Neurotoxic Chemical Exposure Research Articles

Disparities in Toxic Chemical Exposures and Associated Neurodevelopmental Outcomes: A Scoping Review and Systematic Evidence Map of the Epidemiological Literature.

Children are routinely exposed to chemicals known or suspected of harming brain development. Targeting Environmental Neuro-Development Risks (Project TENDR), an alliance of leading scientists, health professionals, and advocates, is working to protect children from these toxic chemicals and pollutants, especially the disproportionate exposures experienced by children from families with low incomes and families of color. This scoping review was initiated to map existing literature on disparities in neurodevelopmental outcomes for U.S. children from population groups who have been historically economically/socially marginalized and exposed to seven exemplar neurotoxicants: combustion-related air pollution (AP), lead (Pb), mercury (Hg), organophosphate pesticides (OPs), phthalates (Phth), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs). Systematic literature searches for the seven exemplar chemicals, informed by the Population, Exposure, Comparator, Outcome (PECO) framework, were conducted through 18 November 2022, using PubMed, CINAHL Plus (EBSCO), GreenFILE (EBSCO), and Web of Science sources. We examined these studies regarding authors' conceptualization and operationalization of race, ethnicity, and other indicators of sociodemographic and socioeconomic disadvantage; whether studies presented data on exposure and outcome disparities and the patterns of those disparities; and the evidence of effect modification by or interaction with race and ethnicity. Two hundred twelve individual studies met the search criteria and were reviewed, resulting in 218 studies or investigations being included in this review. AP and Pb were the most commonly studied exposures. The most frequently identified neurodevelopmental outcomes were cognitive and behavioral/psychological. Approximately a third (74 studies) reported investigations of interactions or effect modification with 69% (51 of 74 studies) reporting the presence of interactions or effect modification. However, less than half of the studies presented data on disparities in the outcome or the exposure, and fewer conducted formal tests of heterogeneity. Ninety-two percent of the 165 articles that examined race and ethnicity did not provide an explanation of their constructs for these variables, creating an incomplete picture. As a whole, the studies we reviewed indicated a complex story about how racial and ethnic minority and low-income children may be disproportionately harmed by exposures to neurotoxicants, and this has implications for targeting interventions, policy change, and other necessary investments to eliminate these health disparities. We provide recommendations on improving environmental epidemiological studies on environmental health disparities. To achieve environmental justice and health equity, we recommend concomitant strategies to eradicate both neurotoxic chemical exposures and systems that perpetuate social inequities. https://doi.org/10.1289/EHP11750.

The Threat Posed by Environmental Contaminants on Neurodevelopment: What Can We Learn from Neural Stem Cells?

Exposure to chemicals may pose a greater risk to vulnerable groups, including pregnant women, fetuses, and children, that may lead to diseases linked to the toxicants' target organs. Among chemical contaminants, methylmercury (MeHg), present in aquatic food, is one of the most harmful to the developing nervous system depending on time and level of exposure. Moreover, certain man-made PFAS, such as PFOS and PFOA, used in commercial and industrial products including liquid repellants for paper, packaging, textile, leather, and carpets, are developmental neurotoxicants. There is vast knowledge about the detrimental neurotoxic effects induced by high levels of exposure to these chemicals. Less is known about the consequences that low-level exposures may have on neurodevelopment, although an increasing number of studies link neurotoxic chemical exposures to neurodevelopmental disorders. Still, the mechanisms of toxicity are not identified. Here we review in vitro mechanistic studies using neural stem cells (NSCs) from rodents and humans to dissect the cellular and molecular processes changed by exposure to environmentally relevant levels of MeHg or PFOS/PFOA. All studies show that even low concentrations dysregulate critical neurodevelopmental steps supporting the idea that neurotoxic chemicals may play a role in the onset of neurodevelopmental disorders.

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 >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<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.

Functional brain MRI in patients complaining of electrohypersensitivity after long term exposure to electromagnetic fields.

Ten adult patients with electromagnetic hypersensitivity underwent functional magnetic resonance imaging (fMRI) brain scans. All scans were abnormal with abnormalities which were consistent and similar. It is proposed that fMRI brain scans be used as a diagnostic aid for determining whether or not a patient has electromagnetic hypersensitivity. Over the years we have seen an increasing number of patients who had developed multi system complaints after long term repeated exposure to electromagnetic fields (EMFs). These complaints included headaches, intermittent cognitive and memory problems, intermittent disorientation, and also sensitivity to EMF exposure. Regular laboratory tests were within normal limits in these patients. The patients refused to be exposed to radioactivity. This of course ruled out positron emission tomography (PET) and single-photon emission computed tomography (SPECT) brain scanning. This is why we ordered fMRI brain scans on these patients. We hoped that we could document objective abnormalities in these patients who had often been labeled as psychiatric cases. Ten patients first underwent a regular magnetic resonance imaging (MRI) brain scan, using a 3 Tesla Siemens Verio MRI open system. A functional MRI study was then performed in the resting state using the following sequences: A three-dimensional, T1-weighted, gradient-echo (MPRAGE) Resting state network. The echo-planar imaging (EPI) sequences for this resting state blood oxygenation level dependent (BOLD) scan were then post processed on a 3D workstation and the independent component analysis was performed separating out the various networks. Arterial spin labeling. Tractography and fractional anisotropy. All ten patients had abnormal functional MRI brain scans. The abnormality was often described as hyper connectivity of the anterior component of the default mode in the medial orbitofrontal area. Other abnormalities were usually found. Regular MRI studies of the brain were mostly unremarkable in these patients. We propose that functional MRI studies should become a diagnostic aid when evaluating a patient who claims electrohypersensitivity (EHS) and has otherwise normal studies. Interestingly, the differential diagnosis for the abnormalities seen on the fMRI includes head injury. It turns out that many of our patients indeed had a history of head injury which was then followed sometime later by the development of EHS. Many of our patients also had a history of exposure to potentially neurotoxic chemicals, especially mold. Head injury and neurotoxic chemical exposure may make a patient more vulnerable to develop EHS.

Noise and neurotoxic chemical exposure relationship to workplace traumatic injuries: A review

IntroductionMore than 5,000 fatalities and eight million injuries occurred in the workplace in 2007 at a cost of $6 billion and $186 billion, respectively. Neurotoxic chemicals are known to affect central nervous system functions among workers, which include balance and hearing disorders. However, it is not known if there is an association between exposure to noise and solvents and acute injuries. Method: A thorough review was conducted of the literature on the relationship between noise or solvent exposures and hearing loss with various health outcomes. Results: The search resulted in 41 studies. Health outcomes included: hearing loss, workplace injuries, absence from work due to sickness, fatalities, hospital admissions due to workplace accidents, traffic accidents, hypertension, balance, slip, trips, or falls, cognitive measures, or disability retirement. Important covariates in these studies were age of employee, type of industry or occupation, or length of employment. Discussion: Most authors that evaluated noise exposure concluded that higher exposure to noise resulted in more of the chosen health effect but the relationship is not well understood. Studies that evaluated hearing loss found that hearing loss was related to occupational injury, disability retirement, or traffic accidents. Studies that assessed both noise exposure and hearing loss as risk factors for occupational injuries reported that hearing loss was related to occupational injuries as much or more than noise exposure. Evidence suggests that solvent exposure is likely to be related to accidents or other health consequences such balance disorders. Conclusions: Many authors reported that noise exposures and hearing loss, respectively, are likely to be related to occupational accidents. Practical applications: The potential significance of the study is that findings could be used by managers to reduce injuries and the costs associated with those injures.

Alterations in Global DNA Methylation/Hydroxymethylation and MicroRNA Expression in a Rat Model of Gulf War Illness

Gulf War Illness (GWI) is a chronic, multisymptom illness that affects 25% of the 700,000 US veterans deployed to the Persian Gulf during the 1990-1991 Gulf War. Central nervous system impairments are among the most common symptoms reported, including memory dysfunction and depression. Epidemiological studies have consistently identified neurotoxic chemical exposures during deployment as the strongest risk factors for the persistent symptoms affecting GW veterans, but after nearly 25 years, treatments are lacking and underlying cellular and molecular mechanisms involved in its pathobiology remain poorly understood. Epigenetic changes including DNA methylation and altered microRNA (miRNA) expression play an important role in in learning, memory, and emotion regulation and have been implicated in various neurological disorders. The aim of this study was to determine in a rat model of GWI whether chronic alterations in global DNA methylation/hydroxymethylation and miRNA expression are mechanisms involved in the pathobiology of GWI. One year after a 28-day exposure regimen of GW chemicals and stress, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) content and expression of 84 mature miRNAs were analyzed in the brains of GWI rats and vehicle controls by ELISA and PCR array, respectively. In GWI rats, hippocampal 5mC content increased 46%, while 5hmC content increased 29% in the cerebellum and decreased 45% in the cortex (p<0.01 for all). Ten miRNAs known to be involved in synaptic plasticity and memory function, DNA methylation, or adult neurogenesis were differentially expressed (>1.5 fold change, p<0.01) in the hippocampus. Results from this study implicate a role for epigenetic alterations in GWI.

Chapter 17 - Neurotoxic exposure and impairment of the chemical senses of taste and smell

The chemical senses of taste and smell determine the flavor of foods and beverages, guide appropriate food intake, and warn of such environmental hazards as spoiled or poisonous food, leaking natural gas, smoke, and airborne pollutants. This chapter addresses the influences of neurotoxic exposures on human chemoreception and provides basic information on the adverse influences of such exposures on rodent epithelia. The focus of the chapter is in olfaction, given dearth of empiric research on the effects of neurotoxic chemical exposures on the sense of taste, i.e., sweet, sour, bitter, salty, and savory sensations. As will be apparent from the chapter, numerous neurotoxins--many of which are encountered in industrial workplaces--alter the ability to smell, including solvents, metals, and particulate matter. The olfactory system is particularly vulnerable to such agents since its receptors are more or less directly exposed to the outside environment. Importantly, some such agents can enter the brain via the olfactory nerve or surrounding perineural spaces, bypassing the blood-brain barrier and damaging central nervous system structures and inducing pathologic processes that appear to be similar to those seen in neurodegenerative diseases such as Alzheimer's and Parkinson's.

Reconsideration of the WHO NCTB strategy and test selection

The World Health Organization-recommended neurobehavioral core test battery (NCTB) became the international standard for identifying adverse human behavioral effects due to neurotoxic chemical exposure when it was first proposed in 1983. Since then the WHO NCTB has been repeatedly cited as the basis for test selection in human neurotoxicology research. A discussion group was held before the International Symposium on Neurobehavioral Methods and Effects in Occupational and Environmental Health to review the NCTB and reconsider its tests. The workshop made three consensus recommendations to the International Congress on Occupational Health (ICOH) Scientific Committee on Neurotoxicology and Psychophysiology (SCNP):.1.A ‘screening’ battery of broadly sensitive tests is needed as guidance to the field of human neurotoxicology2.The SCNP should convene a panel to reconsider the functions measured and the tests in the WHO NCTB3.Three disciplines should be represented in the panel recommending a revised NCTB: neuropsychology; experimental psychology; neurologyThis recommendation will be pursued at the next meeting of the International Congress on Occupational Health (ICOH) Scientific Committee on Neurotoxicology and Psychophysiology (SCNP).

Emerging neurotoxic mechanisms in environmental factors-induced neurodegeneration

Exposure to environmental neurotoxic metals, pesticides and other chemicals is increasingly recognized as a key risk factor in the pathogenesis of chronic neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Oxidative stress and apoptosis have been actively investigated as neurotoxic mechanisms over the past two decades, resulting in a greater understanding of neurotoxic processes. Nevertheless, emerging evidence indicates that epigenetic changes, protein aggregation and autophagy are important cellular and molecular correlates of neurodegenerative diseases resulting from chronic neurotoxic chemical exposure. During the Joint Conference of the 13th International Neurotoxicology Association and the 11th International Symposium on Neurobehavioral Methods and Effects in Occupational and Environmental Health, the recent progress made toward understanding epigenetic mechanisms, protein aggregation, autophagy, and deregulated kinase activation following neurotoxic chemical exposure and the relevance to neurodegenerative conditions were one of the themes of the symposium. Dr. Anumantha G. Kanthasamy described the role of acetylation of histones and non-histone proteins in neurotoxicant-induced neurodegenerative processes in the nigral dopaminergic neuronal system. Dr. Arthi Kanthasamy illustrated the role of autophagy as a key determinant in cell death events during neurotoxic insults. Dr. Ajay Rana provided evidence for posttranslational modification of α-synuclein protein by the Mixed Linage Kinase (MLK) group of kinases to initiate protein aggregation in cell culture and animal models of Parkinson's disease. These presentations outlined emerging cutting edge mechanisms that might set the stage for future mechanistic investigations into new frontiers of molecular neurotoxicology. This report summarizes the views of symposium participants, with emphasis on future directions for study of environmentally and occupationally linked chronic neurodegenerative diseases.

Effects of Biological and Technical Factors on Brain and Muscle Cholinesterases in Nile Tilapia, Oreochromis niloticus: Implications for Biomonitoring Neurotoxic Contaminations

Influence of body length, body weight, gender, sexual maturity, and tissue storage on brain and muscle cholinesterases (ChE) in Nile tilapia was evaluated considering its potential use in biomonitoring neurotoxic contaminations in tropical environments. Results show that ChE activities in both tissues decreased significantly with increased total length (4-24.5 cm) or body weight (1-186 g) of the fish and the relationships were curvilinear. Comparisons of the slopes and elevations of the regression lines of the logarithmic ChE and body size relationships of males with those of females indicated that gender had no significant effect on the body size-specific ChE activities. Response of the ChE of sexually mature males to chlorpyrifos exposure was similar to that of females. Gonadal maturity stage of this fish does not seem to influence ChE activities. Storage of tissues at -80 degrees C for 28 days had no significant effect on ChE activities in the control fish and the fish exposed to carbofuran. However, a partial reactivation of brain ChE activities was observed in the fish exposed to carbosulfan after 28 days of storage. The results emphasize the importance of consideration of body size of the fish and storage time of the tissues in order to formulate accurate conclusions about the neurotoxic chemical exposure when ChE of the fish is used in biomonitoring programs.

Material safety data sheets: their use in Québec workers' compensation appeals involving neurotoxic chemical exposures.

(2003). Material Safety Data Sheets: Their Use in Quebec Workers' Compensation Appeals Involving Neurotoxic Chemical Exposures. Applied Occupational and Environmental Hygiene: Vol. 18, No. 6, pp. 405-412.

Neurotoxicity in single photon emission computed tomography brain scans of patients reporting chemical sensitivities.

The subset of patients reporting chemical sensitivity with neurocognitive complaints usually exhibits specific abnormalities of brain metabolism consistent with neurotoxicity, on imaging with single photon emission computed tomography (SPECT). These recurrent neurotoxic patterns are characterized by a mismatch in tracer uptake between early- and late-phase imaging, multiple hot and cold foci throughout the cortex, temporal asymmetry and increased tracer uptake into the soft tissues and, sometimes, the basal ganglia. Previous studies confirm these neurotoxic findings in patients with neurotoxic chemical exposures and breast implants. Affective processes such as depression do not, alone, show this pattern. These abnormalities in SPECT images correlate with documented neurocognitive impairment. Controlled challenges to ambient chemicals can induce profound neurotoxic changes seen on SPECT imaging in chemically sensitive patients. Detoxification treatment techniques frequently produce significant improvement on brain SPECT brain imaging in these patients. Neurotoxicity appears to be characteristic in many cases of chemical sensitivity.

Neurospect in neurotoxic chemical exposure demonstration of long-term functional abnormalities.

Patients who had experienced well-documented neurotoxic exposure months or years earlier were evaluated. Seventy-two right-handed adults who claimed continuing abnormalities of cognitive and memory function were examined after Xenon-133 inhalation and i.v. HMPAO. Single photon emission computed tomography (SPECT) results were statistically compared with age-matched controls. Bilateral, often asymmetrical, impairment of perfusion was found, mostly in the frontal, temporal, and parietal lobes. This hypoperfusion was predominantly left-sided in young patients and predominantly right-sided in the elderly. Abnormalities were found months and years after neurotoxic exposure had ceased. Our findings suggest that NeuroSPECT can provide evidence of impaired cerebral function and may therefore help to further define neurotoxic exposure and its chronic effects.

Event-Related Potentials in Workers with Ongoing Occupational Exposure

The cognitive impact of occupational exposure to organic solvents has primarily been studied with neuropsychologic and behavioral measures (Hartman 1995). A small literature has addressed aberrations in event-related potentials (ERPs) in persons with clinical complaints associated with neurotoxic chemical exposure (El Massioui et al 1986; Morrow et al 1992, Morrow et al 1996; Teo and Ferguson 1985; Wasch et al 1989). For these exposed individuals, prolongation of latency of the P300 component of the ERP is the most consistently reported finding. Prolongation of P300 latency also has been associated with acquired brain damage such as dementia (Goodin et al 1978) and posttraumatic amnesia (Onofrj et al 1991). ERP data are presented from painters with ongoing workplace exposures who had not previously presented with occupationally-related impairments.

Assessment of behavioral sequelae of traumatic and chemical CNS insult

Twenty patients with traumatic head injury and 20 patients with neurotoxic chemical exposure completed a 68-item Behavior Inventory listing preinsult versus postinsult behavior presence or absence for each item. Forty controls completed the same inventory, covering approximately the same intervals of time involved with CNS insult group. Whereas controls showed nonsignificant behavior changes on any variable, clinical groups reported significant behavior change on the majority of behavioral variables. There were some differential changes between the two clinical groups. Findings suggest an approach to assessing behavior changes due to CNS insult.