Multiple metabolic changes mediate the response of Caenorhabditis elegans to the complex I inhibitor rotenone.

Rotenone, a mitochondrial complex I inhibitor, has been widely used to study the effects of mitochondrial dysfunction on dopaminergic neurons in the context of Parkinson's disease. Although the deleterious effects of rotenone are well documented, we found that young adult Caenorhabditis elegans showed resistance to 24 and 48 h rotenone exposures. To better understand the response to rotenone in C.

Application of a Framework for Grouping and Mixtures Toxicity Assessment of PFAS: A Closer Examination of Dose-Additivity Approaches.

Environmental occurrence and biomonitoring data for per- and polyfluoroalkyl substances (PFAS) demonstrate that humans are exposed to mixtures of PFAS. This article presents a new and systematic analysis of available PFAS toxicity study data using a tiered mixtures risk assessment framework consistent with United States and international mixtures guidance. The lines of evidence presented herein include a critique of whole mixture toxicity studies and analysis of dose-response models based on data from subchronic oral toxicity studies in rats.

Zebrafish CYP1A expression in transgenic Caenorhabditis elegans protects from exposures to benzo[a]pyrene and a complex polycyclic aromatic hydrocarbon mixture.

Polycyclic aromatic hydrocarbons (PAHs) are environmental toxicants primarily produced during incomplete combustion; some are carcinogens. PAHs can be safely metabolized or, paradoxically, bioactivated via specific cytochrome P450 (CYP) enzymes to more reactive metabolites, some of which can damage DNA and proteins. Among the CYP isoforms implicated in PAH metabolism, CYP1A enzymes have been reported to both sensitize and protect from PAH toxicity.

A Mitochondrial Progesterone Receptor Increases Cardiac Beta-Oxidation and Remodeling.

Progesterone is primarily a pregnancy-related hormone, produced in substantial quantities after ovulation and during gestation. Traditionally known to function via nuclear receptors for transcriptional regulation, there is also evidence of nonnuclear action. A previously identified mitochondrial progesterone receptor (PR-M) increases cellular respiration in cell models.

Perfluorohexanoic acid toxicity, part I: Development of a chronic human health toxicity value for use in risk assessment.

Perfluorohexanoic acid (PFHxA) is a short-chain, six-carbon perfluoroalkyl acid (PFAA) and is a primary impurity, degradant, and metabolite associated with the short-chain fluorotelomer-based chemistry used globally today. The transition to short-chain fluorotelomer-based products as a cornerstone in replacement fluorochemistry has raised questions regarding potential human health risks associated with exposure to fluorotelomer-based substances and therefore, PFHxA. Here, we present a critical review of data relevant to such a risk assessment, including epidemiological studies and in vivo and in vitro toxicity studies that examined PFHxA acute, subchronic, and chronic toxicity.

Perfluorohexanoic acid toxicity, part II: Application of human health toxicity value for risk characterization.

Perfluorohexanoic acid (PFHxA) is a short-chain, six-carbon PFAA and is a primary impurity, degradant, and metabolite associated with the short-chain fluorotelomer-based chemistry used in the United States, Europe and Japan today. With the shift towards short-chain PFAA chemistry, uncertainties remain regarding human health risks associated with current exposure levels. Here, we present a critical review and assessment of data relevant to human health risk assessment to today's short-chain PFAA chemistry.

Arsenic Alters Exosome Quantity and Cargo to Mediate Stem Cell Recruitment Into a Cancer Stem Cell-Like Phenotype.

Inorganic arsenic is a human carcinogen that can target the prostate. Accumulating evidence suggests arsenic can disrupt stem cell (SC) dynamics during the carcinogenic process. Previous work demonstrated arsenic-transformed prostate epithelial (CAsE-PE) cells can recruit prostate SCs into rapidly acquiring a cancer SC (CSC) phenotype via the secretion of soluble factors.

Pluripotent Stem Cells in Developmental Toxicity Testing: A Review of Methodological Advances.

Millions of children are born each year with a birth defect. Many of these defects are caused by environmental factors, although the underlying etiology is often unknown. In vivo mammalian models are frequently used to determine if a chemical poses a risk to the developing fetus.

The high-production volume fungicide pyraclostrobin induces triglyceride accumulation associated with mitochondrial dysfunction, and promotes adipocyte differentiation independent of PPARγ activation, in 3T3-L1 cells.

Pyraclostrobin is one of the most heavily used fungicides, and has been detected on a variety of produce, suggesting human exposure occurs regularly. Recently, pyraclostrobin exposure has been linked to a variety of toxic effects, including neurodegeneration and triglyceride (TG) accumulation. As pyraclostrobin inhibits electron transport chain complex III, and as mitochondrial dysfunction is associated with metabolic syndrome (cardiovascular disease, type II diabetes, obesity), we designed experiments to test the hypothesis that mitochondrial dysfunction underlies its adipogenic activity.

Mitochondrial fusion, fission, and mitochondrial toxicity.

Mitochondrial dynamics are regulated by two sets of opposed processes: mitochondrial fusion and fission, and mitochondrial biogenesis and degradation (including mitophagy), as well as processes such as intracellular transport. These processes maintain mitochondrial homeostasis, regulate mitochondrial form, volume and function, and are increasingly understood to be critical components of the cellular stress response. Mitochondrial dynamics vary based on developmental stage and age, cell type, environmental factors, and genetic background.

Deficiencies in mitochondrial dynamics sensitize Caenorhabditis elegans to arsenite and other mitochondrial toxicants by reducing mitochondrial adaptability.

Mitochondrial fission, fusion, and mitophagy are interlinked processes that regulate mitochondrial shape, number, and size, as well as metabolic activity and stress response. The fundamental importance of these processes is evident in the fact that mutations in fission (DRP1), fusion (MFN2, OPA1), and mitophagy (PINK1, PARK2) genes can cause human disease (collectively >1/10,000). Interestingly, however, the age of onset and severity of clinical manifestations varies greatly between patients with these diseases (even those harboring identical mutations), suggesting a role for environmental factors in the development and progression of certain mitochondrial diseases.

Effects of methyl and inorganic mercury exposure on genome homeostasis and mitochondrial function in Caenorhabditis elegans.

Mercury toxicity mechanisms have the potential to induce DNA damage and disrupt cellular processes, like mitochondrial function. Proper mitochondrial function is important for cellular bioenergetics and immune signaling and function. Reported impacts of mercury on the nuclear genome (nDNA) are conflicting and inconclusive, and mitochondrial DNA (mtDNA) impacts are relatively unknown.

Correction: Mitochondrial Morphology and Fundamental Parameters of the Mitochondrial Respiratory Chain Are Altered in Caenorhabditis elegans Strains Deficient in Mitochondrial Dynamics and Homeostasis Processes.

[This corrects the article DOI: 10.1371/journal.pone.

Effects of reduced mitochondrial DNA content on secondary mitochondrial toxicant exposure in Caenorhabditis elegans.

The mitochondrial genome (mtDNA) is intimately linked to cellular and organismal health, as demonstrated by the fact that mutations in and depletion of mtDNA result in severe mitochondrial disease in humans. However, cells contain hundreds to thousands of copies of mtDNA, which provides genetic redundancy, and creates a threshold effect in which a large percentage of mtDNA must be lost prior to clinical pathogenesis. As certain pharmaceuticals and genetic mutations can result in depletion of mtDNA, and as many environmental toxicants target mitochondria, it is important to understand whether reduced mtDNA will sensitize an individual to toxicant exposure.

In Vivo Determination of Mitochondrial Function Using Luciferase-Expressing Caenorhabditis elegans: Contribution of Oxidative Phosphorylation, Glycolysis, and Fatty Acid Oxidation to Toxicant-Induced Dysfunction.

Mitochondria are a target of many drugs and environmental toxicants; however, how toxicant-induced mitochondrial dysfunction contributes to the progression of human disease remains poorly understood. To address this issue, in vivo assays capable of rapidly assessing mitochondrial function need to be developed. Here, using the model organism Caenorhabditis elegans, we describe how to rapidly assess the in vivo role of the electron transport chain, glycolysis, or fatty acid oxidation in energy metabolism following toxicant exposure, using a luciferase-expressing ATP reporter strain.

From the Cover: Arsenite Uncouples Mitochondrial Respiration and Induces a Warburg-like Effect in Caenorhabditis elegans.

Millions of people worldwide are chronically exposed to arsenic through contaminated drinking water. Despite decades of research studying the carcinogenic potential of arsenic, the mechanisms by which arsenic causes cancer and other diseases remain poorly understood. Mitochondria appear to be an important target of arsenic toxicity.

Seahorse Xfe 24 Extracellular Flux Analyzer-Based Analysis of Cellular Respiration in Caenorhabditis elegans.

Mitochondria are critical for their role in ATP production as well as multiple nonenergetic functions, and mitochondrial dysfunction is causal in myriad human diseases. Less well appreciated is the fact that mitochondria integrate environmental and intercellular as well as intracellular signals to modulate function. Because mitochondria function in an organismal milieu, there is need for assays capable of rapidly assessing mitochondrial health in vivo.

Mitochondrial Morphology and Fundamental Parameters of the Mitochondrial Respiratory Chain Are Altered in Caenorhabditis elegans Strains Deficient in Mitochondrial Dynamics and Homeostasis Processes.

Mitochondrial dysfunction has been linked to myriad human diseases and toxicant exposures, highlighting the need for assays capable of rapidly assessing mitochondrial health in vivo. Here, using the Seahorse XFe24 Analyzer and the pharmacological inhibitors dicyclohexylcarbodiimide and oligomycin (ATP-synthase inhibitors), carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (mitochondrial uncoupler) and sodium azide (cytochrome c oxidase inhibitor), we measured the fundamental parameters of mitochondrial respiratory chain function: basal oxygen consumption, ATP-linked respiration, maximal respiratory capacity, spare respiratory capacity and proton leak in the model organism Caenhorhabditis elegans. Since mutations in mitochondrial homeostasis genes cause mitochondrial dysfunction and have been linked to human disease, we measured mitochondrial respiratory function in mitochondrial fission (drp-1)-, fusion (fzo-1)-, mitophagy (pdr-1, pink-1)-, and electron transport chain complex III (isp-1)-deficient C.