Changes in motor behavior and lumbar motoneuron morphology following repeated chlorpyrifos exposure in rats.

Chlorpyrifos is an organophosphate pesticide associated with numerous health effects including motor performance decrements. While many studies have focused on the health effects following acute chlorpyrifos poisonings, almost no studies have examined the effects on motoneurons following occupational-like exposures. The main objective of this study was to examine the broad effects of repeated occupational-like chlorpyrifos exposures on spinal motoneuron soma size relative to motor activity. To execute our objective, adult rats were exposed to chlorpyrifos via oral gavage once a day, five days a week for two weeks. Chlorpyrifos exposure effects were assessed either three days or two months following the last exposure. Three days following the last repeated chlorpyrifos exposure, there were transient effects in open-field motor activity and plasma cholinesterase activity levels. Two months following the chlorpyrifos exposures, there were delayed effects in sensorimotor gating, pro-inflammatory cytokines and spinal lumbar motoneuron soma morphology. Overall, these results offer support that subacute repeated occupational-like chlorpyrifos exposures have both short-term and longer-term effects in motor activity, inflammation, and central nervous system mechanisms.

Indications of Endocrine Disruptor Effects of JP-5 Jet Fuel Using a Rat-Model Reproductive Study and an In Vitro Human Hormone Receptor Assay.

Recent events concerning jet fuel contamination of drinking water have shown that we need a better understanding of the effects of ingested jet fuel. To this end, a reproductive study with ingested jet fuel in rats was undertaken with relatively high concentrations of Jet Propellant (JP)-5 along with a human estrogen receptor activation in vitro assay using JP-5, JP-8, and an alternative jet fuel derived from the camelina plant referred to as HydroRenewable Jet (HRJ) fuel, to help evaluate potential effects of ingested jet fuel. The results of the in vivo study provide evidence that JP-5 can act as an endocrine disruptor, with specific observations including altered hormone levels with JP-5 exposure (significantly lower estradiol levels in male rats and significantly increased Dehydroepiandrosterone levels in females), and a decreased male/female offspring ratio. The in vitro hormone receptor activation assay indicated that JP-5 and JP-8 are capable of upregulating human estrogen receptor (ER) activity, while HRJ was not active in the ER assay. The jet fuels were not able to activate androgen or glucocorticoid receptors in further in vitro assays. These results infer potential endocrine disruption associated with JP-5, with activation of the estrogen receptor as one potential mechanism of action.

Vagus nerve stimulation-induced cognitive enhancement: Hippocampal neuroplasticity in healthy male rats.

BACKGROUND: Vagus nerve stimulation (VNS) improves cognition in humans and rodents, but the effects of a single session of VNS on performance and plasticity are not well understood. OBJECTIVE: Behavioral performance and hippocampal (HC) electrophysiology/neurotrophin expression were measured in healthy adult rats after VNS paired training to investigate changes in cognition and synaptic plasticity. METHODS: Platinum/iridium electrodes were surgically implanted around the left cervical branch of the VN of anesthetized male Sprague-Dawley rats (N = 47). VNS (100 µs biphasic pulses, 30 Hz, 0.8 mA) paired Novel Object Recognition (NOR)/Passive Avoidance Task (PAT) were assessed 24 h after training and post-mortem tissue was collected 48 h after VNS (N = 28). Electrophysiology recordings were collected using a microelectrode array system to assess functional effects on HC slices 90 min after VNS (N = 19). Sham received the same treatment without VNS and experimenters were blinded. RESULTS: Stimulated rats exhibited improved performance in NOR (p < 0.05, n = 12) and PAT (p < 0.05, n = 14). VNS enhanced long-term potentiation (p < 0.05, n = 7-12), and spontaneous spike amplitude (p < 0.05, n = 7-12) and frequency (p < 0.05, n = 7-12) in the CA1. Immunohistochemical analysis found increased brain-derived neurotrophic factor expression in the CA1 (p < 0.05, n = 8-9) and CA2 (p < 0.01, n = 7-8). CONCLUSION: These findings suggest that our VNS parameters promote synaptic plasticity and target the CA1, which may mediate the positive cognitive effects of VNS. This study significantly contributes to a better understanding of VNS mediated HC synaptic plasticity, which may improve clinical utilization of VNS for cognitive enhancement.

Effects of transcranial direct current stimulation on brain cytokine levels in rats.

Transcranial direct current stimulation (tDCS) has shown therapeutic potential to mitigate symptoms of various neurological disorders. Studies from our group and others used rodent models to demonstrate that tDCS modulates synaptic plasticity. We previously showed that 30 min of 0.25 mA tDCS administered to rats induced significant enhancement in the synaptic plasticity of hippocampal neurons. It has also been shown that tDCS induces expression of proteins known to mediate synaptic plasticity. This increase in synaptic plasticity may underly the observed therapeutic benefits of tDCS. However, the anti-inflammatory benefits of tDCS have not been thoroughly elucidated. Here we report that three sessions of tDCS spaced 1-3 weeks apart can significantly reduce levels of several inflammatory cytokines in brains of healthy rats. Rats receiving tDCS experienced enhanced synaptic plasticity without detectable improvement in behavioral tests or significant changes in astrocyte activation. The tDCS-mediated reduction in inflammatory cytokine levels supports the potential use of tDCS as a countermeasure against inflammation and offers additional support for the hypothesis that cytokines contribute to the modulation of synaptic plasticity.

Altered hippocampal function and cytokine levels in a rat model of Gulf War illness.

AIMS: Gulf War illness (GWI) is a disorder affecting military personnel deployed in the Gulf War (GW) from 1990 to 1991. Here, we will use a rat model of GWI to evaluate hippocampal function and cytokine levels. MATERIALS AND METHODS: Rats were exposed to diethyltoluamide and permethrin via dermal absorption and pyridostigmine bromide via gavage with or without a 5-min restraint for 28 days. Immediate and delayed effects of GW chemical exposure were evaluated using electrophysiology to quantitate hippocampal function, behavioral tests to assess cognitive effects and biochemical assays to measure neurotransmitter and cytokine levels. KEY FINDINGS: Behavioral data revealed a statistically significant increase in motor activity at 3 months following completion of exposures, potentially indicating increased excitability, and/or restlessness. Electrophysiology data revealed statistically significant changes in paired pulse facilitation and input-output function of CA1 hippocampal neurons within 24 h and 3 months following completion of exposures. There was also a statistically significant reduction in the frequency of spontaneous firing activity of hippocampal neurons within 24 h following exposures. Naïve hippocampal slices directly incubated in GW chemicals also resulted in similar changes in electrophysiological parameters. Biochemical measurements revealed reduced hippocampal glutamate level at 3 months post-exposure. Furthermore, there was a statistically significant increase in plasma and hippocampal levels of IL-13, as well as decrease in plasma level of IL-1ß. SIGNIFICANCE: Our data support an effect on glutamate signaling within the hippocampus as indicated by changes in PPF and hippocampal level of glutamate, with some activation of T helper type 2 immune response.

Toxicity and human health assessment of an alcohol-to-jet (ATJ) synthetic kerosene.

A toxicological investigation was conducted for alcohol-to-jet (ATJ) fuels intended as a 50:50 blend with petroleum-derived fuel Jet Propulsion (JP)-8. The ATJ synthetic paraffinic kerosene (SPK) fuel was produced by Gevo (Englewood CO) and derived either from biomass (bio) or non-biomass sources. All toxicity tests were performed with one or both ATJ fuels following addition of a standard additive package required for JP-8. The primary fuel, Gevo (bio) ATJ SPK produced from biomass-derived iso-butanol, exhibited the same dermal irritation potential in rabbits as JP-8; the non-biomass-derived fuel was less irritating. The Gevo (bio) fuel was non-clastogenic in micronucleus testing with rats and neither version was mutagenic in the bacterial reverse mutation assay. A 90-day study was performed with Gevo (bio) ATJ SPK by exposing male and female Fischer 344 rats to target concentrations of 0, 200, 700 or 2000 mg/m3 of fuel, 6 hr per day, 5 days a week for 69 exposure days and included neurobehavioral assays and reproductive health evaluations in the study design. Results were negative or limited to irritant effects in the respiratory system due to exposure to a vapor and aerosol mixture in the 2000 mg/m3 exposure group. Occupational exposure limits for JP-8 were proposed for these ATJ fuels since these fuels display similar or somewhat lower toxicity than JP-8. As both versions of the Gevo ATJ jet fuel were similar, handling of either fuel alone or in a blend with petroleum-derived JP-8 appears unlikely to increase human health risks for workers.

Evaluating the validity and applicable domain of the toxic load model: impact of concentration vs. time profile on inhalation lethality of hydrogen cyanide.

The ten Berge model (or "toxic load" model) is often used to estimate the acute toxicity for varying combinations of inhaled concentration and duration. Expressed as C(n) × t = toxic load (TL), TLs are assumed constant for various combinations of concentration (C) and time (t). Experimental data in a recent acute inhalation study of rats exposed to time-varying concentrations of hydrogen cyanide (HCN) supported the validity of the toxic load model except under very brief, discontinuous, high concentration exposures. In the present investigation, experiments were conducted to extend the evaluation of the applicable domain of the model for acute lethality of HCN in the rat (cumulative exposure range of 2900-11,000 ppm min). The lethality of HCN over very short (< 5 min) durations of high concentrations did not conform to the toxic load model. A value of n=1.57 was determined for uninterrupted exposures ⩾ 5 min. For 30-min exposures, the presence or absence of a gap between two exposure pulses of different concentrations, the relative duration, relative height, and the ordering of the pulses (low then high, vs. high then low) did not appear to have a meaningful impact on the toxic load required for median lethality.