Arsenic Poisoning Brandon, Victoria, Rini, and Kevin - PowerPoint Presentation

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Arsenic Poisoning

Brandon, Victoria, Rini, and Kevin

PHM142

Fall 2019

Coordinator

: Jeffrey Henderson

Arsenic: Sources and Human Exposure

Natural Sources

Arsenic is most abundant in the earth’s crust, usually in the form of arsenopyrite.

However, small amounts of arsenic are present in the soil, air, and groundwater.

Human action (leaching from mining, dumping of industrial wastes, and arsenical pesticides) has increased the abundance of arsenic in the soil, air, and groundwater

Arsenic: Sources and Human Exposure

Due to human action, arsenic has become more prevalent in our agricultural practices and our food supply; this plays a significant role in our level of exposure to arsenic.

Human Exposure

Dermal contact with arsenic-containing products

Inhalation of airborne arsenic compounds

Ingestion of arsenic contaminated water and food

Distribution

Once absorbed, inorganic arsenic distributes to the circulation where it reaches the kidneys, the liver, and the testes.

Arsenic: Toxic Forms

After exposure, arsenic exists in two forms: inorganic arsenic and metabolized organic arsenic.Both are able to cause toxicity within the human body.(The evidence on the toxicity of organic arsenicals is premature)

Inorganic Arsenic

Two forms based on their oxidation state: As III and As V

Organic Arsenic

Inorganic arsenic can be metabolized into organic forms (monomethylated arsenic and dimethylated arsenic) via a series of methylation and reduction reactions that occurs in the liver.

Four mechanisms of arsenic toxicity/poisoning

Production of ROS

NADPH oxidase activation by arsenic Arsenic interacts with p22-phox subunitElectron is transferred from NADPH to O2

Production of ROS

Oxidation of NADPH and production of Superoxide Radical

Production of ROS

The many fates of superoxide

Production of ROS

ETC disruption results in: Electron build up + leak, leading to creation of ROSuncoupling of ATP production

Binding to Vicinal Thiols

What are vicinal thiols?Which form of arsenic is responsible?Trivalent arsenic is able to interact with enzymes that contain 2 cysteine residues in its active siteOxidation of these residues results in the inactivation of these enzymesTargeted enzymes are associated with oxidative processes:Pyruvate dehydrogenase (important in glycolysis)Thioredoxin (aids with oxidative stress in cells)Binding of arsenic to the cysteine residues of important enzymatic active or catalytic sites can lead to enzyme dysfunction.Enzyme dysfunction will eventually lead to cell death

thioredoxin

Zinc-Finger

What are zinc-finger proteins? Three mechanisms in which organic arsenic can cause damage to zinc-fingers Organic and inorganic arsenic compete with zinc ion Causes oxidative stress Organic arsenic may engage in both activities and cause dysfunctionality of zinc-finger proteins

Disruption in these proteins can lead to problems in cellular gene expression and DNA repair

Estrogen ReceptorsArsenic exposure can lead to reduced estrogen mediated signalling and lower gene expression of ERE causing disruptions in human reproductive, skeletal, adipose, and cardiovascular systemsPARP-1 and XPA proteins required for DNA repair get damaged Chronic poisoning leads to absence of nucleotide excision repair

Carcinogenicity

Arsenic is able to be a direct genotoxic compound and a chemical promoter. However, the exact mechanisms are unknown. Studies have shown:Organic arsenicals cause mitochondrial dysfunction -- contributing to oxidative stress that can interfere with DNA repair or activate oncogenic pathwaysOrganic arsenicals deplete the activity of S-adenosylmethionine (SAM) which can have profound epigenetic changesIARC lists arsenic as a known carcinogen -- associated with skin, lung, bladder, kidney, liver, and prostate cancers

SUMMARY SLIDE

Arsenic is ubiquitous in soil, water, and airArsenic exposure through consumption of arsenic contaminated food and waterOrganic and inorganic arsenic can cause poisoning/toxicity

Mechanism

Brief Explanation

Toxic Consequences

ROS Production

Increased ROS through NAPDH oxidase (Nox) activation

Dysregulation of mitochondrial ATP production through interruption of ETC complex II and IV

ROS-mediated cytotoxicity & Energetic Imbalance

Oxidation of Vicinal Thiols

Causes enzyme dysfunction as arsenic oxidizes thiol residues necessary for catalytic function

Cytotoxicity, apoptosis of various tissues

Interruption of Zinc Fingers

Causes DNA binding proteins to dysfunction, disturbing gene expression and DNA repair

Absence of nucleotide excision repair

Carcinogenicity

Can cause epigenetic changes that promote tumor development (alteration of methylation, global hypomethylation)

Skin, lung, prostate, kidney, liver cancers

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