The effects of ozone exposure and sedentary lifestyle on neuronal microglia and mitochondrial bioenergetics of female Long-Evans rats.

Ozone (O) is a widespread air pollutant that produces cardiovascular and pulmonary dysfunction possibly mediated by activation of central stress centers. Epidemiological data suggest that sedentary lifestyles may exacerbate responses to air pollutants such as O. We sought to assess neurological changes in response to O exposure and an active lifestyle.

Acute in vitro effects on embryonic rat dorsal root ganglion (DRG) cultures by in silico predicted neurotoxic chemicals: Evaluations on cytotoxicity, neurite length, and neurophysiology.

The Hard-Soft Acid and Base hypothesis can be used to predict the potential bio-reactivity (electrophilicity) of a chemical with intracellular proteins, resulting in neurotoxicity. Twelve chemicals predicted to be neurotoxic were evaluated in vitro in rat dorsal root ganglia (DRG) for effects on cytotoxicity (%LDH), neuronal structure (total neurite length/neuron, NLPN), and neurophysiology (mean firing rate, MFR). DRGs were treated acutely on days in vitro (DIV) 7 (1-100 μM) with test chemical; %LDH and NLPN were measured after 48 h.

Mitochondrial Bioenergetics in Brain Following Ozone Exposure in Rats Maintained on Coconut, Fish and Olive Oil-Rich Diets.

Dietary supplementation with omega-3 and omega-6 fatty acids offer cardioprotection against air pollution, but these protections have not been established in the brain. We tested whether diets rich in omega-3 or -6 fatty acids offered neuroprotective benefits, by measuring mitochondrial complex enzyme I, II and IV activities and oxidative stress measures in the frontal cortex, cerebellum, hypothalamus, and hippocampus of male rats that were fed either a normal diet, or a diet enriched with fish oil olive oil, or coconut oil followed by exposure to either filtered air or ozone (0.8 ppm) for 4 h/day for 2 days.

The influence of maternal and perinatal high-fat diet on ozone-induced pulmonary responses in offspring.

There is growing interest in understanding how maternal diet might affect the sensitivity of offspring to environmental exposures. Previous studies demonstrated that adult rat offspring (approximately 6-months-old) from dams given a high-fat diet (HFD) prior to, during, and after pregnancy displayed elevated pulmonary responses to an acute ozone (O) exposure. The aim of this study was to examine the influence of maternal and perinatal HFD on pulmonary and metabolic responses to O in male and female young-adult offspring (approximately 3-month old).

Interaction of Diet and Ozone Exposure on Oxidative Stress Parameters within Specific Brain Regions of Male Brown Norway Rats.

Oxidative stress (OS) contributes to the neurological and cardio/pulmonary effects caused by adverse metabolic states and air pollutants such as ozone (O₃). This study explores the interactive effects of O₃ and diet (high-fructose (FRUC) or high⁻fat (FAT)) on OS in different rat brain regions. In acute exposure, there was a decrease in markers of reactive oxygen species (ROS) production in some brain regions by diet and not by O₃.

A Device that Allows Rodents to Behaviorally Thermoregulate when Housed in Vivariums.

Laboratories and vivariums typically are maintained at ambient temperatures of 20 to 24 °C, leading to cold stress in mice. When mice are inactive and sleeping during the light phase, their zone of thermoneutrality associated with a basal metabolic rate is 30 to 32 °C. If given a choice, mice will use thermoregulatory behavior to seek out thermoneutral temperatures during the light phase.

Effects of an environmentally-relevant mixture of pyrethroid insecticides on spontaneous activity in primary cortical networks on microelectrode arrays.

Pyrethroid insecticides exert their insecticidal and toxicological effects primarily by disrupting voltage-gated sodium channel (VGSC) function, resulting in altered neuronal excitability. Numerous studies of individual pyrethroids have characterized effects on mammalian VGSC function and neuronal excitability, yet studies examining effects of complex pyrethroid mixtures in mammalian neurons, especially in environmentally relevant mixture ratios, are limited. In the present study, concentration-response functions were characterized for five pyrethroids (permethrin, deltamethrin, cypermethrin, β-cyfluthrin and esfenvalerate) in an in vitro preparation containing cortical neurons and glia.

A multi-laboratory evaluation of microelectrode array-based measurements of neural network activity for acute neurotoxicity testing.

There is a need for methods to screen and prioritize chemicals for potential hazard, including neurotoxicity. Microelectrode array (MEA) systems enable simultaneous extracellular recordings from multiple sites in neural networks in real time and thereby provide a robust measure of network activity. In this study, spontaneous activity measurements from primary neuronal cultures treated with three neurotoxic or three non-neurotoxic compounds was evaluated across four different laboratories.

A noninvasive method to study regulation of extracellular fluid volume in rats using nuclear magnetic resonance.

Time-domain nuclear magnetic resonance (TD-NMR)-based measurement of body composition of rodents is an effective method to quickly and repeatedly measure proportions of fat, lean, and fluid without anesthesia. TD-NMR provides a measure of free water in a living animal, termed %fluid, and is a measure of unbound water in the vascular and extracellular spaces. We hypothesized that injecting a bolus of fluid into the peritoneal cavity would lead to an abrupt increase in %fluid and the rate of clearance monitored with TD-NMR would provide a noninvasive assessment of the free water homeostasis in an awake rat.

Improving in vitro to in vivo extrapolation by incorporating toxicokinetic measurements: a case study of lindane-induced neurotoxicity.

Approaches for extrapolating in vitro toxicity testing results for prediction of human in vivo outcomes are needed. The purpose of this case study was to employ in vitro toxicokinetics and PBPK modeling to perform in vitro to in vivo extrapolation (IVIVE) of lindane neurotoxicity. Lindane cell and media concentrations in vitro, together with in vitro concentration-response data for lindane effects on neuronal network firing rates, were compared to in vivo data and model simulations as an exercise in extrapolation for chemical-induced neurotoxicity in rodents and humans.

Behaviorally mediated, warm adaptation: a physiological strategy when mice behaviorally thermoregulate.

Laboratory mice housed under standard vivarium conditions with an ambient temperature (Ta) of ~22°C are likely to be cold stressed because this Ta is below their thermoneutral zone (TNZ). Mice raised at Tas within the TNZ adapt to the warmer temperatures, developing smaller internal organs and longer tails compared to mice raised at 22°C. Since mice prefer Tas equal to their TNZ when housed in a thermocline, we hypothesized that mice reared for long periods (e.

Thermal stress and toxicity.

Elevating ambient temperature above thermoneutrality exacerbates toxicity of most air pollutants, insecticides, and other toxic chemicals. On the other hand, safety and toxicity testing of toxicants and drugs is usually performed in mice and rats maintained at sub-thermoneutral temperatures of ~22∘C. When exposed to chemical toxicants under these relatively cool conditions, rodents typically undergo a regulated hypothermic response, characterized by preference for cooler ambient temperatures and controlled reduction in core temperature.

Burst and principal components analyses of MEA data for 16 chemicals describe at least three effects classes.

Microelectrode arrays (MEAs) can be used to detect drug and chemical induced changes in neuronal network function and have been used for neurotoxicity screening. As a proof-of-concept, the current study assessed the utility of analytical "fingerprinting" using principal components analysis (PCA) and chemical class prediction using support vector machines (SVMs) to classify chemical effects based on MEA data from 16 chemicals. Spontaneous firing rate in primary cortical cultures was increased by bicuculline (BIC), lindane (LND), RDX and picrotoxin (PTX); not changed by nicotine (NIC), acetaminophen (ACE), and glyphosate (GLY); and decreased by muscimol (MUS), verapamil (VER), fipronil (FIP), fluoxetine (FLU), chlorpyrifos oxon (CPO), domoic acid (DA), deltamethrin (DELT) and dimethyl phthalate (DMP).

Thermoregulatory deficits in adult Long Evans rat exposed perinatally to the antithyroidal drug, propylthiouracil.

Developmental exposure to endocrine disrupting drugs and environmental toxicants has been shown to alter a variety of physiological processes in mature offspring. Body (core) temperature (T(c)) is a tightly regulated homeostatic system but is susceptible to disruptors of the hypothalamic pituitary thyroid (HPT) axis. We hypothesized that thermoregulation would be disrupted in adult offspring exposed perinatally to an HPT disruptor.

Transcriptional responses in rat brain associated with sub-chronic toluene inhalation are not predicted by effects of acute toluene inhalation.

A primary public health concern regarding environmental chemicals is the potential for persistent effects from long-term exposure, and approaches to estimate these effects from short-term exposures are needed. Toluene, a ubiquitous air pollutant, exerts well-documented acute and persistent CNS-mediated effects from a variety of exposure scenarios, and so provides a useful case for determining whether its persistent effects can be predicted from its acute effects on the CNS. We recently reported that acute inhalation of toluene produced transcriptional effects in rat brain 18 h following a single, acute 6-h exposure to toluene.

Acute toluene exposure alters expression of genes in the central nervous system associated with synaptic structure and function.

Toluene is a volatile organic compound (VOC) and a ubiquitous air pollutant of interest to EPA regulatory programs. Whereas its acute functional effects are well described, several modes of action in the CNS have been proposed. Therefore, we sought to identify potential pathways mediating direct or indirect effects of VOCs by investigating the genomic response of the rat CNS to acutely-inhaled toluene.

Microelectrode arrays: a physiologically based neurotoxicity testing platform for the 21st century.

Microelectrode arrays (MEAs) have been in use over the past decade and a half to study multiple aspects of electrically excitable cells. In particular, MEAs have been applied to explore the pharmacological and toxicological effects of numerous compounds on spontaneous activity of neuronal and cardiac cell networks. The MEA system enables simultaneous extracellular recordings from multiple sites in the network in real time, increasing spatial resolution and thereby providing a robust measure of network activity.

Pyrethroid modulation of spontaneous neuronal excitability and neurotransmission in hippocampal neurons in culture.

Pyrethroid insecticides have potent actions on voltage-gated sodium channels (VGSC), inhibiting inactivation and increasing channel open times. These are thought to underlie, at least in part, the clinical symptoms of pyrethroid intoxication. However, disruption of neuronal activity at higher levels of organization is less well understood.

Direct innervation of the Drosophila melanogaster larval aorta.

The heart rate of larval Drosophila is modulated by various biogenic amines and peptides. The actions have always been assumed to be due to direct action on the heart since the larval heart was not known to be innervated. A recent study showed a difference in the sensitivity of the larval heart to serotonin when the CNS was ablated, thus suggesting a direct neural input.