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Presented by Bennette King, Matt Segura, Matt Simmons, and Sarah Matte

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This presentation will cover: Basic geologic and biological implications of Arsenic Historical significance Natural and man made sources Kinetics regarding absorption and excretion And the mechanisms of action and the effects on body tissues and organs.

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Arsenic is a naturally occurring silver metalloid Two main types: organic and inorganic Accumulates in Earths crust: gets into food and water sources Is also present in small concentrations in the atmosphere. Image from: http://www.galleries.com/Arsenic

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Organic arsenic is a naturally present element in Earths crust, mineral deposits, and local bedrock Due to many stable oxidative states of organic arsenic, it can dwell in many minerals at different pHs. Gold mining releases arsenic to the environment due to the fact that they co-reside together in mineral deposits.

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Synthesized by laboratory means Has extremely long half-life Is utilized in fertilizers Those fertilizers are then used to nourish food crops. One crop that has extremely high concentrations of inorganic arsenic is rice Water supplies that are used to hydrate crops foster the absorption of water-soluble arsenic into the root, and eventually the hulls of the rice grains during growth.

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http://www.sciencedirect.com/scienc e/article/pii/S037842740200084X Arsenate being the more reactive and toxic http://www.2the4.net/assets/images/MOLECUL E.GIF

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Inorganic arsenic is contaminating food sources through out the world. Pesticide run off soaks into the rock layer where the water table dwells, contaminating water sources as well as food. Arsenic, both organic and inorganic forms, is toxic http://students.cis.uab.edu/fauzia/arsenic1.jpg http://3.bp.blogspot.com/_QdDgbVlfeAg/TAGA Kc165nI/AAAAAAAAAZM/0_BczlPbaug/s1600/a rsenic-hands.jpg

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Arsenic has been used for years as Pesticide Chemotherapy agent Treatment for eczema, psoriasis, malaria, and syphilis Homicidal agent (poison)

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Arsenics toxic use really became popularized in the Middle Ages Dubbed King of Poisons Used by Florences Medici Family to eradicate rivals Arsenic was the element used to kill French Emperor Napoleon Bonaparte Used by Madam LaFarge whose was charged with poisoning her husband via arsenic cakes http://farm9.staticflickr.com/8188/8127555423_a3082b0fda_z.jpg

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Arsenic, as a basic element, is toxic to most organic life by itself, however it is extremely reactive and produces many chemical species that are even more toxic, such as Arsine. Arsenic and its derivatives are toxic by ingestion, injection (both subcutaneous and intramuscular) and by inhalation of arsenic dust. The rate of absorption via the respiratory tract is based on the size of the particles and the ease that they cross over into the blood stream due to solubility factors. Arsenic oxidizes readily when heated in air, conditions easily found in labs or mining operations, and produces toxic fumes that are very quickly absorbed within the respiratory system. Arsenic is also able to enter the body via dermal absorption, with different levels of effective absorption based on chemical species of the arsenic compound. Arsine (AsH3) image taken from: http://upload.wikimedia.org/wikipedia /commons/4/44/Arsine.png

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Inorganic arsenic compounds are metabolized using two main reaction types: These reactions process the arsenic into DMA and MMA (mono- and di- methyl arsenic), which are easily processed in the kidneys to the urine.

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Most inorganic arsenic is processed and eliminated via the urine in most animal species via the kidneys. In adult males, 45-75% of ingested arsenic is reported to have been excreted in urine within the first day to within a week. Fecal matter is also a major route of excretion, as some arsenic material is never absorbed in the gastro intestinal tract (different rates of absorption between arsenic species is mainly determined by the compounds solubility, with highly soluble molecules being absorbed more readily) Sweat, to a very minor degree, as well as breast milk in lactating females also play a very small role in excreting arsenic. Arsenic tends to accumulate in keratin tissues, such as hair, nails, and skin, isolating the compounds away from the blood stream and serving as a containment/excreting system (to a very small degree)

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Commonly ingested as Arsenobetaine, or fish arsenic, in humans after eating any number of marine fish or crustaceans. Unlike inorganic arsenic compounds, organic arsenicals are rapidly and almost entirely absorbed via the gastrointestinal tract. Very little data exists concerning the dermal or inhalation routes of arsenic exposure, however laboratory animals have shown that organic arsenic is also absorbed via these routes, although to a much less degree. Images taken from: http://steelturman.typepad.com/photos/uncategorized/arsenic_fish_carp_poison_war ning.png http://steelturman.typepad.com/photos/uncategorized/arsenic_fish_carp_poison_war ning.png http://www.undercurrentnews.com/2012/11/14/danish-shrimp-trawlers-on-enhanced- control-in-russia/ http://upload.wikimedia.org/wikipedia/commons/thumb/a/a3/ArsenobetainePIC.svg/ 160px-ArsenobetainePIC.svg.png

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Most organic arsenicals in the forms of MMA and DMA are excreted as it, or processed by further methylation into DMA and TMA (in limited amounts) to also be excreted via urine TMA is also subjected to in vivo redox reactions to yield TMAO, which is rapidly excreted out in urine. Additionally, some TMA is excreted with exhaled air, but this amount is unquantified and under further investigation. Arsenobetaine is excreted in urine normally, without demethylation or any noted biotransformation. In fact, some other organic arsenics are extensively processed to arsenobetaine to be eliminated.

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It is metabolized by reduction/methylation, catalyzed by glutathione-S- transferase omega-1 (GSTO1) and arsenic (III) methyltransferase. GSTO1 reduces Arsenate Arsenite Arsenite is detoxified by arsenic (III) methyltransferase (liver) methylarsonate and dimethylarsinate http://fc00.deviantart.net/fs43/i/2009/075/e/b/La b_Rat_by_OralGiacomini.jpg

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ATP synthase is a multi-subunit, protein complex that catalyzes the phosphorylation of ADP to ATP at the expense of a protons generated by an electron transport chain in energy generating membranes. Arsenate mimics the - phosphate of ATP. It inhibits ATP synthesis at the active site of ATP synthase by competing with phosphate. http://upload.wikimedia.org/wikipedia/comm ons/thumb/0/00/Atp_synthase.PNG/300px- Atp_synthase.PNG

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Arsenate blocks the Pi H2O exchange and also the ATP Pi exchange catalyzed by ATP. Thus arsenics binding to an ADP molecule or competing with the gamma subunit of ATP will prevent cellular respiration from occurring properly, resulting in energy loss and possibly cell death. http://biochem.co/wp- content/uploads/2010/02/glycolysi s-simple.png

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Leads to Chromosome aberration and defects.

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Conversion of pyruvate to acetyl CoA is used during tissue respiration via: pyruvate dehydrogenase complex. Arsenic alters the enzymes in this complex so that Acetyl CoA and CoASH do not form.

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arsenate reacts with glucose and gluconate to form glucose-6-arsenate and 6-arsenogluconate. These compounds resemble glucose-6-phosphate and 6-phosphogluconate. Glucose-6-arsenate is a substrate for glucose-6- phosphate dehydrogenase and can inhibit hexokinase.

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The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is vital for facilitating normal functions of different cytokines within the hematopoietic and immune system.

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Sodium Arsenite directly inactivates the JAK tyrosine kinase protein, thus inhibiting STAT 3 activation, which regulates tyrosine phosphorylation. It activates map K activity How this affects tissues is not completely known.

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Arsenic attacks at the cellular level in a very nonspecific way Therefore every organ system is effected We'll cover the fun ones Heart GI/Hepatic Reproductive Neurologic Renal

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Cardiogenic Shock Vascular permeability Cardiomyopathy Hypertension (chronic exposure) Arsenic in gas form causes Hemolysis evateuling.blogspot.c om

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Hemorrhagic Gastroenteritis Permeability Hepatitis Hepatic Necrosis acute exposures medical- dictionary.thefreedictionary.com

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Encephelopathy Hepatic failure permeability (yet again) Neuropathy Axon Destruction Pain/numbness to limbs Loss of vision

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Acute Renal Failure Tubular necrosis perfusion due to cardiovascular symptoms High As accumulations leads to cancers www.osmonicwater.c om

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As easily crosses the Placenta Toxic to fetus 'Spontaneous' abortions Tetrogenic effects (most fetuses don't make it to birth)

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Hopefully this presentation provided you with more information concerning this poisonous element, particularly in the areas of: Natural sources and forms of Arsenic Historical use and significance Kinetics concerning absorption and excretion Metabolism The effects of arsenical compounds on the bodies tissues and organs.

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Arsenic in your food. 11.2012. ConsumerReport.org. Arsenic. Mechanics and Kinetics. April 16, 2013. Wikipedia: The Free Encyclopedia. http://en.wikipedia.org/wiki/Arsenic. Arsenic: Occupational Safety and Health Administration. 03.21.2012. OSHA. Cheng H.Y., Li. P., David M., Smithgall T.E., Feng L. Lieberman M.W. 2004. Arsenic inhibition of the JAK-STAT pathway. Nature Publishing group: Oncogene. 23, 36033612. Hughes M.F. 2002. Arsenic toxicity and potential mechanisms of action. Elsevier;Toxicology Letters. Volume 133, Issue 1: 116. Pelicano H., Martin D.S., Xu R-H., Huang P. 2006. Glycolysis inhibition for anticancer treatment. Nature Publishing group: Oncogene. 25, 46334646.