Differential Effects Of Methyl
João Barbosa MartinsJoão Paulo Capela
1REQUIMTE , Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
2Faculty of Health Sciences, University Fernando Pessoa, Rua Carlos da Maia 296, 4200-150 Porto, Portugal
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Abstract
1. Introduction
The lack of adequate cellular and/or animal models of PD has prompted the screening of many putative neurotoxic compounds. Paraquat has received recently a wide attention as a possible inducer of PD. In fact, occupational exposure, especially in farming, has been associated with Parkinsonism and also, it was demonstrated that patients who died from PQ poisoning had severe brain damage . This was corroborated by studies, in animals, where besides the affection of the lung which is the main target organ for PQ toxicity, it was also demonstrated to be toxic to dopaminergic neurons . Several mechanisms have been postulated for PQ-induced neurotoxicity, including increase in ROS formation, excitotoxicity, and mitochondrial complex I inhibition . Nonetheless, the mechanisms by which PQ promotes neurotoxicity still remain to be fully elucidated.
2. Materials and Methods
2.1. Materials
2.2. Cell Line and Culture Conditions
2.3. Experimental Protocol
2.4. Life-Death Assays
2.4.1. Lactate Dehydrogenase Kinetic Assay
2.4.2. MTT Assay
2.5. Statistical Analysis
3. Results
Signs Of Paraquat Poisoning
After a person ingests or inhales a toxic amount of Paraquat, he or she is likely to have swelling and pain in the mouth and in the throat.
The herbicide causes immediate damage through direct contact.
What follows are gastrointestinal symptoms, such as:
- nausea
- abdominal pain
- diarrhea that may be bloody
These gastrointestinal problems tend to be severe, and may result in dehydration, low blood pressure, and electrolyte abnormalities.
Even the ingestion of small to medium amounts of Paraquat may cause a person to experience heart failure, kidney failure, liver failure, lung scarring, respiratory failure, and failure of multiple organs within several days to several weeks.
On the other hand, the ingestion of large amounts of Paraquat will result in severe symptoms that may occur within several hours to several days, including:
- confusion
- liver failure
- respiratory failure which could possibly lead to death
Despite these dangers related to the use of the toxic chemical, Paraquat use in the US is still on the rise.
In fact, according to a 2016 report from the National Water-Quality Assessment project, usage of the herbicide in the country has doubled between 2006 and 2016.
That increase in use of Paraquat means that there will also be an increase in exposure to Paraquat, as well as in the harms associated with the chemical.
The bad news?
Cellular Pathophysiology Of Pd
Figure 1. Cellular iron metabolism. Ferric iron is transported into cells via binding to transferrin receptor and subsequent endocytosis, while ferrous iron enters cells through divalent metal transporter1 . Within the endosomes, Fe3+ is reduced to Fe2+ through the action of the six-transmembrane epithelial antigen of the prostate and released into the cytosol via DMT1. Ferritin is served as the intracellular reservoir of iron. In DA neurons, neuromelanin works as the iron storage protein instead of ferritin. Fe2+ stored in ferritin/NM is released into the cytosol as the cytosolic labile iron pool via ferritinophagy. Excess in the cytosolic labile iron pool leads to the export of excess iron via ferroportin. In Parkinsons disease patients as well as PD models, cellular iron uptake and release were increased and decreased, respectively, in DA neurons. Also, ferritinophagy is upregulated in the PD model. All of these contribute to the increase of cytoplasmic labile iron pool, which leads to an increase of ferroptosis susceptibility of DA neurons in PD.
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The Rise Of Parkinson’s Disease
Neurological disorders are the worlds leading cause of disability. And the fastest growing of these conditions is not Alzheimers but Parkinsons disease.
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- The number of people with Parkinsons disease more than doubled from 1990 to 2015 and could double again by 2040. An aging population alone does not account for this rise.
- Air pollution, metal production, certain industrial chemicals, and some synthetic pesticides are linked to Parkinsons. Yet we are doing little to manage known risk factors.
- The authors contend that the United States should ban trichloroethylene, paraquat, and other chemicals linked to Parkinsons, which many other countries have already done.
From 1990 to 2015, the number of people living with Parkinsons more than doubled from 2.6 million to 6.3 million, according to a 2015 study in Lancet Neurology. By 2040, the number is projected to double again to at least 12.9 million, a stunning rise .
The number of people with Parkinsons disease more than doubled between 1990 and 2015 and is projected to double again by 2040.
Figure adapted from E. R. Dorsey and B. R. Bloem, 2018.
Figure adapted from R. Dorsey et al., 2020.
The number of people who succumb to Parkinsons each year has been increasing steadily.
Data from: U.S. National Center for Health Statistics, National Vital Statistics System, Mortality Data.
Christophe Vander Eecken / Reporters / Science Source
Integrated Evidence For Paraquat Hazard Identification
For proper categorization of paraquat in one of the five categories of hazard , evidence coming from human and animal studies will be integrated with mechanistic data that may be relevant to support biological plausibility and increase or decrease the hazard classification.
Among the factors that can support biological plausibility and increase the hazard classification, the magnitude of the effect, the doseresponse gradient, and the direct and indirect consistencies between outcomes from studies with different biological levels will be considered. On the contrary, hazard classification may be reduced by the identification of risk of bias, unexplained inconsistencies between studies with related outcomes, non-relevance of the paraquat mechanism of toxicity to humans and dose levels not relevant to real human exposure.
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Exposure To Paraquat: What Are The Risks
In 1997, the Environmental Protection Agency announced that exposure to Paraquat primarily happens during the application and post-application of the herbicide.
And even though only licensed applicators are given access to the chemical, exposure is still possible for individuals who reside near farms where Paraquat is used.
In which case, Paraquat poisoning is possible.
The Danger Of Paraquat Today
The United States banned DDT, Agent Orange, and heptachlor in the 1970s and 1980s. However, the United States has not banned all pesticides linked to Parkinsons. The one with perhaps the strongest link to the disease is still in widespread use: paraquat.
The United States has not banned all pesticides linked to Parkinsons. The one with perhaps the strongest link to the disease is still in widespread use: paraquat.
Paraquat has been used as a pesticide since the 1950s and is marketed as an alternative to the worlds most popular weed killer, glyphosate, more commonly known as Roundup. Paraquat takes care of weeds that not even Roundup can kill. Today, it is used on farm fields across the United States, and its use continues to increase. The pesticides primary uses are for corn, soybeans, wheat, cotton, and grapes.
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In the laboratory, paraquat reproduces the features of Parkinsons disease. In a 1999 study in Brain Research, A. I. Brooks of the University of Rochester and colleagues gave paraquat to mice, and their activity decreased. Paraquat also killed dopamine-producing nerve cells in the rodents substantia nigras. The greater the amount of paraquat administered, the greater the number of nerve cells lost.
Table adapted from: www.panna.org.
Figure adapted from R. Dorsey et al., 2020.
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What Is Paraquat Used In
Paraquat is a herbicide that is widely used by farmers as a fast-acting weed killer. Its also known by the brand name Gramoxone.
It was first introduced for commercial purposes in 1961, and has since been one of the most widely used herbicides around the world.
In the United States, due to the toxicity of the herbicide, Paraquat is not registered for residential use. It is only available for use by commercially licensed users, or those individuals who have completed an Environmental Protection Agency or EPA-approved training program.
The Centers for Disease Control and Prevention considers Paraquat to be more toxic compared to other herbicides.
The herbicides toxicity can present itself upon inhalation, skin absorption, and ingestion of the chemical.
Aside from poisonings, Paraquat has also been known as a possible cause of cancer and birth defects, as well as Parkinsons disease.
Modelling Pd In Rodents And Simple Organisms
Impaired mitochondrial function is a predominant feature in cases of Parkinson’s disease due to genetic or environmental modifications, which result in mitochondrial stress. This may directly compromise the neuron or cause alterations in neurotransmitter release, resulting in post-synaptic damage. A pro-inflammatory component is increasingly considered to be important in the pathogenesis of several neurodegenerative conditions including PD, and pro-inflammatory activation of glial cells may be pivotal in disease onset.,
Although many of the genes involved in PD have been identified, their interactions are still unclear. Mutations of -synuclein or duplications of -synuclein are linked to familial PD and -synuclein is a component of Lewy bodies. -synuclein tends to form intracellular fibrils and aggregates, particularly after oxidative stress. Loss of an ubiquitin ligase, Parkin, is responsible for autosomal recessive juvenile parkinsonism. Finally, mutations in genes coding for UCH-L1 and Pink-1 are linked to autosomal recessive PD, whereas mutations in LRRK2 are linked with autosomal dominant PD. Recent work has shown that mutations in the mitochondrial protease HtrA2 are also linked to PD downstream of the kinase, Pink 1. Mutations in Parkin are recognized as the most common cause of familial parkinsonism and may be involved in sporadic PD. Parkin seems to work as a broad-spectrum neuroprotectant, the efficacy of which decreases with ageing.
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The Ghosts Of Pesticides Past
Over the past half century, we have begun to identify the worst risks and address them. The insecticide DDT was once considered a miracle compound. In the 1930s, the Swiss chemist Paul Hermann Müller was looking for a chemical that could kill insects that were destroying crops and spreading diseasewithout harming the plants. Müller, a nature lover, tested hundreds of chemicals before coating the inside of a glass box with DDT, a colorless, tasteless, and almost odorless nerve toxin. He placed houseflies into the container, and they bit the dust. Müller had found his answer.
In the 1940s DDT was considered harmless to humans and regularly sprayed on neighborhoods here children play in the sprays at the beach in New York. Even though DDT was banned half a century ago, it persists in the environmentand in our food supply. It becomes more concentrated as it makes its way up the chain to human consumption. The pesticide is then stored in fatty tissues, including the brain. DDT has been linked to Parkinsons disease. Because of the widespread use of the pesticide, DDT and its breakdown products are detectable in nearly everyone in the United States. It has also been found in the breast milk of women living in Spain, Nicaragua, Taiwan, and the Spanish Canary Islands as recently as 2014.
Pictorial Press Ltd/Alamy Stock Photo
We eat fruits, vegetables, nuts, and grains every day that have been doused in pesticides. What kind of risk are we all exposed to? We do not know.
Has Anything Changed Over Time
Since most of the studies concerning PD and rural living were done decades ago, a recent study sought to revisit this issue since farming life has changed in recent times. Pesticide use is reduced, there has been a large migration from rural to urban areas, and there is less dependence on well water in rural communities.
The new study was conducted in Finland and looked at the incidence of PD in rural versus urban areas. Interestingly, rural living remained a risk factor for PD. It is possible that current diagnoses of PD continue to reflect the environmental exposures of decades ago, and that risk reduction in rural areas due to decreased pesticide use and other changes in farming life may show more benefits in the future. However, the study suggests that we may not yet fully understand how the rural environment affects Parkinsons risk.
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Chemical Properties And Distribution
PQ is a member of a chemical class known as bipyridyl derivatives, which includes diquat and cyperquat that has the same structure as the MPTP metabolite MPP+ . One-electron reduction of PQ, , , probably underlies its toxic effects in the lung after accidental ingestion. Reduced PQ is then rapidly re-oxidized to its cation form by molecular oxygen with the formation of superoxide radicals in a classical redox-cycling reaction.
Because PQ is highly polar, it is poorly absorbed from the gastrointestinal tract. Over 50% of a single dose administered to rats localizes to the gut at some 32h after administration and only approximately 5 to 10% of an ingested dose is absorbed, although the presence of emulsifiers and/or co-solvents may enhance absorption. Excretion occurs in urine and faeces with approximately 45% of a single dose being excreted after 48h in rats. Because of these properties and some early evidence that PQ is largely excluded from the brain, it has been assumed that PQ would not cross the blood-brain barrier to a significant extent. After a single administration, most of the PQ that reaches the brain is apparently associated with structures outside the BBB or with three areas of the brain: the anterior portion of the olfactory bulb, the hypothalamus and the area postrema, which do not have a tight BBB.
Specific Pesticides And Their Link To Pd
The evidence that pesticide use is associated with an increased risk in PD, begs the question are there specific pesticides that are most concerning? When data is collected on this topic in large populations, often the participants in the study are unaware of which specific pesticide exposures they have had. This makes it difficult to determine which pesticides to avoid.
Some studies however were able to investigate the risks of specific chemicals. A recent review summarized the current state of knowledge on this topic. The chemical with the most data linking it to an increased PD risk is paraquat, with exposure associated with a 2-3 fold increased PD risk over the general population.
One particularly comprehensive study investigated exposure to 31 pesticides and their association with PD risk. From that data emerged paraquat and rotenone as the two most concerning pesticides.
- Paraquats mechanism of action is the production of reactive oxygen species, intracellular molecules that cause oxidative stress and damage cells.
- Rotenones mechanism of action is disruption of the mitochondria, the component of the cell that creates energy for cell survival.
Interestingly, both mitochondrial dysfunction and oxidative stress are common themes in our general understanding of what causes death of nerve cells in PD.
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Chemically Induced Models Of Parkinsons Disease: History And Perspectives For The Involvement Of Ferroptosis
- Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
Ferroptosis is a newly discovered form of necrotic cell death characterized by its dependency on iron and lipid peroxidation. Ferroptosis has attracted much attention recently in the area of neurodegeneration since the involvement of ferroptosis in Parkinsons disease , a major neurodegenerative disease, has been indicated using animal models. Although PD is associated with both genetic and environmental factors, sporadic forms of PD account for more than 90% of total PD. Following the importance of environmental factors, various neurotoxins are used as chemical inducers of PD both in vivo and in vitro. In contrast to other neurodegenerative diseases such as Alzheimers and Huntingtons diseases , many of the characteristics of PD can be reproduced in vivo by the use of specific neurotoxins. Given the indication of ferroptosis in PD pathology, several studies have been conducted to examine whether ferroptosis plays role in the loss of dopaminergic neurons in PD. However, there are still few reports showing an authentic form of ferroptosis in neuronal cells during exposure to the neurotoxins used as PD inducers. In this review article, we summarize the history of the uses of chemicals to create PD models in vivo and in vitro. Besides, we also survey recent reports examining the possible involvement of ferroptosis in chemical models of PD.
Who Is At Risk Of Paraquat Exposure
Field and Agricultural workers who have used Paraquat are most likely to feel the effects of exposure with the chemical.
Since Paraquat is primarily used as a spray, the EPA has claimed it can also pose a threat to bystanders via spray drift, making Paraquat toxic not only to workers, but those living near farms and facilities that use Paraquat products.
Other herbicides that contain paraquat dichloride are recognizable under brand names like
-
Gramoxone
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Nih Study Finds Two Pesticides Associated With Parkinsons Disease
New research shows a link between use of two pesticides, rotenone and paraquat, and Parkinson’s disease. People who used either pesticide developed Parkinsons disease approximately 2.5 times more often than non-users.
The study was a collaborative effort conducted by researchers at the National Institute of Environmental Health Sciences , which is part of the National Institutes of Health, and the Parkinson’s Institute and Clinical Center in Sunnyvale, Calif.
“Rotenone directly inhibits the function of the mitochondria, the structure responsible for making energy in the cell,” said Freya Kamel, Ph.D., a researcher in the intramural program at NIEHS and co-author of the paper appearing online in the journal Environmental Health Perspectives. “Paraquat increases production of certain oxygen derivatives that may harm cellular structures. People who used these pesticides or others with a similar mechanism of action were more likely to develop Parkinson’s disease.
There are no home garden or residential uses for either paraquat or rotenone currently registered. Paraquat use has long been restricted to certified applicators, largely due to concerns based on studies of animal models of Parkinson’s disease. Use of rotenone as a pesticide to kill invasive fish species is currently the only allowable use of this pesticide.
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