Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases

Neurodegenerative diseases including Alzheimer (AD) and Parkinson (PD) have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment, from diet to the new nanomaterials as putative risk factors has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metals such as lead, mercury, aluminum, cadmium and arsenic, as well as some pesticides and metal-based nanoparticles have been involved in AD due to their ability to increase beta-amyloid (Aβ) peptide and the phosphorylation of Tau protein (P-Tau), causing senile/amyloid plaques and neurofibrillary tangles characteristic of AD. The exposure to lead, manganese, solvents and some pesticides has been related to hallmarks of PD such as mitochondrial dysfunction, alterations in metal homeostasis and aggregation of proteins such as α-synuclein (α-syn), which is a key constituent of Lewy bodies, a crucial factor in PD pathogenesis. Common mechanisms of environmental pollutants to increase Aβ, P-Tau, α-syn and neuronal death have been reported, including the oxidative stress mainly involved in the increase of Aβ and α-syn, and the reduced activity/protein levels of Aβ degrading enzymes such as neprilysin or insulin degrading enzyme. In addition, epigenetic mechanisms by maternal nutrient supplementation and exposure to heavy metals and pesticides have been proposed to lead phenotypic diversity and susceptibility to neurodegenerative diseases. This review discusses data from epidemiological and experimental studies about the role of environmental factors in the development of idiopathic AD and PD, and their mechanisms of action

Association of Pesticide Exposure with Neurologic Dysfunction and Disease

Poisoning by acute high-level exposure to certain pesticides has well-known neurotoxic effects, but whether chronic exposure to moderate levels of pesticides is also neurotoxic is more controversial. Most studies of moderate pesticide exposure have found increased prevalence of neurologic symptoms and changes in neurobehavioral performance, reflecting cognitive and psychomotor dysfunction. There is less evidence that moderate exposure is related to deficits in sensory or motor function or peripheral nerve conduction, but fewer studies have considered these outcomes. It is possible that the most sensitive manifestation of pesticide neurotoxicity is a general malaise lacking in specificity and related to mild cognitive dysfunction, similar to that described for Gulf War syndrome. Most studies have focused on organophosphate insecticides, but some found neuro-toxic effects from other pesticides, including fungicides, fumigants, and organochlorine and carbamate insecticides. Pesticide exposure may also be associated with increased risk of Parkinson disease; several classes of pesticides, including insecticides, herbicides, and fungicides, have been implicated. Studies of other neurodegenerative diseases are limited and inconclusive. Future studies will need to improve assessment of pesticide exposure in individuals and consider the role of genetic susceptibility. More studies of pesticides other than organophosphates are needed. Major unresolved issues include the relative importance of acute and chronic exposure, the effect of moderate exposure in the absence of poisoning, and the relationship of pesticide-related neurotoxicity to neurodegenerative disease

Global DNA methylation profiling of manganese-exposed human neuroblastoma SH-SY5Y cells reveals epigenetic alterations in Parkinson’s disease-associated genes

Manganese (Mn) is an essential trace element required for optimal functioning of cellular biochemical pathways in the central nervous system. Elevated exposure to Mn through environmental and occupational exposure can cause neurotoxic effects resulting in manganism, a condition with clinical symptoms identical to idiopathic Parkinson’s disease. Epigenetics is now recognized as a biological mechanism involved in the etiology of various diseases. Here, we investigated the role of DNA methylation alterations induced by chronic Mn (100 µM) exposure in human neuroblastoma (SH-SY5Y) cells in relevance to Parkinson’s disease. A combined analysis of DNA methylation and gene expression data for Parkinson’s disease-associated genes was carried out. Whole-genome bisulfite conversion and sequencing indicate epigenetic perturbation of key genes involved in biological processes associated with neuronal cell health. Integration of DNA methylation data with gene expression reveals epigenetic alterations to PINK1, PARK2 and TH genes that play critical roles in the onset of Parkinsonism. The present study suggests that Mn-induced alteration of DNA methylation of PINK1–PARK2 may influence mitochondrial function and promote Parkinsonism. Our findings provide a basis to further explore and validate the epigenetic basis of Mn-induced neurotoxicity

Glyphosate’s Suppression of Cytochrome P450 Enzymes and Amino Acid Biosynthesis by the Gut Microbiome: Pathways to Modern Diseases

Glyphosate, the active ingredient in Roundup[superscript ®], is the most popular herbicide used worldwide. The industry asserts it is minimally toxic to humans, but here we argue otherwise. Residues are found in the main foods of the Western diet, comprised primarily of sugar, corn, soy and wheat. Glyphosate's inhibition of cytochrome P450 (CYP) enzymes is an overlooked component of its toxicity to mammals. CYP enzymes play crucial roles in biology, one of which is to detoxify xenobiotics. Thus, glyphosate enhances the damaging effects of other food borne chemical residues and environmental toxins. Negative impact on the body is insidious and manifests slowly over time as inflammation damages cellular systems throughout the body. Here, we show how interference with CYP enzymes acts synergistically with disruption of the biosynthesis of aromatic amino acids by gut bacteria, as well as impairment in serum sulfate transport. Consequences are most of the diseases and conditions associated with a Western diet, which include gastrointestinal disorders, obesity, diabetes, heart disease, depression, autism, infertility, cancer and Alzheimer’s disease. We explain the documented effects of glyphosate and its ability to induce disease, and we show that glyphosate is the “textbook example” of exogenous semiotic entropy: the disruption of homeostasis by environmental toxins.Quanta Computer (Firm

Does Glyphosate Acting as a Glycine Analogue Contribute To ALS?

 Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease involving several protein mutations in glycine-rich regions with limited treatment options. 90 - 95% of all cases are non-familial with epidemiological studies showing a significant increased risk in glyphosate-exposed workers. In this paper, we propose that glyphosate, the active ingredient in Roundup®, plays a role in ALS, mainly through mistakenly substituting for glycine during protein synthesis, disruption of mineral homeostasis as well as setting up a state of dysbiosis. Mouse models of ALS reveal a pre-symptomatic profile of gut dysbiosis. This dysbiotic state initiate a cascade of events initially impairing metabolism in the gut, and, ultimately, through a series of intermediate stages, leading to motor neuron axonal damage seen in ALS. Lipopolysaccharide, a toxic by-product of dysbiosis which contributes to the pathology, is shown to be statistically higher in ALS patients. In this paper we paint a compelling view of how glyphosate exerts its deleterious effects, including mitochondrial stress and oxidative damage through glycine substitution. Furthermore, its mineral chelation properties disrupt manganese, copper and zinc balance, and it induces glutamate toxicity in the synapse, which results in a die-back phenomenon in axons of motor neurons supplying the damaged skeletal muscles

Anacardium microcarpum extract and fractions protect against paraquat-induced toxicity in Drosophila melanogaster

Anacardium microcarpum Ducke (Anacardiaceae) is a native species of Brazil used in folk medicine for the treatment of several illnesses although its antioxidant activity has been reported in vitro, there is no evidence of this effect in an in vivo model. Here, we investigated the potential protective effect of hydroalcoholic extract (AMHE), methanol (AMMF) and acetate (AMAF) fraction of A. microcarpum against paraquat toxicity on survivorship, locomotor performance, antioxidant enzymes activity and reactive species using Drosophila melanogaster. Flies were exposed to the extract or fractions (1 and 10 mg/ml) in the presence or absence of paraquat (5 mM) in sucrose solution for 72 h. In addition, total phenolic content of extract and fractions was evaluated as well as ABTS radical scavenging capacity. Our results demonstrated that AMAF presented higher content of phenols and ABTS chelating potential. Treatment of flies with the extract or fractions did not alter the survivorship, locomotor ability, and acetylcholinesterase (AchE) activity per se. Paraquat caused 85 % mortality of flies and 30 % increase in reactive species generation, which were significantly attenuated by AMHE and AMMF. AAMF increased catalase activity (from 66.77 ± 6.64 to 223.94 ± 25.92 mU/mg of protein), while AMAF increased GST activity (from 477.76 ± 92 to 770.19 ± 147.92 mU/mg of protein) and catalase activity (from 66.77 ± 6.64 to 220.54 ± 26.63 mU/mg of protein). AMHE and AMMF were more effective in protecting against paraquat toxicity. Taken together, the data indicate the potential of this plant in acting as a protective and antioxidant agent in vivo

Neuron-microglia interactions in motor neuron degeneration. The inflammatory hypothesis in amyotrophic lateral sclerosis revisited.

Research into the pathogenesis of amyotrophic lateral sclerosis (ALS) has obtainedd notable gene discoveries, although, to date, only progress with regard to treatment has been very modest. Currently ALS is considered a multifactorial disease that presents diverse clinical presentations, ranging from a monogenic inherited disease to an autoimmune pathology, and develops with misfolded protein aggregation and neuroinflammation. An important factor related to ALS pathogenesis is the microglial activation associated with degenerative motor neurons. This activation leads to changes in the expression of a wide range of genes related to phagocytosis and inflammation, and to profound modifications in the dynamic interactions between neurons and glial cells. Overactivation and deregulation of microglial activity causes deleterious effects and leads to neuronal death. However, the involvement of microglia in non-inflammatory functions challenges our concept of neuroinflammation and opens up new possibilities for the study of the pathophysiological mechanisms of ALS. In this review we summarize the current knowledge on the adaptive interactions between neurons and microglia in ALS. We also discuss the hypothesis that controlling the extent of microglial activation and neuroinflammation may have clinical and therapeutic benefits for the condition

Neurodegenerative Diseases: An Overview of Environmental Risk Factors

The population of the United States is aging, and an ever-increasing number of Americans are afflicted with neurodegenerative diseases. Because the pathogenesis of many of these diseases remains unknown, we must consider that environmental factors may play a causal role. This review provides an overview of the epidemiologic evidence for environmental etiologies for neurodegenerative diseases such as Alzheimer disease, Parkinson disease, parkinsonian syndromes (multiple system atrophy and progressive supranuclear palsy), and amyotrophic lateral sclerosis. Epidemiologic evidence for an association between environmental agents’ exposure and neurodegenerative diseases is not conclusive. However, there are indications that there may be causal links, and the need for more research is obvious

The association between chronic Dicofol exposure and the risk of Alzheimer's disease

Alzheimer’s Disease (AD) is a disorder that causes progressive cognitive impairment. It’s a unique neurodegenerative disorder in which beta amyloid plaques and neurofibrillary tangles begin to preoccupy brain tissue. AD has been a historically difficult disease for society to examine partially because it’s etiology is still not well understood. One of the risk factors associated with AD development that has been researched is exposure to pesticides, primarily focused on the pesticide Dichlorodiphenyltrichloroethane (DDT). Studies have shown that DDT disrupts both the neurological and endocrine systems. As a result, this disruption leads to hyperexcitability of axons as well as a loss of neuroprotection thereby causing an increased susceptibility to Alzheimer’s Disease. Although DDT has been extensively studied, other pesticides are still used in large amounts throughout the world. One pesticide that’s particularly used to do it’s low cost and availability is Dicofol. Dicofol is a DDT derivative in which it’s structure is similar to the structure of DDT. Although Dicofol is similar to DDT in terms of structure and use, research into the effects of Dicofol exposure has not been extensively performed. The following study has been proposed in order to investigate a relationship between Dicofol exposure and the risk of developing AD. The study performed is a retrospective cohort study of 1134 people consisting of pesticide applicators collected from the Agricultural Health Study. A licensed neurologist using the Mini Mental Status Exam will assess if cognitive impairment is present in the participants. Those that are believed to be cognitively impaired will then undergo neuroimaging to confirm the presence of beta amyloid plaques, which are indicative of AD. Finally a Chi Square analysis will be used in order to determine if there are associations between exposure status and AD diagnosis. This study has both clinical and public health significance. As stated previously, dicofol is still used widely in many countries due to it’s availability and low cost. Therefore, many agricultural workers may be unknowingly exposing themselves to a pesticide that can increase their susceptibility to neurodegenerative disease. This concern is primarily the reason as to why a study such as the one proposed is needed