1,3-Dinitrobenzene neurotoxicity - Passage effect in immortalized astrocytes.

Age-related disturbances in astrocytic mitochondrial function are linked to loss of neuroprotection and decrements in neurological function. The immortalized rat neocortical astrocyte-derived cell line, DI-TNC1, provides a convenient model for the examination of cellular aging processes that are difficult to study in primary cell isolates from aged brain. Successive passages in culture may serve as a surrogate of aging in which time-dependent adaptation to culture conditions may result in altered responses to xenobiotic challenge.

The mechanisms of neurotoxicity and the selective vulnerability of nervous system sites.

The spatial heterogeneity of the structure, function, and cellular composition of the nervous system confers extraordinary complexity and a multiplicity of mechanisms of chemical neurotoxicity. Because of its relatively high metabolic demands and functional dependence on postmitotic neurons, the nervous system is vulnerable to a variety of xenobiotics that affect essential homeostatic mechanisms that support function. Despite protection from the neuroglia and blood-brain barrier, the central nervous system is prone to attack from lipophilic toxicants and those that hijack endogenous transport, receptor, metabolic, and other biochemical systems.

Repeated dose (28-day) administration of silver nanoparticles of varied size and coating does not significantly alter the indigenous murine gut microbiome.

Silver nanoparticles (AgNPs) have been used as antimicrobials in a number of applications, including topical wound dressings and coatings for consumer products and biomedical devices. Ingestion is a relevant route of exposure for AgNPs, whether occurring unintentionally via Ag dissolution from consumer products, or intentionally from dietary supplements. AgNP have also been proposed as substitutes for antibiotics in animal feeds.

Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment.

Veterans of Operation Desert Storm/Desert Shield - the 1991 Gulf War (GW) - are a unique population who returned from theater with multiple health complaints and disorders. Studies in the U.S.

Rapid Kinetics of Size and pH-Dependent Dissolution and Aggregation of Silver Nanoparticles in Simulated Gastric Fluid.

As silver nanoparticles (AgNPs) are used in a wide array of commercial products and can enter the human body through oral exposure, it is important to understand the fundamental physical and chemical processes leading to changes in nanoparticle size under the conditions of the gastrointestinal (GI) tract. Rapid AgNP growth was observed using nanoparticle tracking analysis with 30 s resolution over a period of 17 min in simulated gastric fluid (SGF) to explore rapid kinetics as a function of pH (SGF at pH 2, 3.5, 4.

Effects of particle size and coating on toxicologic parameters, fecal elimination kinetics and tissue distribution of acutely ingested silver nanoparticles in a mouse model.

Consumer exposure to silver nanoparticles (AgNP) via ingestion can occur due to incorporation of AgNP into products such as food containers and dietary supplements. AgNP variations in size and coating may affect toxicity, elimination kinetics or tissue distribution. Here, we directly compared acute administration of AgNP of two differing coatings and sizes to mice, using doses of 0.

The role of astrocyte mitochondria in differential regional susceptibility to environmental neurotoxicants: tools for understanding neurodegeneration.

In recent decades, there has been a significant expansion in our understanding of the role of astrocytes in neuroprotection, including spatial buffering of extracellular ions, secretion of metabolic coenzymes, and synaptic regulation. Astrocytic neuroprotective functions require energy, and therefore require a network of functional mitochondria. Disturbances to astrocytic mitochondrial homeostasis and their ability to produce ATP can negatively impact neural function.

1,3-dinitrobenzene induces age- and region-specific oxidation to mitochondria-related proteins in brain.

Regions of the brain with high energy requirements are especially sensitive to perturbations in mitochondrial function. Hence, neurotoxicant exposures that target mitochondria in regions of high energy demand have the potential to accelerate mitochondrial damage inherently occurring during the aging process. 1,3-Dinitrobenzene (DNB) is a model neurotoxicant that selectively targets mitochondria in brainstem nuclei innervated by the eighth cranial nerve.

Fortification and health: challenges and opportunities.

Fortification is the process of adding nutrients or non-nutrient bioactive components to edible products (e.g., food, food constituents, or supplements).

Morphometric assessment of toxicant induced neuronal degeneration in full and restricted contact co-cultures of embryonic cortical rat neurons and astrocytes: using m-Dinitrobezene as a model neurotoxicant.

With m-Dinitrobenzene (m-DNB) as a selected model neurotoxicant, we demonstrate how to assess neurotoxicity, using morphology based measurement of neurite degeneration, in a conventional "full-contact" and a modern "restricted-contact" co-culture of rat cortical neurons and astrocytes. In the "full-contact" co-culture, neurons and astrocytes in complete physical contact are "globally" exposed to m-DNB. A newly emergent "restricted-contact" co-culture is attained with a microfluidic device that polarizes neuron somas and neurites into separate compartments, and the neurite compartment is "selectively" exposed to m-DNB.

Effects of local pH on the formation and regulation of cristae morphologies.

Cristae, folded subcompartments of the inner mitochondrial membrane (IMM), have complex and dynamic morphologies. Since cristae are the major site of adenosine triphosphate synthesis, morphological changes of cristae have been studied in relation to functional states of mitochondria. In this sense, investigating the functional and structural significance of cristae may be critical for understanding progressive mitochondrial dysfunction.

Biophysical significance of the inner mitochondrial membrane structure on the electrochemical potential of mitochondria.

The available literature supports the hypothesis that the morphology of the inner mitochondrial membrane is regulated by different energy states, that the three-dimensional morphology of cristae is dynamic, and that both are related to biochemical function. Examination of the correlation between the inner mitochondrial membrane (IMM) structure and mitochondrial energetic function is critical to an understanding of the links between mesoscale morphology and function in progressive mitochondrial dysfunction such as aging, neurodegeneration, and disease. To investigate this relationship, we develop a model to examine the effects of three-dimensional IMM morphology on the electrochemical potential of mitochondria.

Physiologically based pharmacokinetic modeling of polyethylene glycol-coated polyacrylamide nanoparticles in rats.

Nanoparticles' health risks depend on their biodistribution in the body. Phagocytosis may greatly affect this distribution but has not yet explicitly accounted for in whole body pharmacokinetic models. Here, we present a physiologically based pharmacokinetic model that includes phagocytosis of nanoparticles to explore the biodistribution of intravenously injected polyethylene glycol-coated polyacrylamide nanoparticles in rats.

Modulation of hydrogel nanoparticle intracellular trafficking by multivalent surface engineering with tumor targeting peptide.

Surface engineering of a hydrogel nanoparticle (NP) with the tumor-targeting ligand, F3 peptide, enhances both the NP's binding affinity for, and internalization by, nucleolin overexpressing tumor cells. Remarkably, the F3-functionalized NPs consistently exhibited significantly lower trafficking to the degradative lysosomes than the non-functionalized NPs, in the tumor cells, after internalization. This is attributed to the non-functionalized NPs, but not the F3-functionalized NPs, being co-internalized with Lysosome-associated Membrane Protein-1 (LAMP1) from the surface of the tumor cells.

Incorporating new technologies into toxicity testing and risk assessment: moving from 21st century vision to a data-driven framework.

Based on existing data and previous work, a series of studies is proposed as a basis toward a pragmatic early step in transforming toxicity testing. These studies were assembled into a data-driven framework that invokes successive tiers of testing with margin of exposure (MOE) as the primary metric. The first tier of the framework integrates data from high-throughput in vitro assays, in vitro-to-in vivo extrapolation (IVIVE) pharmacokinetic modeling, and exposure modeling.

One-dimensional patterning of cells in silicone wells via compression-induced fracture.

We have adapted our existing compression-induced fracture technology to cell culture studies by generating linear patterns on a complex cell culture well structure rather than on simple solid constructs. We present a simple method to create one-dimensional (1D), submicron, and linear patterns of extracellular matrix on a multilayer silicone material. We identified critical design parameters necessary to optimize compression-induced fracture patterning on the wells, and applied stresses using compression Hoffman clamps.

A comparative study of protein carbonylation and mitochondrial dysfunction using the neurotoxicants 1,3-dinitrobenzene, 3-nitropropionic acid, and 3-chloropropanediol.

This comparative evaluation of neurotoxicants previously identified as models of chemical-induced mitochondrial dysfunction and energy deprivation demonstrated that subtoxic concentrations of 1,3-dinitrobenzene (1,3-DNB), 3-nitropropionic acid (3-NPA), and 3-chloropropanediol (3-CPD) each led to concentration-dependent loss of the mitochondrial membrane potential (ΔΨm) associated with similar patterns of protein carbonylation. Subtoxic concentrations of each neurotoxicant were determined by measuring DI TNC1 cell viability using the MTS cell proliferation assay. Although exposure 1 μM, 10 μM, and 100 μM concentrations of each toxicant did not result in loss of cell viability after 48 h, exposure to each toxicant at these concentrations led to concentration-dependent loss of tetramethyl rhodamine methyl ester (TMRM) fluorescence over the same exposure period.

Radon, smoking, and lung cancer: the need to refocus radon control policy.

Exposure to radon is the second leading cause of lung cancer, and the risk is significantly higher for smokers than for nonsmokers. More than 85% of radon-induced lung cancer deaths are among smokers. The most powerful approach for reducing the public health burden of radon is shaped by 2 overarching principles: public communication efforts that promote residential radon testing and remediation will be the most cost effective if they are primarily directed at current and former smokers; and focusing on smoking prevention and cessation is the optimal strategy for reducing radon-induced lung cancer in terms of both public health gains and economic efficiency.

Handling worker and third-party exposures to nanotherapeutics during clinical trials.

The article focuses on issues relating to occupational exposures of researchers and lab workers, and exposures of bystanders such as health care workers and family members during HSR using nanomaterials. Such third-party exposures give rise to unique challenges relating to oversight as well as exposures to worker groups not previously studied. Given the current state of knowledge regarding health risks from such exposures, a more precautionary approach to oversight seems advisable.

Recommendations for nanomedicine human subjects research oversight: an evolutionary approach for an emerging field.

The nanomedicine field is fast evolving toward complex, "active," and interactive formulations. Like many emerging technologies, nanomedicine raises questions of how human subjects research (HSR) should be conducted and the adequacy of current oversight, as well as how to integrate concerns over occupational, bystander, and environmental exposures. The history of oversight for HSR investigating emerging technologies is a patchwork quilt without systematic justification of when ordinary oversight for HSR is enough versus when added oversight is warranted.

Multicolored stain-free histopathology with coherent Raman imaging.

Conventional histopathology with hematoxylin & eosin (H&E) has been the gold standard for histopathological diagnosis of a wide range of diseases. However, it is not performed in vivo and requires thin tissue sections obtained after tissue biopsy, which carries risk, particularly in the central nervous system. Here we describe the development of an alternative, multicolored way to visualize tissue in real-time through the use of coherent Raman imaging (CRI), without the use of dyes.