Quiz 3- Lectures 7,8,9 Flashcards
Bangladesh Arsenic poisoning
- There are naturally occurring sources of arsenic in the ground all over the world
- Prior to 1970s, Bangladesh was having a lot of infant modalities due to ineffective water treatment (dirty water) and sewage removal
- UNICEF invested in millions of water wells for Bangladesh that sourced water deep in the earth
- A problem, however, was that approximately 1 in 5 of these wells tapped into arsenic contaminated water sources, leading to many of the people of Bangladesh to get arsenic poisoning
- WHO set the acceptable arsenic levels in drinking water at 0.01 mg/L, but the government of Bangladesh set it at 0.05 mg/L b/c they couldn’t meet WHO’s requirements
- Still, 7 in `19 of the districts in Bangladesh had levels above 0.05
Symptoms of arsenic poisoning
- Arsenic poisoning can lead to skin diseases/conditions such as blackfoot disease and keratosis
Biggest exposure to toxicity
- Environmental exposure, thorough hazardous waste?
Lead poisoning in Flint, Michigan
- In efforts to get cheaper water, Flint, Michigan started sourcing its water from its own lake?
- The water itself didn’t have lead in it, but it was relatively acidic, and when it traveled through the pipes it leeched lead out of the pipes
Symptoms of Lead poisoning
Acute poisoning
- Typical neurological signs are pain, muscle weakness, and paraesthesia, and rarely symptoms associated with encephalitis
- Other symptoms include abdominal pain, nausea, vomiting, diarrhea, and constipation
Chronic poisoning
- Usually presents itself with symptoms affecting multiple systems, but is associated mainly with three main types of symptoms/problems: gastrointestinal, neuromuscular, and neurological
- Lead poisoning can also lead to problems with vision, taste, central nervous system, reproductive organs, and even kidney failure
Mechanisms of Lead Toxicity
- Lead toxicity can activate oxidative stress due to a generation of reactive oxygen species (ROS)
- It can also deplete antioxidant reserves
- ROS can react with and destroy all kinds of compounds in your body, especially proteins, lipids, and DNA
- Lead ions can also damage the body by messing up ionic mechanisms: lead can replace other bivalent ions, such as Ca2+, Mg2+, and Fe2+, even in picomolar concentrations of lead.
- This can lead to major problems in the brain, as well as other neurological problems
- Lead is absorbed by the normal transport system of Iron
- B: Lead can bind to sulfhydryl and other active sites in many enzymes, leading to inactivation
- Heavy metals like mercury and lead are able to be transported around the body more easily than other toxins b/c they can be mistaken for nutritionally essential metals due to their similarities
Examples of Environmental Exposure
Paper Production
- Big source of contamination and waste
- Use lots of chlorine based bleaches, which get released into the environment
- Are situated near sources of water to cool down the chemical reactions taking place, and effluent often gets released into the bodies of water
- Are often situated near railroads and use railroads a lot to get the supplies they need quickly, and railroads pose their own problem
Railroads and Railyards
- Also a source of hazardous waste
- People who live in close proximity to rail yards have a much higher risk of getting cancer
Logging
- Biggest source of water pollution, after agriculture
Herbicides
- Typically contain dioxide/dioxin molecules to kill weeds
- Have been shown to kill birds as well
- “Agent Orange”
- Furans are other commonly used compounds in herbicides
Effluent
- liquid waste or sewage discharged into the river or sea (online def)
Dioxins
- Is a an environmental contaminant
- “Dioxin” refers to a group of molecules that have a 3-ring structure and contain carbon, oxygen, nitrogen, and chlorine
- Are part of a class of compounds referred to as the “dirty dozen,” and is an organic compound found in many manufacturing industries
- It has the ability to affect many different mechanisms in the body, like lead
- We say it has “highly potentiated toxic effects”
- They are hydrophobic, meaning they can go into the fat and stay there for a very long time period because fat tissues aren’t well perfused
- The half life of dioxins is between 7-11 YEARS
- Dioxins can get into the animals we eat, and can get passed on through the food chain
Highly potentiated toxic effects
- Something that can affect many different mechanisms/aspect of the body, such as lead and dioxins
Seveso _______ Contamination
- Dioxin
- A Top 10 World environmental disaster
- There was a chemical leak/explosion
- 3,000-4,000 livestock died within 24 hours, and up to 80,000 cattle had to be euthanized so the toxin didn’t get into the food supply
- Many children the lived around the area developed chloracne within 10 days
Mercury poisoning effects
- There are many different forms of mercury, and they each have different effects on the body
- The form we are most concerned about/see most often is methyl mercury
- Methyl-mercury can affect the fetus by affecting limb development, leading to lots of deformities
- Symptoms of mercury poisoning can include high fever, convulsions, psychosis, loss of consciousness, coma, and finally death
- While methyl-mercury is bad, dimethyl-mercury is even worse, as it is very good at penetrating the blood-brain barrier
- Dimethyl mercury is what Karen wetterhahn was exposed to
Mechanisms of Mercury poisoning
- Methyl-mercury tends to be absorbed through the intestine due to consumption, or through the skin, both of which are fairly effective ways of it getting absorbed
- Upon entry to the bloodstream, methyl-mercury interferes with sulfhydryl (thiol) groups, particularly those in cysteine
- Methyl-mercury is deposited throughout the body with equilibrium between blood and body occurring approximately four days after exposure
- Methyl-mercury tends to concentrate in the brain, liver, kidneys, placenta, peripheral nerves, bone marrow, and fetus, especially the fetal brain
- The distribution of methyl-mercury to the peripheral tissues seems to occur through one of more transporters, especially in the cysteine transporters, probably adhering to the sulfhydryl group in the cysteine
- The excretory half-life of methyl-mercury in human is about 70 days, with approximately 90% being excreted in stools
- That being said, these heavy metals, like mercury, are difficult to flush out of the body, and once inserted into the TISSUES, it is very difficult to get out
- B: Mercury can interfere with heme synthesis
Superfund and Love Canal Case
Background:
- Man-made waterfall near Niagara Falls was made to provide cheap electrical power, so lots of chemical plants started popping up
- One was the hooker chemical corp, which used it as a chemical landfill for 20+ years, dumping halogenated organics, pesticides, chorobenzenes, and dioxins
- Filled up the land once done with it and later sold it to the Niagara Board of Education, and the 99th street elementary school was built
- Houses started to pop up near the school as well, since this is where their children are going to school
Problem:
- Lois Gibbs kid was sick, and she found it the school was built on top of a hazardous waste site, so she got the community involved
- The school got shut down and the state began buying out houses
- This started the superfund, also called CERCA, which provided annual? government inspections of land all across America
Love Canal Toxicities:
- There was an unusually high number of newborn deformities, blood disease, cancer, epilepsy, and hyperactivity
- Miscarriage rate was 50% in the mid 1960s, but went down 29% in 78, which is still really high
Stages in the Development of Toxicity: Overview
- Toxic effects can be elicited at almost any stage on the way to the main/end result toxicity
- First you are exposed to a toxicant
- The toxicant is then distributed throughout the body to its target molecule, and during this distribution, it can elicit a toxic effect from some mechanism
- Once the toxicant interacts with its target molecule, it can lead to cellular dysfunction, which can lead to toxic effects through some mechanism
- This cellular dysfunction can then potentially lead to dysrepair, which leads to a toxic effect
- Another end result that can be brought on by cellular dysfunction is cellular dysregulation of signal transduction pathways
Mechanism of Toxicity: Broad Overview
- Someone is first exposed to a toxicant, whether it be though the skin, GI tract, respiratory tract, injection/bite site, or placenta
- The toxicant then makes its way to its target molecule, which it will interact with as the ultimate toxicant, which could be what it exists as when it enters the body, or could be an alteration of it made by the body
- The target molecule can be a protein, lipid, nucleic acid complex, etc
-On its way to the target molecule, some processes contribute to its toxic effect, and some oppose it
Contribute: - Absorption, especially via the lipids, can help
-Distribution towards the target molecule via transporters
-Reabsorption in the ERC, and kidney when they are trying to excrete it
-Toxication, via biotransformation
Oppose: - Pre-systematic elimination due to the first pass effect
- Distribution away from target, by binding plasma proteins, like albumin
- Excretion: the route and speed of excretion of toxicants is largely depended on the physicochemical properties of the toxicants. For example, the major excretory organs, the kidney and liver, and only efficiently remove highly hydrophilic compounds, so lipid soluble compounds typically take much longer to be excreted out
-Detoxification
Ultimate Toxicant
- The chemical that reacts with an endogenous molecule or alters the biological environment resulting in toxicity. It may be a metabolite or byproduct of the primary toxicant to which the organism is exposed
Biotransformation: Induce or Oppose Toxicity?
Induce Toxicity
- The body may transform the toxicant you take in to an even more toxic/reactive species through biotransformation
- This increased reactivity may be due to conversion to electrophiles, free radicals, nucleophiles, or redox-active reagents
- Ex: Radical O2 (superoxide ion) is very reactive, as it can produce three other radicals via reactions
- Original toxicant itself may cause toxic effects other than its “main” effect through the overall toxicant pathway ending in either cellular dysfunction or dysrepair b/c toxicants are often times promiscuous/broadly reactive
Oppose Toxicity
- Body may undergo biotransformations that eliminate the ultimate toxicant, or prevent its formation (detoxification)
- Detoxification can include adding functional groups by P450s and coupling with endogenous acids, masking the nucleophilic region of the toxicant via conjugation of some other group, or conjugation of electrophilic toxicant to the nucleophile, since the nucleophile is generally less reactive?
Biotransformation
- Chemical alteration of a substance, typically a drug, within the body
Detoxification
- Def: biotransformation that eliminates an ultimate toxicant or prevents its formation
- Generally involves metabolism
- For toxicants with no functional groups: Can add function groups by P450s and then couple to an endogenous acid like glucaronic acid, or an amino acid. The final product is an inactive, highly hydrophilic organic acid that is readily excreted
- For nucleophilic toxicants: Can undergo conjugation of the toxicant’s nucleophilic atom with a functional group to make it non-reactive (eg sulfonation, glucaronidation, methylation).
- For electrophilic toxicants: Can undergo conjugation of electrophilic toxicant to the nucleophile
- For free radicals: superoxide dismutases (SOD) can help, as can peroxidases and peroxisomes
Endogenous
- having an internal cause or effect
- I think the term “endogenous acids” refers to acids the body naturally makes?
Target Molecules of Toxicants
- Toxicants are very promiscuous, and usually go after biomolecules such as proteins, nucleic acids, and lipids, and they can also affect metabolism by interacting with P450s
- Toxicants can interact with their target molecules via non-covalent binding (such as ionic interactions, non-polar interactions), covalent binding, hydrogen bonding, electron transfer, enzymatic reactions, etc
- Interaction of a toxicant with its target molecule can lead to outcomes such as dysfunction, destruction, and neoantigen formation, which is the induction of the immune response
Neoantigen formation
- Induction of the immune response
- Can be an outcome of toxicants interacting with target molecules.
Covalent interactions
- Typically, interactions between electrophiles and nucleophiles
- Electrophiles are electron loving, and are typically positively charged, polarizable, or have an empty orbital or breakable bond
- Nucleophiles are nucleus loving, react with positively charged atoms, and typically have lone pairs of electrons or pi bonds
- This is one of the mechanisms of interaction that toxicants can have with their target molecule
- Toxicants that are electrophiles tend to be more toxic/reactive thats those that are nucleophiles for some reason
- These interactions are especially problematic because the are practically irreversible
Xenobiotics
- Substances that are foreign to the body, or to an ecological system
Effects of Toxicants
Effects of toxicants on target molecules include:
-Dysfunction of target molecules
-Destruction of target molecules
- Neoantigen formation
Toxicity can also be initiated without interactions with target molecules by altering the biological microenvironment:
- Alter H+ ion concentrations
-Can be a solvent/detergent that disrupts the lipid bilayer and destroys transmembrane gradients
- Some can cause harm by simply occupying a site or space
Target Molecule Dysfunction
- One of the outcomes of the toxicant interacting with the target molecule
Dysfunction can be brought on by the toxicant: - Mimicking endogenous molecules
-Inhibiting function of molecules/transmitters/enzymes
-Altering the structure of a protein through covalent binding so the protein can no longer perform its function
-Altering DNA template through covalent binding, leading to the template being misread, or mutation occurring. The covalent binding of chemicals to DNA causes nucleotide mispairing during replication
Target Molecule Destruction
- One of the outcomes of the toxicant interacting with the target molecule
Types of destruction toxicants can bring about include: - Cross-linking: formation of disulfide bonds between cysteine residues in a protein by converting them into radicals? to change the protein’s shape, potentially making it non-functional
-Promoting fragmentation by HO radicals, which can attack the 4’ carbon of purines and pyrimidines (DNA fragmentation) - Induce lipid peroxidation, which is the degradation of lipids (mainly polyunsaturated fatty acids) via radicals
- So it looks like the formation of radicals by a toxicant is a main cause of destruction
How alteration of target molecules by toxicant can lead to Cellular dysfunction and/or dysregulation
For Target molecules involved in cell regulation (signaling):
- Toxicants can lead to the dysregulation of gene expression. This can lead to inappropriate cell divisions –> neoplasia, teratogenesis, inappropriate Apoptosis –> tissue involution, teratogenesis, and/or inappropriate protein synthesis, such as peroxisome proliferation
- Can lead to dysregulation of ongoing cell function, such as inappropriate neuromuscular activity, like tremors, convulsions, paralysis, etc
Ex. Thalidomide, which was once used as a sleeping pill for pregnant women that led to deformities in the children, dysregulates gene transcription via DNA methylation
For Target molecules involved in Cell Maintenance:
- Can lead to impaired internal maintenance, which can lead to cell injury/death. The three main biochemical ways chemicals can inflict cell death are by depleting ATP, introducing a sustained rise in intracellular Ca2+, and promoting an overproduction of ROS
- Can lead to impaired external maintenance, such as impaired function of integrated systems, and impaired homeostasis mechanisms. Toxicants can do so by interfering with cells that are specialized to provoke support to other cells, tissues, or the whole organism. For example, chemicals acting on the liver invoke this kind of toxicity
Teratogenesis
-the process by which congenital malformations are produced in an embryo or fetus
