition and toxicity of legacy AFFF mixtures are unknown, presenting great uncertainties in risk assessment and affected communities.

Perfluorooctanesulfonic acid (PFOS) and perfluorobutanesulfonic acid (PFBS) impaired reproduction and altered offspring physiological functions in Caenorhabditis elegans.

Perfluorobutanesulfonic acid (PFBS), a shorter chain Per- and polyfluoroalkyl substances (PFASs) cognate of perfluorooctanesulfonic acid (PFOS), has been used as replacement for the toxic surfactant PFOS. However, emerging evidences suggest safety concerns for PFBS and its effect on reproductive health is still understudied. Therefore, the current work aimed to investigate the effect of PFBS, in comparison to PFOS, on reproductive health using Caenorhabditis elegans as an in vivo animal model.

The sulfate metabolite of 3,3'-dichlorobiphenyl (PCB-11) impairs Cyp1a activity and increases hepatic neutral lipids in zebrafish larvae (Danio rerio).

The environmental contaminant 3,3'-dichlorobiphenyl (PCB-11) is widely detected in environmental samples, and this parent compound along with its metabolites 4-OH-PCB-11 and 4-PCB-11-Sulfate are detected in human serum. Our previous research in zebrafish (Danio rerio) embryos shows exposure to 20 μM PCB-11 inhibits Cyp1a enzyme activity and perturbs lipid metabolism pathways. In this study, wildtype AB embryos underwent acute exposures from 1 to 4 days post fertilization (dpf) to 0.

Embryonic exposures to mono-2-ethylhexyl phthalate induce larval steatosis in zebrafish independent of Nrf2a signaling.

Mono-2-ethylhexyl phthalate (MEHP) is the primary metabolite of the ubiquitous plasticizer and toxicant, di-2-ethylhexyl phthalate. MEHP exposure has been linked to abnormal development, increased oxidative stress, and metabolic syndrome in vertebrates. Nuclear factor, Erythroid 2 Like 2 (Nrf2), is a transcription factor that regulates gene expression in response to oxidative stress.

Perfluorobutanesulfonic Acid (PFBS) Induces Fat Accumulation in HepG2 Human Hepatoma.

Per- and poly-fluoroalkyl substances, especially perfluorooctanesulfonic acid, have been extensively used for over 50 years. A growing body of evidence has emerged demonstrating the potential adverse effects of these substances, including its effect on the development of non-alcoholic fatty liver disease, as one of the most prevalent chronic liver diseases. Nonetheless, there is no report of effects of perfluorobutanesulfonic acid, the major replacement for perfluorooctanesulfonic acid, on non-alcoholic fatty liver disease.

The emerging contaminant 3,3'-dichlorobiphenyl (PCB-11) impedes Ahr activation and Cyp1a activity to modify embryotoxicity of Ahr ligands in the zebrafish embryo model (Danio rerio).

3,3'-dichlorobiphenyl (PCB-11) is an emerging PCB congener widely detected in environmental samples and human serum, but its toxicity potential is poorly understood. We assessed the effects of three concentrations of PCB-11 on embryotoxicity and Aryl hydrocarbon receptor (Ahr) pathway interactions in zebrafish embryos (Danio rerio). Wildtype AB or transgenic Tg(gut:GFP) strain zebrafish embryos were exposed to static concentrations of PCB-11 (0, 0.

Mapping glutathione utilization in the developing zebrafish (Danio rerio) embryo.

Glutathione (GSH), the most abundant vertebrate endogenous redox buffer, plays key roles in organogenesis and embryonic development, however, organ-specific GSH utilization during development remains understudied. Monochlorobimane (MCB), a dye conjugated with GSH by glutathione-s-transferase (GST) to form a fluorescent adduct, was used to visualize organ-specific GSH utilization in live developing zebrafish (Danio rerio) embryos. Embryos were incubated in 20 μM MCB for 1 h and imaged on an epifluorescence microscope.