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Current Opinion in Toxicology

Sarah J Blossom, Kathleen M Gilbert
The concordance rate for developing autoimmune disease in identical twins is around 50% demonstrating that gene and environmental interactions contribute to disease etiology. The environmental contribution to autoimmune disease is a wide-ranging concept including exposure to immunotoxic environmental chemicals. Because the immune system is immature during development suggests that adult-onset autoimmunity may originate when the immune system is particularly sensitive. Among the pollutants most closely associated with inflammation and/or autoimmunity include Bisphenol-A, mercury, TCDD, and trichloroethylene...
August 2018: Current Opinion in Toxicology
Anthony M Franchini, B Paige Lawrence
Significant advances have been made recent years elucidating antiviral immune mechanisms that protect the host from viral infection. Similarly, our understanding of how viruses bind, enter, and replicate within host cells has continued to grow. Yet, viruses continue to take a toll on human health. The influence of chemicals in the environment is among key factors that influence outcomes of viral infection. There is a growing appreciation of the effects that exogenous environmental chemical exposures have on the immune system and antiviral immunity...
August 2018: Current Opinion in Toxicology
Nasser B Alsaleh, Jared M Brown
Engineered nanomaterials (ENM) are utilized in many applications due to their unique physicochemical properties. The increasing use of ENMs in consumer products raises concerns of potential adverse effects in humans and the environment. A common outcome of exposure (intentional, environmental or occupational) to ENMs is altered immune responses including inflammation, hypersensitivity, and immunosuppression. ENMs have been shown to interact with the immune system through key effector cells (i.e. mast cells and antigen presenting cells) or via complement activation leading to consequences to both innate and adaptive immunity...
August 2018: Current Opinion in Toxicology
K Michael Pollard, Joseph M Christy, David M Cauvi, Dwight H Kono
Susceptibility to autoimmune diseases is dependent on multigenic inheritance, environmental factors, and stochastic events. Although there has been substantial progress in identifying predisposing genetic variants, a significant challenge facing autoimmune disease research is the identification of the specific events that trigger loss of tolerance, autoreactivity and ultimately autoimmune disease. Accordingly, studies have indicated that a wide range of extrinsic factors including drugs, chemicals, microbes, and other environmental factors can induce autoimmunity, particularly systemic autoimmune diseases such as lupus...
August 2018: Current Opinion in Toxicology
Yu-Mei Tan, Jeremy A Leonard, Stephen Edwards, Justin Teeguarden, Alicia Paini, Peter Egeghy
Over time, risk assessment has shifted from establishing relationships between exposure to a single chemical and a resulting adverse health outcome, to evaluation of multiple chemicals and disease outcomes simultaneously. As a result, there is an increasing need to better understand the complex mechanisms that influence risk of chemical and non-chemical stressors, beginning at their source and ending at a biological endpoint relevant to human or ecosystem health risk assessment. Just as the Adverse Outcome Pathway (AOP) framework has emerged as a means of providing insight into mechanism-based toxicity, the exposure science community has seen the recent introduction of the Aggregate Exposure Pathway (AEP) framework...
June 2018: Current Opinion in Toxicology
Gerald T Ankley, Stephen W Edwards
The adverse outcome pathway (AOP) framework serves as a knowledge assembly, interpretation, and communication tool designed to support the translation of pathway-specific mechanistic data into responses relevant to assessing and managing risks of chemicals to human health and the environment. As such, AOPs facilitate the use of data streams often not employed by risk assessors, including information from in silico models, in vitro assays and short-term in vivo tests with molecular/biochemical endpoints. This translational capability can increase the capacity and efficiency of safety assessments both for single chemicals and chemical mixtures...
June 1, 2018: Current Opinion in Toxicology
Carla Garza-Lombó, Annika Schroder, Elsa M Reyes-Reyes, Rodrigo Franco
The mechanistic (or mammalian) target of rapamycin (mTOR) and the adenosine monophosphate-activated protein kinase (AMPK) regulate cell survival and metabolism in response to diverse stimuli such as variations in amino acid content, changes in cellular bioenergetics, oxygen levels, neurotrophic factors and xenobiotics. This Opinion paper aims to discuss the current state of knowledge regarding how mTOR and AMPK regulate the metabolism and survival of brain cells and the close interrelationship between both signaling cascades...
April 2018: Current Opinion in Toxicology
Anton M Jetten, Yukimasa Takeda, Andrzej Slominski, Hong Soon Kang
Cholesterol and its metabolites are bioactive lipids that interact with and regulate the activity of various proteins and signaling pathways that are implicated in the control of a variety of physiological and pathological processes. Recent studies revealed that retinoic acid-related orphan receptors, RORα and γ, members of the ligand-dependent nuclear receptor superfamily, exhibit quite a wide binding specificity for a number of sterols. Several cholesterol intermediates and metabolites function as natural ligands of RORα and RORγ and act as agonists or inverse agonists...
April 2018: Current Opinion in Toxicology
Marco Clementino, Xianglin Shi, Zhuo Zhang
Cr(VI)-containing compounds are well-established lung carcinogens. Chronic exposure of the normal human epithelial cells is able to induce malignant cell transformation, the first stage of metal carcinogenesis. These Cr(VI)-transformed cells exhibit increased level of antioxidants, reduced capacity of generating reactive oxygen species (ROS), and development of apoptosis resistance, promoting tumorigenesis of Cr(VI)-transformed cells, the second stage of metal carcinogenesis. The mechanism of Cr(VI) induced carcinogenesis is still under investigation...
April 2018: Current Opinion in Toxicology
James M Samet, Phillip A Wages
Oxidative stress is arguably the most common mechanism in the toxicology of environmental agents, unifying the action of broad classes of physichochemically disparate environmental pollutants, including oxidant gases, organic compounds, particulate surfaces, and metal ions. As advances in redox biology identify previously unrecognized targets for disruption by exposure to xenobiotics, redox toxicology has emerged as a new field of investigation. Environmental contaminants can induce oxidative stress on cells through mechanisms that are direct, indirect or involve the disruption of metabolic or bioenergetic processes that are regulated by thiol redox switches...
February 20, 2018: Current Opinion in Toxicology
Shahid P Baba, Aruni Bhatnagar
A well-regulated redox state is essential for normal physiological function and cellular metabolism. In most eukaryotic cells, protein cysteine thiols are most sensitive to fluctuations in the cellular redox state. Under normal physiological conditions, the cytosol has a highly reducing environment, which is due to high levels of reduced glutathione and complex system of redox enzymes that maintain glutathione in the reduced state. The reducing environment of the cytosol maintains most protein thiols in the reduced state; although some non-exposed cysteine could be present as disulfides...
February 2018: Current Opinion in Toxicology
Matthew Neal, Jason R Richardson
The annual cost for neurological disorders in the United States was $789 billion in 2014, and with an aging population these numbers are expected to significantly increase in the next 50 years [1]. Neurodegenerative diseases make up a significant portion of these costs. Neurodegenerative diseases are characterized by the loss of neuronal populations in specific regions of the brain. Although the cause is still unknown for most of these diseases, both genetic and environmental factors are thought to play important roles...
February 2018: Current Opinion in Toxicology
Anthony E Archibong, Meredith L Rideout, Kenneth J Harris, Aramandla Ramesh
Oxidative stress (OS) has been implicated in the causation of environmentally-induced diseases. However, the role of toxicants in the pathophysiology of disorders and diseases affecting the reproductive system are less understood. This review focuses on some of the mechanisms that underlie OS-induced reproductive toxicity at the cellular- and organ levels (germ cell damage and perturbed organ responses to endocrine stimuli). While most of the reproductive and developmental studies conducted in adult animals and transgenerational adult animals point to the involvement of genotoxicity, the part played by epigenetic alterations is accorded a recent recognition, thus warranting more studies in this area...
February 2018: Current Opinion in Toxicology
Krithika Lingappan
The transcription factor nuclear factor-κB (NF-κB) modulates gene expression in diverse cellular processes such as innate immune response, embryogenesis and organ development, cell proliferation and apoptosis, and stress responses to a variety of noxious stimuli. When cellular production of reactive oxygen species (ROS) overwhelms its antioxidant capacity, it leads to a state of oxidative stress, which in turn contributes to the pathogenesis of several human diseases. Different models of oxidative stress have been studied to elucidate the effects of oxidant stress on NF-κB related activities...
February 2018: Current Opinion in Toxicology
M Firoze Khan, Gangduo Wang
Oxidative stress (OS) plays an important role in the pathogenesis of a variety of autoimmune diseases (ADs) and many environmental agents participate in this process. Environmental agents, including trichloroethylene (TCE), silica, pristane, mercury, and smoke, are known to induce an autoimmune response, potentially through OS-mediated mechanisms. Here, we focus on unraveling the targets and signaling pathways that have been mechanistically linked with OS, as a result of exposure to these and numerous other environmental agents, and their impact on the immune system in triggering ADs...
February 2018: Current Opinion in Toxicology
Alex Veith, Bhagavatula Moorthy
The cytochrome P450 (CYP) enzymes are a diverse group of heme monooxygenases that, through the course of their reaction cycle, contribute to cellular reactive oxygen species (ROS). CYP enzymes play a crucial role in human physiology and are involved in drug and xenobiotic metabolism as well as biosynthesis of endogenous molecules and are expressed throughout the human body. However, during the course of the CYP catalytic cycle, ROS can be generated through uncoupling of the enzymatic cycle. ROS is known to modify endogenous molecules, included lipids, proteins, and nucleic acids, which can lead to cell damage and death and contribute to disease development...
February 2018: Current Opinion in Toxicology
Daric J Wible, Shawn B Bratton
Reactive oxygen species (ROS) are important signaling molecules that mediate oxidative stress and cellular damage when improperly regulated. ROS and oxidative stress can activate autophagy, which generally serves as a cytoprotective negative feedback mechanism to selectively eliminate sources of ROS, including mitochondria and peroxisomes. In this review we describe the mechanisms by which ROS directly and indirectly activate autophagy, and conversely, how selective autophagy suppresses the formation of ROS...
February 2018: Current Opinion in Toxicology
Tammy R Dugas
To date, numerous clinical studies examining correlations between oxidative stress biomarkers and cardiovascular diseases (CVD) have repeatedly suggested a role for oxidant injury in the pathogenesis of diseases such as atherosclerosis. Despite this, antioxidant supplementation trials have not demonstrated a reduction in disease progression. Nevertheless, small animal and epidemiological studies have linked exposures to certain toxicants with increased CVD risk involving putative oxidative stress mechanisms...
February 2018: Current Opinion in Toxicology
Anup Ramachandran, Hartmut Jaeschke
Reactive oxygen species have long been implicated in the pathophysiology of acute liver injury. However, the translation of these findings to the clinic and the development of therapeutic agents have been slow mainly due to the poor mechanistic understanding of the pathophysiology and the many indirect approaches used to characterize the role of oxidant stress in liver injury. The current review discusses in depth the sources of reactive oxygen, the oxidants involved and the impact of this oxidant stress in the mechanism of cell death in 3 different clinically relevant acute liver injury models...
February 2018: Current Opinion in Toxicology
Marcelo G Bonini, Robert M Sargis
Rates of type 2 diabetes mellitus (T2DM) are rising rapidly across the globe and the impact of this devastating disease threatens to plague the 21st century. While some contributing factors are well-recognized (e.g. sedentary lifestyles and caloric excess), others diabetes-promoting risk factors are less established or poorly appreciated. The latter category includes environmental exposures to diabetogenic contaminants. Herein we review some of the latest concepts and mechanisms by which environmental exposures may contribute to rising rates of T2DM with a particular focus on mechanisms involving mitochondrial dysfunction and imbalances in reactive oxygen species (ROS)...
February 2018: Current Opinion in Toxicology
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