Neurotoxic Exposure Research Articles

Family life stress, maternal depression and child behavioral health in industrialized Italian cities

Abstract Although family life stress adversely impacts child health, few tools measure its relationship to child outcomes in the setting of maternal variables. This study validates the Italian version of Crisis in Family Systems-Revised (CRISYS-R) and characterizes relationships between family life stress, maternal depression and child behavior in two Italian cities. This cross-sectional study was nested in current research on health impacts of neurotoxic environmental exposures in children. 101 mother-child pairs (child age=9.91±2.17yrs; 53% female) and children's teachers were enrolled in Taranto (south Italy) and Brescia (north Italy). Mothers performed the Italian CRISYS-R and PHQ9; teachers completed Child Behavior Checklist (CBCL/6-18). Spearman's rank correlation coefficients showed associations of family CRISYS-R, maternal PHQ9 and child CBCL/6-18. Wilcoxon Rank-Sum test compared groups of continuous variables. Mothers with depressive symptoms (PHQ9≥5) reported higher ongoing stress and proportion of negative stressors on CRISYS-R than non-depressed mothers (p < 0.05). Children of depressed mothers performed worse in all CBCL/6-18 domains: Internalizing Problems, Externalizing Problems and Total Problems (p < 0.01). Specifically, children of depressed mothers scored higher on subscales of Anxious-Depressed (p < 0.05), Withdrawn-Depressed (p < 0.01), Rule-Breaking (p < 0.01) and Aggressive Behavior (p < 0.05). Maternal depressive symptoms correlated with ongoing stress (rs = 0.27; p < 0.01), child Internalizing Problems (rs = 0.34; p < 0.001), Externalizing Problems (rs = 0.28; p < 0.01) and Total Problems (rs = 0.35; p < 0.001). This study describes links among maternal depression, family life stress, and child behavioral health. It is first to validate Italian CRISYS-R and to explore these factors conjointly in Italian contexts with known neurotoxic exposures. Findings support considering maternal depression and family life stress in child behavioral and environmental health research and policy. Key messages Family life stress, maternal depressive symptoms, and preadolescent behavioral health were highly interrelated in two industrialized Italian cities. The Italian version of CRISYS-R is a useful instrument for assessing and understanding family life stress, a crucial yet under-explored contributor to child behavioral health outcomes.

Associations of the Behavioral Assessment and Research System (BARS) neurobehavioral outcomes with attention problems in children living near coal ash storage sites

Environmental exposures have been linked to childhood problems with overactivity, attention, and impulse control, and an increased risk of attention deficit hyperactivity disorder (ADHD) diagnosis. Two approaches to identify these types of exposure-related neurobehavioral problems include the use of computerized tests, such as the Behavioral Assessment and Research System (BARS), as well as the use of behavior rating scales. To assess comparability of these two types of measures, we analyzed data from 281 children aged 6 to 14 years enrolled in a 5-year research study investigating coal ash exposure and neurobehavioral health. All children lived in proximity of coal ash storage sites. We administered six computer tests from the BARS and obtained behavior measures from the parent-completed Child Behavior Checklist (CBCL) ADHD DSM oriented scale. BARS test performance was associated with age indicating that the tests could be used to evaluate neurodevelopmental changes over time or across a wide age range. Tests within the BARS including Continuous Performance (CPT) false alarm (standardized estimate 1.57, 95% confidence interval (CI) (0.67, 2.48), adjusted p = 0.006), Selective Attention (SAT) wrong count (standardized estimate 2.8, 95% CI (1.17, 4.44), adjusted p = 0.006), and SAT proportion correct (standardized estimate -2.45, 95% CI (-4.01, -0.88), adjusted p = 0.01) were associated with attention and impulse control problems on the CBCL after adjustment for multiple comparisons. Findings support that the BARS can contribute to research on environmental exposures by assessing subclinical behaviors related to ADHD such as sustained attention, impulse control, response inhibition, associative learning, and short-term memory. Future research can examine relationships of these BARS measures with biomarkers of neurotoxic exposures related to living near coal ash storage sites to better identify the potential risk for ADHD-related behaviors among children living near coal ash storage sites.

NF-κB Signaling in Astrocytes Modulates Brain Inflammation and Neuronal Injury Following Sequential Exposure to Manganese and MPTP During Development and Aging.

Chronic exposure to manganese (Mn) is associated with neuroinflammation and extrapyramidal motor deficits resembling features of Parkinson's disease. Activation of astrocytes and microglia is implicated in neuronal injury from Mn but it is not known whether early life exposure to Mn may predispose glia to more severe inflammatory responses during aging. We therefore examined astrocyte nuclear factor kappa B (NF-κB) signaling in mediating innate immune inflammatory responses during multiple neurotoxic exposures spanning juvenile development into adulthood. MnCl2 was given in drinking water for 30-day postweaning to both wildtype mice and astrocyte-specific knockout (KO) mice lacking I kappa B kinase 2, the central upstream activator of NF-κB. Following juvenile exposure to Mn, mice were subsequently administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at 4 months of age. Animals were evaluated for behavioral alterations and brain tissue was analyzed for catecholamine neurotransmitters. Stereological analysis of neuronal and glial cell counts from multiple brain regions indicated that juvenile exposure to Mn amplified glial activation and neuronal loss from MPTP exposure in the caudate-putamen and globus pallidus, as well as increased the severity of neurobehavioral deficits in open field activity assays. These alterations were prevented in astrocyte-specific I kappa B kinase 2 KO mice. Juvenile exposure to Mn increased the number of neurotoxic A1 astrocytes expressing C3 as well as the number of activated microglia in adult mice following MPTP challenge, both of which were inhibited in KO mice. These results demonstrate that exposure to Mn during juvenile development heightens the innate immune inflammatory response in glia during a subsequent neurotoxic challenge through NF-κB signaling in astrocytes.

A Scoping Review of Non-Occupational Exposures to Environmental Pollutants and Adult Depression, Anxiety, and Suicide.

Despite a call for better understanding of the role of environmental pollutant influences on mental health and the tremendous public health burden of mental health, this issue receives far less attention than many other effects of pollutants. Here we summarize the body of literature on non-occupational environmental pollutant exposures and adult depression, anxiety, and suicide-in PubMed, Embase, Web of Science, and PsychINFO through the end of year 2018. One hundred twelve articles met our criteria for further review. Of these, we found 88 articles on depression, 33 on anxiety, and 22 on suicide (31 articles covered multiple outcomes). The earliest article was published in 1976, and the most frequent exposure of interest was air pollution (n = 33), followed by secondhand smoke (n = 20), metals (n = 18), noise (n = 17), and pesticides (n = 10). Other exposures studied less frequently included radiation, magnetic fields, persistent organic pollutants (POPs), volatile organic compounds, solvents, and reactive sulfur compounds. The current literature, although limited, clearly suggests many kinds of environmental exposures may be risk factors for depression, anxiety, and suicide. For several pollutants, important limitations exist with many of the studies. Gaps in the body of research include a need for more longitudinal, life-course studies, studies that can measure cumulative exposures as well as shorter-term exposures, studies that reduce the possibility of reverse causation, and mechanistic studies focused on neurotoxic exposures.

Longitudinal Assessment of Health Symptoms in Relation to Neurotoxicant Exposures in 1991 Gulf War Veterans: The Ft. Devens Cohort.

Objective:This analysis examined the relationship between Gulf War (GW) exposures and health symptoms reported in three time periods over 20 years in Ft. Devens Cohort veterans.Methods:Repeated logistic regression models examined the association of exposures and health symptoms over time. Models included baseline age, active duty status, post-traumatic stress disorder status, sex, and time since deployment as covariates.Results:Exposure to tent heaters was associated with increased odds of crying easily and muscle twitching. Exposure to pyridostigmine bromide (PB) pills was associated with increased odds of depression and fatigue. Exposure to the Khamisiyah sarin plume was associated with increased odds of trouble concentrating and crying easily.Conclusion:This longitudinal analysis demonstrated an association between neurotoxicant exposures and increased odds of cognitive/mood, fatigue, and neurological symptoms. In addition, most symptoms increased over time since deployment regardless of exposure.

Regional wheat grain manganese and its potential risks affected by soil pH and precipitation

Neurotoxicant exposure by the over intake of manganese (Mn) and crop Mn accumulation related with fertilization and other agronomical measures had attracted wide attentions, while information is limited about variations in grain Mn with geographical changes in both soil and precipitation. A total of 438 wheat-grain site samples were therefore collected from two regions that were categorized by soil pH (non-acidic, pH > 7 and acidic, pH < 7) across the major Chinese wheat production areas, to determine the distribution of grain Mn, the potential Mn risk and the rational grain Mn concentration to human health. Results showed that grain Mn ranged from 13.9 to 98.3 mg kg−1, with an average of 43.7 mg kg−1. On the one hand, soil pH in the acidic region had significantly negative, while annual precipitation had positive influence on grain Mn due to their different effects on soil DTPA-Mn. On the other hand, grain Mn in the non-acidic region insignificantly correlated with soil pH or soil DTPA-Mn, but negatively correlated with annual precipitation. In addition, the yield-dilution effect was not observed in this present study. Simulating assessment showed that long-term consumption of whole wheat grains with high Mn concentrations could cause potential hazards to children, and the upper limits of the daily whole grain Mn intake for local residents at different ages were also recommended. Results from this study could provide insight into rational strategies to curb Mn toxicity to human beings in wheat production areas around the world.

Energy Balance as a Moderator of Neurologic Disease Risk and Progression.

Amyotrophic lateral sclerosis (ALS) is a devastating disease that like multiple other neurologic diseases has no curative treatment currently available. Environmental exposures to known neurotoxic compounds (e.g., pesticides, heavy metals, cyanobacterial toxins, etc.) are identified as risk factors associated with ALS. Assuming these environmental factors have causative roles in disease risk and given the ubiquity of these types of exposures for the modern human, why are not more people afflicted with ALS? Herein is proposed an energy balance moderation framework (EBMF)-a framework that postulates energy balance as a key moderator of neurologic disease risk. The EBMF proposes that the ability of the body to handle toxic compound exposures through excretion, metabolism, and/or storage impacts the acute and chronic tissue-specific toxicity which is moderated by energy balance. In this model, positive energy balance (weight gain or excess body weight/mass) would be protective against acute neurotoxic exposure permitting the assimilation and sequestration of toxic compounds within body stores separate from the nervous system. However, this protective buffering could be lost during sustained negative energy balance (weight loss) with the release of sequestered compounds redistributing to the nervous system. The EBMF may have relevance beyond ALS for other neurologic diseases with demonstrated environmental risks (such as Alzheimer's and Parkinson's disease) and offers new insights into potential strategies to reduce disease risk and develop novel treatments.

The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure

BackgroundAllele-specific DNA methylation (ASM) describes genomic loci that maintain CpG methylation at only one inherited allele rather than having coordinated methylation across both alleles. The most prominent of these regions are germline ASMs (gASMs) that control the expression of imprinted genes in a parent of origin-dependent manner and are associated with disease. However, our recent report reveals numerous ASMs at non-imprinted genes. These non-germline ASMs are dependent on DNA methyltransferase 1 (DNMT1) and strikingly show the feature of random, switchable monoallelic methylation patterns in the mouse genome. The significance of these ASMs to human health has not been explored. Due to their shared allelicity with gASMs, herein, we propose that non-traditional ASMs are sensitive to exposures in association with human disease.ResultsWe first explore their conservancy in the human genome. Our data show that our putative non-germline ASMs were in conserved regions of the human genome and located adjacent to genes vital for neuronal development and maturation. We next tested the hypothesized vulnerability of these regions by exposing human embryonic kidney cell HEK293 with the neurotoxicant rotenone for 24 h. Indeed,14 genes adjacent to our identified regions were differentially expressed from RNA-sequencing. We analyzed the base-resolution methylation patterns of the predicted non-germline ASMs at two neurological genes, HCN2 and NEFM, with potential to increase the risk of neurodegeneration. Both regions were significantly hypomethylated in response to rotenone.ConclusionsOur data indicate that non-germline ASMs seem conserved between mouse and human genomes, overlap important regulatory factor binding motifs, and regulate the expression of genes vital to neuronal function. These results support the notion that ASMs are sensitive to environmental factors such as rotenone and may alter the risk of neurological disease later in life by disrupting neuronal development.

Acute neurotoxicant exposure induces hyperexcitability in mouse lumbar spinal motor neurons

Spinal motor neurons (MNs) are susceptible to glutamatergic excitotoxicity, an effect associated with lumbar MN degeneration in amyotrophic lateral sclerosis (ALS). MN susceptibility to environmental toxicant exposure, one prospective contributor to sporadic ALS, has not been systematically studied. The goal of this study was to test the ability of a well-known environmental neurotoxicant to induce hyperexcitability in mouse lumbar MNs. Methylmercury (MeHg) causes neurotoxicity through mechanisms involving elevated intracellular Ca2+ concentration ([Ca2+]i), a hallmark of excitotoxicity. We tested whether acute exposure to MeHg induces hyperexcitability in MNs by altering synaptic transmission, using whole cell patch-clamp recordings of lumbar spinal MNs in vitro. Acute MeHg exposure (20 μM) led to an increase in the frequency of both spontaneous excitatory postsynaptic currents (EPSCs) and miniature EPSCs. The frequency of inhibitory postsynaptic currents (IPSCs) was also increased by MeHg. Action potential firing rates, both spontaneous and evoked, were increased by MeHg, despite increases in both EPSCs and IPSCs, indicating a shift toward hyperexcitability. Also consistent with hyperexcitability, fluo 4-AM microfluorimetry indicated that MeHg exposure induced an increase in [Ca2+]i. Spinal cord hyperexcitability is partially mediated by Ca2+-permeable AMPA receptors, as MeHg-dependent increases in EPSCs were blocked by 1-napthyl spermine. Therefore, spinal MNs appear highly susceptible to MeHg exposure, leading to significant increases in spontaneous network excitability and disruption of normal function. Prolonged hyperexcitability could lead to eventual neurodegeneration and loss of motor function as observed in spinal cord after MeHg exposure in vivo and may contribute to MeHg-induced acceleration of ALS symptoms.NEW & NOTEWORTHY Spinal motor neurons (MN) are susceptible to glutamatergic excitotoxicity, an effect associated with lumbar MN degeneration in amyotrophic lateral sclerosis (ALS). This study investigated MN susceptibility to environmental toxicant exposure, one prospective contributor to sporadic ALS. Spinal MNs appear highly susceptible to methylmercury exposure, leading to significant increases in spontaneous network excitability and disruption of normal function. Prolonged hyperexcitability could lead to neurodegeneration and loss of motor function as observed in ALS spinal cord symptoms.

Sex as a biological variable in the rat model of diisopropylfluorophosphate-induced long-term neurotoxicity.

Sex differences in response to neurotoxicant exposure that initiates epileptogenesis are understudied. We used telemetry-implanted male and female adult rats exposed to an organophosphate (OP) neurotoxicant, diisopropylflourophosphate (DFP), to test sex differences in the severity of status epilepticus (SE) and the development of spontaneous recurrent seizures (SRS). Females had significantly less severe SE and decreased epileptiform spikes compared with males, although females received a higher dose of DFP than males. The estrous stages had no impact on seizure susceptibility, but rats with severe SE had a significantly prolonged diestrus. A previously demonstrated disease-modifying agent, an inducible nitric oxide synthase inhibitor, 1400W, was tested in both sexes. None of the eight males treated with 1400W developed convulsive SRS during 4 weeks post-DFP exposure, while two of seven females developed convulsive SRS. Concerning gliosis and neurodegeneration, there were region-specific differences in the interaction between sex and SE severity. As SE severity influences epileptogenesis, and as females had significantly less severe SE, sex as a biological variable should be factored into the design of future OP nerve agent experiments while evaluating neurotoxicity and optimizing potential disease-modifying agents.

Impact of an Oomen feeding with a neonicotinoid on daily activity and colony development of honeybees assessed with an AI based monitoring device.

Feeding experiments are standard tools in the pollinator risk assessment. The design (Oomen et al. 1992) was developed to test insect growth regulators and herbicides. In recent years there was an update (Luckmann & Schmitzer 2015) on the outline in order to also focus on the advantage of different rates making a dose response design possible where exposure levels are known. Additionally, this design gives the possibility to test different rates for honey bee colonies foraging in the same landscape. The main objective of the experiment presented here was to determine the natural variability of foragers losses of hives fed with a sub-lethal neonicotinoid concentration compared to an untreated control. Other objectives were to see if the neurotoxic exposure results in any observable sub-lethal effects and to find out if losses can be correlated to hive development. This was assessed with traditional methods and a novel, visual monitoring device.

HIV-Associated Neurocognitive Disorder (HAND): Relative Risk Factors.

This chapter will address the issue of risk for HIV-associated neurocognitive disorder (HAND), focusing on HIV-associated dementia (HAD), among persons living with HIV in relationship to the risk for other dementias. Advances in effective antiretroviral therapy (ART) have led to an increase in the prevalence of older persons surviving with HIV - in addition to older persons who become infected by HIV later in life. Hence, HIV is no longer a disease of younger persons, and additional attention has been brought to bear against the plight of older persons living with HIV - not only as it pertains to treatment but also to prevention. The additional risk caused by aging among older persons living with HIV is complex to asses, and HIV infection is a research area that requires a robust approach to multiple other factors causing neurocognitive impairment with older age. The long-term and potentially neurotoxic exposure to ART and the deleterious consequences of chronic infection with HIV and its associated neuro-inflammation have been described for health. This aids in the understanding of dementia risk factors in this patient population, but the comorbidities (HIV- and non-HIV-associated) occurring among older persons living with HIV must also be addressed to properly assess the overall impact on dementia risk in this group. This need also warrants our examination of the risk factors for other dementias (and comorbid dementias) in persons living with HIV versus the general population through the assessment and quantification of modifiable and non-modifiable risk factors identified as major contributors toward dementia.

Using the delayed spatial alternation task to assess environmentally associated changes in working memory in very young children

BackgroundWorking memory (WM) is critical for problem solving and reasoning. Beginning in infancy, children show WM capacity increasing with age but there are few validated tests of WM in very young children. Because rapid brain development may increase susceptibility to adverse impacts of prenatal neurotoxicant exposure, such as lead, tests of WM in very young children would help to delineate onset of developmental problems and windows of susceptibility. PurposeOur objective was to assess the feasibility of administering a Delayed Spatial Alternation Task (DSAT) to measure WM among 18- and 24-month old children enrolled in an ongoing longitudinal birth cohort study and compare DSAT performance with age and general cognitive development. We further explored whether prenatal lead exposure impacted DSAT performance. MethodsWe assessed 457 mother-child pairs participating in the Programming Research in Obesity, GRowth, Environment and Social Stressors (PROGRESS) Study in Mexico City. The DSAT and Bayley Scales of Infant Development (BSID-III) were administered at 18- and 24-months. Lead was measured in maternal blood collected during pregnancy (MBPb) and in a subsample of children at 24-months (CBPb). We regressed DSAT measures on MBPb and CBPb, child sex, and maternal age, education, socioeconomic status, and household smoking. We compared DSAT performance to BSID-III performance with adjusted residuals. Results24-month children perform better on the DSAT than 18-month children; 24-month subjects reached a higher level on the DSAT (3.3 (0.86) vs. 2.4 (0.97), p < 0.01), and had a higher number of correct responses (20.3 vs. 17.2, p < 0.01). In all DSAT parameters, females performed better than males. Maternal education predicted better DSAT performance; household smoking predicted worse DSAT performance. A higher number of correct responses was associated with higher BSID-III Cognitive scales at 18 months (r = 0.20, p < 0.01) and 24 months (r = 0.27, p < 0.01). MBPb and CPBb did not significantly predict DSAT performance. ConclusionImproved performance on the DSAT with increasing age, the positive correlation with the BSID-III cognitive and language scales and the correlation with common sociodemographic predictors of neurodevelopment demonstrate the validity of the DSAT as a test of infant development.

Neuropsychological Findings in Gulf War Illness: A Review.

This review paper summarizes the accumulation of research investigating neuropsychological outcomes in veterans with Gulf War illness (GWI). Earlier research focused on Gulf War veterans (GW) who were deployed versus non-deployed, as well as those who were symptomatic versus asymptomatic, or compared neuropsychological test results to published norms. Further research became more sophisticated, investigating specific GWI criteria, as well as the result of neurotoxicant exposure and the relationship to possible neurocognitive outcomes. As the early research supported both psychological and physiological effects on GWI; current research as summarized in this literature review supports the presence of neuropsychological deficits, particularly in the domains of attention, executive functioning, memory, and motor functioning related to chemical exposures that can be exacerbated by comorbid mood-related conditions. The same test battery has not been used consistently making it difficult to compare results among studies. Therefore, researchers created a resource to provide recommendations for the recently listed Neuropsychological Tests for Common Data Elements (CDEs) for use in all future GWI studies. Future research is necessary to further understand patterns of neuropsychological test data and how these decrements may relate to immunological or other biological markers, and the impact of trauma from physical and psychological stressors. In conclusion, there is consistent evidence that GWI is characterized by neuropsychological decrements – with future research these findings may aid in the diagnosis and assessment of treatment trial efficacy of GW veterans.

Issue Cover (August 2019)

Journal of NeurochemistryVolume 150, Issue 4 Issue CoverFree Access Issue Cover (August 2019) First published: 05 August 2019 https://doi.org/10.1111/jnc.14518 Read the full article: ‘Astrocyte-specific transcriptome analysis using the ALDH1L1 bacTRAP mouse reveals novel biomarkers of astrogliosis in response to neurotoxicity’ by L. T. Michalovicz, K. A. Kelly, S. Vashishtha, R. Ben-Hamo, S. Efroni, J. V. Miller, A. R. Locker, K. Sullivan, G. Broderick, D. B. Miller, J. P. O’Callaghan (J. Neurochem. 2019, vol. 150 (4), pp. 420–440) on doi: 10.1111/jnc.14800 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract Front cover:A central problem in neurotoxicology is detecting the unpredictable damage to specific cells in select brain regions. However, the accompanying astrogliosis, indicated by increased expression of glial fibrillary acidic protein (GFAP), can mark the areas of the brain that are damaged by toxicant exposure. Unfortunately, there are not many biomarkers of astrogliosis. Aldehyde dehydrogenase 1 family member L1 bacterial artificial chromosome, translating ribosome affinity purification (ALDH1L1 bacTRAP) transgenic mice provide the opportunity to selectively measure transcriptional changes in astrocytes in response to exposures or conditions, in vivo. In this study, we evaluated the use of ALDH1L1 bacTRAP mice in neurotoxicology research and used these transgenic mice to identify novel biomarkers of toxicant-induced astrogliosis that are useful across different neurotoxic exposures. Our analyses identified TIMP1 and miR-147 as potential markers of astrogliosis that were validated using both MPTP and trimethyl tin (TMT) exposures. Overall, we demonstrated that the ALDH1L1 bacTRAP transgenic mice provide a useful, in vivo tool for the discovery of astrogliosis biomarkers and the genes identified here, as well as those that may be identified in the future, may serve as targets for intervention in treating or preventing neurotoxic damage. Image content: The image shows that native ALDH1L1 protein (green) colocalizes with GFAP-positive astrocytes (red) in the hippocampus of adult male Long-Evans rats 72 hours after exposure to TMT (8 mg/kg, i.p.), confirming that ALDH1L1-driven bacTRAP transgene expression is astrocyte-specific and unaffected by neurotoxicant exposure. Read the full article ‘Astrocyte-specific transcriptome analysis using the ALDH1L1 bacTRAP mouse reveals novel biomarkers of astrogliosis in response to neurotoxicity’ by L. T. Michalovicz, K. A. Kelly, S. Vashishtha, R. Ben-Hamo, S. Efroni, J. V. Miller, A. R. Locker, K. Sullivan, G. Broderick, D. B. Miller, J. P. O’Callaghan (J. Neurochem. 2019, vol. 150 (4), pp. 420–440) on doi: 10.1111/jnc.14800 Volume150, Issue4August 2019 RelatedInformation

Валідація нейротоксикологічних методів скринінгу хімічних речовин з застосуванням референтних сполук з різноспрямованим впливом на нервову систему

Validation of the methods at the stage of their implementation and with subsequent application is an important part of ensuring the quality of toxicological study data State Enterprise “Scientific Center for Preventive Toxicology, Food and Chemical Safety named after Academician L. I. Medved of the Ministry of Health of Ukraine” has implemented methods of screening of neurotoxic exposure of chemical substances — a set of clinical and functional tests (CFT) and a method for evaluation of motor activity in the “open field” for rats. Objective. Determination of specificity, sensitivity and reliability of the implemented methods under exposure to reference neurotropic substances with differently directed effects — chlorpromazine and caffeine on the parameters of the neurological conditions of female Wistar Han rats. Results. It has been shown that the set of CFT and the method for evaluation of motor activity in the “open field” are relevant for the determination of specific exposure and toxicodynamics of reference substances having differently directed effects on the nervous system of rats. The sensitivity of these methods under the lowest active dose of caffeine and chlorpromazine was determined. Data on the reproducibility of test results have been obtained.

Therapeutic Inhibition of MicroRNA‐124‐3p Induces Histone Modification Changes in the Hippocampus in a Rat Model of Gulf War Illness

Gulf War Illness (GWI) is a chronic, multisymptomillness that continues to affect 30% of the 700,000 US veterans deployed to the Persian Gulf during the 1990–1991 Gulf War. Memory dysfunction and depression are common symptoms. Epidemiological studies have consistently identified neurotoxic chemical exposures as the strongest risk factors for GWI, but after 28 years, useful treatments are lacking and underlying cellular and molecular mechanisms involved in its pathobiology remain poorly understood. Using an established rat model of GWI, we previously identified chronic elevation of microRNA‐124‐3p(miR‐124) levels in the hippocampus whose gene targets are involved in cognition‐associated pathways and neuroendocrine function. We further showed that intracerebro ventricular (icv) infusion of locked nucleic acid (LNA)‐miR‐124 inhibitor increased hippocampal expression of downstream target genes important for synaptic plasticity, glucocorticoid signaling, and neurogenesis compared to LNA‐scrambled oligonucleotide, suggesting that miR‐124 inhibition may be a promising therapeutic approach to improve cognition and neuroendocrine dysfunction in GWI. This strategy has also been proposed to improve memory deficits and/or depression in patients with multiple sclerosis, major depressive disorder, amyotrophic lateral sclerosis, and Alzheimer's disease. Because histone post‐translational modifications are critical for gene expression during memory processes, the aim of this study was to determine whether miR‐124 inhibition alters histone modifications in the hippocampus of GWI rats. Nine months after a 28‐day exposure regimen of GW chemicals and stress, rats underwent icv infusion of LNA‐miR‐124 inhibitor or LNA‐scrambled control from implanted osmotic pumps delivering 0.1 nmol/day for 28 days (n=5 per group). Hippocampi were harvested and underwent extraction of histones. Targeted analysis of &gt;80 unmodified and modified histone peptides was performed in triplicate using mass spectrometry (Active Motif). LNA‐miR‐124 inhibitor induced 11 histone modification changes, with histone H3 methylationat lysine (K) residues 18, 27, 36, and 79 being the most predominant changes observed. These included a 22% decrease (p&lt;0.001) in H3K27me3, a marker of gene repression known to be elevated in neuro degenerative diseases and during aging, and a 20% increase (p=0.008) in H3K36me3, a marker of transcriptional activation known to increase during object recognition memory and decrease during aging. Results suggest that miR‐124 inhibition induces histone modifications in the hippocampus that likely correspond with enhanced transcription of genes important for synaptic plasticity and neuroendocrine signaling shown previously to occur in GWI rats treated with LNA‐miR‐124 inhibitor. Future work is needed to identify the transcriptional targets of these histone markers to better understand the potential therapeutic benefits of miR‐124inhibition for GWI and other cognitive disorders.Support or Funding InformationDoD CDMRP Gulf War Illness Research Program grant award GW150132. Content is that of the authors and does not reflect the official policy or position of the Department of the Army, Department of Defense, or the US government.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A preliminary study on prenatal polybrominated diphenyl ether serum concentrations and intrinsic functional network organization and executive functioning in childhood.

The prenatal period is a period of vulnerability during which neurotoxic exposures exert persistent changes in brain development and behavior. Polybrominated diphenyl ethers (PBDEs), used as flame retardants in commercial products, are known to be developmental neurotoxicants. PBDEs were phased out of use in the United States a decade ago, but exposure remains widespread due to their release from existing products and biopersistence. Despite consistent animal and epidemiological evidence of developmental neurotoxicity, the neural substrates linking prenatal PBDE serum concentrations to impaired neurodevelopment are poorly understood. In the present study, we used resting state functional magnetic resonance imaging (fMRI) to examine associations between prenatal PBDE concentrations measured in maternal serum and intrinsic functional network organization (i.e., global and local efficiency; estimated using agraph-theoretical approach) in 5-year-old children (n=34). We explored whether PBDE serum concentrations were associated with executive functioning (EF) assessed using a parent-report questionnaire (BRIEF-P) (n=106) and whether changes in intrinsic functional network organization linked the association between prenatal PBDE serum concentrations and EF problems. Children with higher prenatal PBDE serum concentrations showed: (a) increased global efficiency of brain areas involved in visual attention (e.g., inferior occipital gyrus) (β's=.01, FDR-corrected p's≤.05); (b) more reported EF problems (β's=.001, FDR-corrected p's≤.05). Higher global efficiency of brain areas involved in visual attention was associated with more EF problems (β's=.01, FDR-corrected p's<.05). Intrinsic functional network organization of visual attention brain areas linked prenatal PBDE concentrations to EF problems in childhood. Visual attention may contribute to the development of higher-order cognitive functions, such as EF, which could be explored in future studies.

The attention set-shifting test is sensitive for revealing sex-based impairments in executive functions following developmental lead exposure in rats

The literature on lead (Pb) exposure has focused in large part on hippocampal-based learning and memory deficits, although frontoexecutive dysfunctions are known to exist in Pb-exposed humans. This study examined the effects of perinatal (PERI) and early postnatal (EPN) developmental low-level Pb-exposures in rats on frontoexecutive functions, using the Attention Set-Shift Test (ASST). Control males and females performed the ASST similarly. Male EPN rats had difficulty with simple discrimination (SD) of odors and failed to complete the compound discrimination (CD) stage of the ASST. All other Pb-exposed rats completed the training and testing. Male PERI rats performed worse on the SD, intradimensional (ID), and intradimensional-reversal (ID-Rev) ASST stages when compared to male Control rats. Female EPN rats performed similar to Controls on the ID-Rev rats, whereas PERI rats performed better the trials-to-criterion on the ID-Rev than EPN and Control rats. Pb-exposed female rats had significant difficulty performing the ED/ED-Rev stages, with the number of trials-to-criterion double that required by Pb-exposed and Control male rats and Control female rats. Together, the ASST results showed that developmental Pb-exposure induces frontoexecutive dysfunction that persists into adulthood, with different sex-based vulnerabilities dependent upon the time-period of neurotoxicant exposure.

Environmental neurotoxicant-induced dopaminergic neurodegeneration: a potential link to impaired neuroinflammatory mechanisms.

With the increased incidence of neurodegenerative diseases worldwide, Parkinson's disease (PD) represents the second-most common neurodegenerative disease. PD is a progressive multisystem neurodegenerative disorder characterized by a marked loss of nigrostriatal dopaminergic neurons and the formation of Lewy pathology in diverse brain regions. Although the mechanisms underlying dopaminergic neurodegeneration remain poorly characterized, data from animal models and postmortem studies have revealed that heightened inflammatory responses mediated via microglial and astroglial activation and the resultant release of proinflammatory factors may act as silent drivers of neurodegeneration. In recent years, numerous studies have demonstrated a positive association between the exposure to environmental neurotoxicants and the etiology of PD. Although it is unclear whether neuroinflammation drives pesticide-induced neurodegeneration, emerging evidence suggests that the failure to dampen neuroinflammatory mechanisms may account for the increased vulnerability to pesticide neurotoxicity. Furthermore, recent studies provide additional evidence that shifts the focus from a neuron-centric view to glial-associated neurodegeneration following pesticide exposure. In this review, we propose to summarize briefly the possible factors that regulate neuroinflammatory processes during environmental neurotoxicant exposure with a focus on the potential roles of mitochondria-driven redox mechanisms. In this context, a critical discussion of the data obtained from experimental research and possible epidemiological studies is included. Finally, we hope to provide insights on the pivotal role of exosome-mediated intercellular transmission of aggregated proteins in microglial activation response and the resultant dopaminergic neurodegeneration after exposure to pesticides. Collectively, an improved understanding of glia-mediated neuroinflammatory signaling might provide novel insights into the mechanisms that contribute to neurodegeneration induced by environmental neurotoxicant exposure.