Data-Driven Characterization of Genetic Variability in Disease Pathways and Pesticide-Induced Nervous System Disease in the United States Population.

BACKGROUND: Genetic susceptibility to chemicals is incompletely characterized. However, nervous system disease development following pesticide exposure can vary in a population, implying some individuals may have higher genetic susceptibility to pesticide-induced nervous system disease. OBJECTIVES: We aimed to build a computational approach to characterize single-nucleotide polymorphisms (SNPs) implicated in chemically induced adverse outcomes and used this framework to assess the link between differential population susceptibility to pesticides and human nervous system disease. METHODS: We integrated publicly available datasets of Chemical-Gene, Gene-Pathway, and SNP-Disease associations to build Chemical-Pathway-Gene-SNP-Disease linkages for humans. As a case study, we integrated these linkages with spatialized pesticide application data for the US from 1992 to 2018 and spatialized nervous system disease rates for 2018. Through this, we characterized SNPs that may be important in states with high disease occurrence based on the pesticides used there. RESULTS: We found that the number of SNP hits per pesticide in US states positively correlated with disease incidence and prevalence for Alzheimer's disease, Parkinson disease, and multiple sclerosis. We performed frequent itemset mining to differentiate pesticides used over time in states with high and low disease occurrence and found that only 19% of pesticide sets overlapped between 10 states with high disease occurrence and 10 states with low disease occurrence rates, and more SNPs were implicated in pathways in high disease occurrence states. Through a cross-validation of subsets of five high and low disease occurrence states, we characterized SNPs, genes, pathways, and pesticides more frequently implicated in high disease occurrence states. DISCUSSION: Our findings support that pesticides contribute to nervous system disease, and we developed priority lists of SNPs, pesticides, and pathways for further study. This data-driven approach can be adapted to other chemicals, diseases, and locations to characterize differential population susceptibility to chemical exposures. https://doi.org/10.1289/EHP14108.

Egg White Hydrolysate Mitigates Cadmium-induced Neurological Disorders and Oxidative Damage.

We aimed to investigate whether the consumption of Egg White Hydrolysate (EWH) acts on nervous system disorders induced by exposure to Cadmium (Cd) in rats. Male Wistar rats were divided into (a) Control (Ct): H2O by gavage for 28 days + H2O (i.p. - 15th - 28th day); (b) Cadmium (Cd): H2O by gavage + CdCl2 - 1 mg/kg/day (i.p. - 15th - 28th day); (c) EWH 14d: EWH 1 g/kg/day by gavage for 14 days + H2O (i.p.- 15th - 28th day); (d) Cd + EWH cotreatment (Cd + EWHco): CdCl2 + EWH for 14 days; (e) EWH 28d: EWH for 28 days; (f) EWHpre + Cd: EWH (1st - 28th day) + CdCl2 (15th - 28th day). At the beginning and the end of treatment, neuromotor performance (Neurological Deficit Scale); motor function (Rota-Rod test); ability to move and explore (Open Field test); thermal sensitivity (Hot Plate test); and state of anxiety (Elevated Maze test) were tested. The antioxidant status in the cerebral cortex and the striatum were biochemically analyzed. Cd induces anxiety, and neuromotor, and thermal sensitivity deficits. EWH consumption prevented anxiety, neuromotor deficits, and alterations in thermal sensitivity, avoiding neuromotor deficits both when the administration was performed before or during Cd exposure. Both modes of administration reduced the levels of reactive species, and the lipid peroxidation increased by Cd and improved the striatum's antioxidant capacity. Pretreatment proved to be beneficial in preventing the reduction of SOD activity in the cortex. EWH could be used as a functional food with antioxidant properties capable of preventing neurological damage induced by Cd.

Fungicides as a risk factor for the development of neurological diseases and disorders in humans: a systematic review.

Although studies show that pesticides, especially insecticides, may be toxic to humans, publications on the neurological effects of fungicides are scarce. As fungicides are used widely in Brazil, it is necessary to gather evidence to support actions aimed at safely using of these chemicals. We investigated through a systematic review of publications on the use of fungicides and consequences of exposure related to nervous system diseases or neurological disorders in humans. The protocol review was registered on PROSPERO and followed the guidelines of the PRISMA-Statement. As far as it is known, there is no apparent systematic review in the literature on this topic. The search was comprised of the following databases: PubMed; Web of Science; Scopus and EMBASE, using groups of Mesh terms and strategies specific to each database. Thirteen articles were selected for this review. Regarding the substances analyzed in the studies, some reported the use of fungicides in general, without separating them by type, while others summarized the categories of all pesticides by their function (insecticides, herbicides, fungicides, etc.) or chemical class (dithiocarbamate, dicarboximide, inorganic, etc.). However, most of the articles referred to fungicides that contain the metal manganese (Mn) in their composition. As for neurological disorders, articles addressed Parkinson's disease (PD), neurodevelopmental outcomes, extrapyramidal syndrome resembling PD, cognitive disorders, depression, neural tube defects, motor neurone disease, and amyotrophic lateral sclerosis. Most investigations pointed to exposure to fungicides, mainly maneb and mancozeb, leading to the development of at least one neurological disease, which suggests the need for further multicentric clinical trials and prospective studies for greater clarity of the research problem.

Functional neurologic disorder as a rare complication of dental local anaesthetics: two contrasting cases.

Adverse reactions to dental local anaesthetics are fortunately rare. However, when they occur, they can be severe and debilitating to the patient. Adverse reactions may be either prolonged anaesthesia, with or without dysaesthesia, or systemic reactions. Although these systemic reactions are commonly thought to be allergies, this is rarely the case. Much more commonly, these adverse systemic reactions are either cardiovascular or from the central nervous system. This paper describes two contrasting cases of functional neurologic disorder which illustrates the consequences and appropriate management. The responsibilities of the dentist who injected the local anaesthetic are outlined.

Neurological Manifestations Induced by Nitrous Oxide Abuse: A Case Series and Review of Literature.

INTRODUCTION: Nitrous oxide (NO) abuse is increasing among young people. This can result in severe neurological disorders such as myelopathy and/or peripheral neuropathy. We report the clinical presentations, biological, radiologic and electrophysiological findings of 5 patients hospitalized with neurological symptoms consecutive to NO abuse. In addition, a literature review was conducted to describe the neurological characteristics and to identify factors associated with a poor recovery. CASE REPORT: Among the 5 patients included, 2 had a myeloneuropathy, 2 had a sensorimotor neuropathy, and 1 had a normal spinal cord magnetic resonance imaging and electromyography despite neurological manifestations consistent with myeloneuropathy. After vitamin B 12 supplementation, recovery was reported in 4 patients, and 1 was lost to follow-up.From the literature review, 154 patients were included [94 males; median age 22 (19 to 26) y; NO exposure 9 (3 to 18) mo]. A myelopathy was identified in 116 patients (75%) and a peripheral neuropathy was documented in 89 patients (58%). Compared with patients who recovered, those with sequelae were more likely to have a motor deficit at presentation ( P <0.001), to use NO regularly ( P <0.001), to have a lower vitamin B 12 level ( P =0.04), and a higher concentration of homocysteine ( P =0.04). A less extensive myelopathy was more frequently found in the group with favorable outcomes ( P =0.002). CONCLUSION: Neurological disorders caused by NO may be challenging with severe clinical patterns. We identified several factors associated with a poor recovery, to make clinicians aware of NO-induced neurotoxicity.

Noxious ramifications of cosmetic pollutants on gastrointestinal microbiome: A pathway to neurological disorders.

On exposure to cosmetic pollutants, gastrointestinal dysbiosis, which is characterised by a disturbance in the gut microbiota, has come into focus as a possible contributor to the occurrence of neurotoxic consequences. It is normal practice to use personal care products that include parabens, phthalates, sulphates, triclosans/triclocarbans and micro/nano plastics. These substances have been found in a variety of bodily fluids and tissues, demonstrating their systemic dispersion. Being exposed to these cosmetic pollutants has been linked in recent research to neurotoxicity, including cognitive decline and neurodevelopmental problems. A vital part of sustaining gut health and general well-being is the gut flora. Increased intestinal permeability, persistent inflammation, and impaired metabolism may result from disruption of the gut microbial environment, which may in turn contribute to neurotoxicity. The link between gastrointestinal dysbiosis and the neurotoxic effects brought on by cosmetic pollutants may be explained by a number of processes, primarily the gut-brain axis. For the purpose of creating preventative and therapeutic measures, it is crucial to comprehend the intricate interactions involving cosmetic pollutants, gastrointestinal dysbiosis, and neurotoxicity. This review provides an in-depth understanding of the various hazardous cosmetic pollutants and its potential role in the occurrence of neurological disorders via gastrointestinal dysbiosis, providing insights into various described and hypothetical mechanisms regarding the complex toxic effects of these industrial pollutants.

Network pharmacology and molecular docking approaches predict the mechanisms of Corididius chinensis in treating manganese-induced nervous system diseases: A review.

Neurotoxicity could be induced by long exposure to manganese (Mn). The traditional Chinese medicine, Corididius chinensis (Cc) has been proven to have a certain curative effect on Mn poisoning. Therefore, network pharmacology was performed to explore potential therapeutic targets and pharmacological mechanisms of Cc. We found ingredients by building our own database through literature, (which is the first to screen traditional Chinese medicine without traditional Chinese medicine systems pharmacology database and analysis platform databases and it is applicable whenever a Chinese medicine is not found in the traditional Chinese medicine systems pharmacology database and analysis platform database) and potential targets of Mn-induced nervous system diseases from the OMIM, GeneCards, and DrugBank database were identified. A protein-protein interaction network was constructed using Cytoscape. Gene ontology and Kyoto encyclopedia of genes and genomes pathway enrichment analysis was performed for the treatment of Mn-induced nervous system disease, and molecular docking was carried out to verify the results of network pharmacology analysis. After screening disease-related genes, 12 intersecting genes overlapped between 284 target proteins of the active compound and 195 potential disease targets. The pathways of neurodegeneration_multiple diseases and Alzheimer disease pathway may be the most potential pathway of Cc treating Mn-induced nervous system diseases. CASP9 and PTGS2 in neurodegeneration_multiple diseases, NOS1, NOS2 in Alzheimer disease pathway were identified as core targets. Especially, molecule docking analysis unveil that aspongpyrazine A docking NOS2 is the most potential therapeutic drug and target, which primarily involved in the processes of oxidative stress and inflammation.

Prenatal DEHP exposure predicts neurological disorders via transgenerational epigenetics.

Recent experimental and observational research has suggested that childhood allergic asthma and other conditions may be the result of prenatal exposure to environmental contaminants, such as di-(2-ethylhexyl) phthalate (DEHP). In a previous epidemiological study, we found that ancestral exposure (F0 generation) to endocrine disruptors or the common plasticizer DEHP promoted allergic airway inflammation via transgenerational transmission in mice from generation F1 to F4. In the current study, we employed a MethylationEPIC Beadchip microarray to examine global DNA methylation in the human placenta as a function of maternal exposure to DEHP during pregnancy. Interestingly, global DNA hypomethylation was observed in placental DNA following exposure to DEHP at high concentrations. Bioinformatic analysis confirmed that DNA methylation affected genes related to neurological disorders, such as autism and dementia. These results suggest that maternal exposure to DEHP may predispose offspring to neurological diseases. Given the small sample size in this study, the potential role of DNA methylation as a biomarker to assess the risk of these diseases deserves further investigation.

Neurologic Complications With Vaccines: What We Know, What We Don't, and What We Should Do.

Over the previous half century, vaccines have shaped human life by eradicating or nearly eradicating infections that were once a major cause of morbidity and mortality. The number of infections for which vaccines are now available has steadily increased. The types of vaccines have evolved over the years from crude extracts to more refined messenger RNA or protein-based vaccines. With these well-defined manufacturing processes, the safety profile has also improved. Despite such measures, vaccines are not without side effects, including those that affect the nervous system. Numerous case reports and case series point to these possibilities. These issues have gathered much attention during the current mass vaccination against severe acute respiratory syndrome coronavirus 2 and have resulted in some members of the public raising concerns about vaccine safety. The vaccine manufacturers have legal protection against vaccine side effects; however, there are active and passive surveillance programs put in place by the Center for Disease Control and Prevention, the US Food and Drug Administration, the World Health Organization, and the European Union. Action is needed that brings together manufactures, healthcare agencies, clinical and bench scientists, and legislatures on a global platform to investigate vaccine-related neurologic adverse events and develop ways to prevent and treat them.

Successful management of poisoning with ivermectin (Mectizan) in the Obala health district (Centre Region, Cameroon): a case report.

BACKGROUND: Ivermectin (Mectizan) is an anthelmintic drug that plays a major role in the fight against two major filarial diseases, onchocerciasis and lymphatic filariasis. Unlike previous drugs that had serious and sometimes fatal side effects, ivermectin has been considered to be safe and, therefore, is widely used. Data reporting the clinical presentation of poisoning with ivermectin are very scanty, even in experimental studies. CASE PRESENTATION: In this paper, we report the case of a 19-year-old Black African female student residing in Obala (Centre Region, Cameroon) who was admitted to a health facility in Central Cameroon for a neurological disorder after intoxication with about 400 tablets of ivermectin 3 mg (~100 times the standard doses). This neurological disorder was characterized by somnolence, kinetic ataxia, increase of tendon reflex, and central visual disturbance. Management of this intoxication consisted of symptomatic treatment and monitoring of hemodynamic parameters for 5 days, with a favorable course. CONCLUSIONS: This is the first report of a poisoning with ivermectin at ~100 times the recommended dose. This case report confirms the safety and tolerability of ivermectin, even at exceptionally high dose.

Adverse Reactions Associated with Intravenous Immunoglobulin Administration in the Treatment of Neurological Disorders: A Systematic Review.

Intravenous immunoglobulin (IVIg), which is used to treat multiple neurological conditions, may be associated with serious adverse reactions. The individual neurological disease characteristics associated with adverse reactions, along with strategies to prevent and treat adverse reactions, are uncertain. A systematic review was conducted of the databases PubMed, Embase, and Cochrane Library to summarise studies that report adverse reactions of IVIg therapy in patients with neurological disease. There were 65 studies included in the review. The reported rates of adverse reactions vary widely, but the best evidence suggests rates between 25 and 34% per patient. Common adverse reactions include headache and laboratory abnormalities. Less common but serious adverse reactions included thromboembolic complications and anaphylaxis. Overall, there is a lack of high-quality comparative data to definitively determine if any specific neurological indications are associated with a higher risk of adverse reactions. However, individual neurological disease characteristics possibly associated with an increased likelihood of adverse reactions include limited mobility (as in certain neuromuscular conditions), paraproteinaemia (as in certain peripheral neuropathies), and cardiomyopathy (as in certain myopathies). There is limited evidence to support the effectiveness of prevention and treatment strategies, which may include modification to dose, reduced infusion rate, and premedication. Further studies regarding methods to prevent and treat IVIg-ARs in neurology patients are required.

Dysautonomia associated with immune checkpoint inhibitors.

OBJECTIVE: The purpose of this study is to report the clinical characteristics of dysautonomia associated with immune checkpoint inhibitors (ICIs). METHODS: We reported two patients with autoimmune autonomic ganglionopathy (AAG) occurring as immune-related adverse events (irAEs). We also performed a review of previous case reports presenting dysautonomia during ICI therapy. Moreover, we conducted pharmacovigilance analyses using the US Food and Drug Administration Adverse Events Reporting System (FAERS) to investigate dysautonomia associated with ICI. RESULTS: Two patients in our care developed both AAG and autoimmune encephalitis following ICI therapy for lung cancers. We comprehensively reviewed 13 published cases (M:F = 11:2, mean onset age of 53 years) with ICI-associated dysautonomia including AAG (n = 3) and autonomic neuropathy (n = 10). Of these, ICI monotherapy was performed in seven and combination ICI use in six. In 6 of 13 patients, dysautonomia appeared within one month after the start of ICIs. Orthostatic hypotension was observed in 7 and urinary incontinence or retention in five. All patients except three showed gastrointestinal symptoms. Anti-ganglionic acetylcholine receptor antibodies were undetectable. All but two patients received immune-modulating therapy. Immuno-modulating therapy was effective in three patients with AAG and two patients with autonomic neuropathy, but ineffective in the others. Five patients died, of either the neurological irAE (n = 3) or cancer (n = 2). The pharmacovigilance analyses using FAERS showed that ipilimumab monotherapy and the combination of nivolumab and ipilimumab constituted significant risks for developing dysautonomia, consistent with the review of literature. CONCLUSION: ICIs can cause dysautonomia including AAG, and autonomic neuropathy is a neurological irAE.

Risk of longer-term neurological conditions in the Deepwater Horizon Oil Spill Coast Guard Cohort Study - Five years of follow-up.

BACKGROUND: Long-term neurological health risks associated with oil spill cleanup exposures are largely unknown. We aimed to investigate risks of longer-term neurological conditions among U.S. Coast Guard (USCG) responders to the 2010 Deepwater Horizon (DWH) oil spill. METHODS: We used data from active duty members of the DWH Oil Spill Coast Guard Cohort Study (N=45224). Self-reported oil spill exposures were ascertained from post-deployment surveys. Incident neurological outcomes were classified using International Classification of Diseases, 9th Revision, codes from military health encounter records up to 5.5 years post-DWH. We used Cox Proportional Hazards regression to calculate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for various incident neurological diagnoses (2010-2015). Oil spill responder (n=5964) vs. non-responder (n= 39260) comparisons were adjusted for age, sex, and race, while within-responder comparisons were additionally adjusted for smoking. RESULTS: Compared to those not responding to the spill, spill responders had reduced risks for headache (aHR=0.84, 95% CI: 0.74-0.96), syncope and collapse (aHR=0.74, 95% CI: 0.56-0.97), and disturbance of skin sensation (aHR=0.81, 95% CI: 0.68-0.96). Responders reporting ever (n=1068) vs. never (n=2424) crude oil inhalation exposure were at increased risk for several individual and grouped outcomes related to headaches and migraines (aHR range: 1.39-1.83). Crude oil inhalation exposure was also associated with elevated risks for an inflammatory nerve condition, mononeuritis of upper limb and mononeuritis multiplex (aHR=1.71, 95% CI: 1.04-2.83), and tinnitus (aHR=1.91, 95% CI: 1.23-2.96), a condition defined by ringing in one or both ears. Risk estimates for those neurological conditions were higher in magnitude among responders reporting exposure to both crude oil and oil dispersants than among those reporting crude oil only. CONCLUSION: In this large study of active duty USCG responders to the DWH disaster, self-reported spill cleanup exposures were associated with elevated risks for longer-term neurological conditions.

Ambient air pollution and the risk of neurological diseases in residential areas near multi-purposed industrial complexes of korea: A population-based cohort study.

Emerging evidence suggest that long-term exposure to air pollution may induce adverse effects on the central nervous system. However, no study explored the associations in large industrial complex (IC) areas which are one of the major contributors to air pollution. Therefore, we aimed to investigate the pollution status and the association between residential proximity and incidence of neurological diseases near two major ICs characterized as multi-purposed ICs in Korea. A retrospective cohort of residents near the ICs was constructed using Korea's health insurance data and monitored from 2008 to 2019. Emission amounts of the ICs and the air pollution status in the nearby (exposed) and remote (control) area were evaluated using data from national regulatory networks, and hazard ratios (HRs) and 95% confidence intervals (CIs) for neurological diseases of the exposed group compared to the control group were calculated using Cox proportional regression models. Overall, the complexes emitted large amounts of VOCs, CO, NOx, and PM10, and annual levels of ambient PM (2.5, 10), gaseous substances (NO2, SO2), VOCs and PAHs were higher in the exposed area compared to the control and/or the national average. The risk of inflammatory disease of the CNS (G00-09) and extrapyramidal and movement disorders (G20-26) were higher in the exposed area with a HR (95% CI) of 1.36 (1.10-1.68) and 1.33 (1.27-1.39) respectively. Among the subclasses, other extrapyramidal and movement disorders (G25) and epilepsy (G40) were associated with higher risks in the exposed area (HR (95%CI): 1.11 (1.04-1.18), 1.08 (1.00-1.16)) after adjusting for potential confounders. These results suggest that people living near ICs are more likely to be exposed to higher air pollution levels and have higher risks of developing several neurological disorders. However, further epidemiological studies in these industrial areas supplemented with other indicators of environmental exposure and control of other diverse factors are warranted.

Lead-induced neurodevelopmental lesion and epigenetic landscape: Implication in neurological disorders.

Lead (Pb) was implicated in multiple genotoxic, neuroepigenotoxic, and chromosomal-toxic mechanisms and interacted with varying synaptic plasticity pathways, likely underpinning previous reports of links between Pb and cognitive impairment. Epigenetic changes have emerged as a promising biomarker for neurological disorders, including cognitive disorders, Alzheimer's disease (AD), and Parkinson's disease (PD). In the present review, special attention is paid to neural epigenetic features and mechanisms that can alter gene expression patterns upon environmental Pb exposure in rodents, primates, and zebrafish. Epigenetic modifications have also been discussed in population studies and cell experiment. Further, we explore growing evidence of potential linkage between Pb-induced disruption of regulatory pathway and neurodevelopmental and neurological disorders both in vivo and in vitro. These findings uncover how epigenome in neurons facilitates the development and function of the brain in response to Pb insult.

The Roles of Histone Modifications in Metal-Induced Neurological Disorders.

Increasing research is illuminating the intricate roles of metal ions in neural development as well as neurological disorders, which may stem from misregulation or dysfunction of epigenetic modifiers. Lead (Pb), cadmium (Cd), aluminum (Al), and arsenic were chosen for critical review because they have become serious public health concerns due to globalization and industrialization. In this review, we will introduce various modes of action of metals and consider the role of two posttranslational modifications: histone acetylation and methylation and how each of them affects gene expression. We then summarize the findings from previous studies on the neurological outcomes and histone alterations in response to the metals on each of the previously described histone modifications mechanisms. Understanding metal-induced histone modifications changes could provide better insight on the mechanism through which neurotoxicity occurs, to propose and validate these modifications as possible biomarkers for early identification of neurological damage, and can help model targeted therapies for the diseases of the brain.

Elucidations of Molecular Mechanism and Mechanistic Effects of Environmental Toxicants in Neurological Disorders.

Due to rising environmental and global public health concerns associated with environmental contamination, human populations are continually being exposed to environmental toxicants, including physical chemical mutagens widespread in our environment causing adverse consequences and inducing a variety of neurological disorders in humans. Physical mutagens comprise ionizing and non-ionizing radiation, such as UV rays, IR rays, X-rays, which produces a broad spectrum of neuronal destruction, including neuroinflammation, genetic instability, enhanced oxidative stress driving mitochondrial damage in the human neuronal antecedent cells, cognitive impairment due to alterations in neuronal function, especially in synaptic plasticity, neurogenesis repression, modifications in mature neuronal networks drives to enhanced neurodegenerative risk. Chemical Mutagens including alkylating agents (EMS, NM, MMS, and NTG), Hydroxylamine, nitrous acid, sodium azide, halouracils are the major toxic mutagen in our environment and have been associated with neurological disorders. These chemical mutagens create dimers of pyrimidine that cause DNA damage that leads to ROS generation producing mutations, chromosomal abnormalities, genotoxicity which leads to increased neurodegenerative risk. The toxicity of four heavy metal including Cd, As, Pb, Hg is mostly responsible for complicated neurological disorders in humans. Cadmium exposure can enhance the permeability of the BBB and penetrate the brain, driving brain intracellular accumulation, cellular dysfunction, and cerebral edema. Arsenic exerts its toxic effect by induction of ROS production in neuronal cells. In this review, we summarize the molecular mechanism and mechanistic effects of mutagens in the environment and their role in multiple neurological disorders.