Week 3: Toxicology, Genes, Genomics, and Environmental Health Flashcards
Define toxicology.
The study of adverse effects of chemicals on biological systems
What is the difference between a toxin and a toxicant?
A toxin has a natural origin and a toxicant is synthetic
What important quote did Paracelcus say in the 1500s? How true is his statement
“The dose makes the poison”
Mostly true but some chemicals toxic at low doses, with no increase in toxicity at higher doses
Identify the examples of different toxicity effects at the 7 levels of a human.
Molecule: DNA mutations due to radiation or chemical mutagen
Organelle: mitochondrial disruption due to pesticide exposure
Cell: cellular loss due to apoptosis from toxicant exposure
Functional unit: infertility due to damage to supportive Leydig cells in testes
Organ: renal failure due to heavy metal exposure
Body: weight loss due to impaired nutrient absorption in gut
Population: increased cancer incidence due to exposure to arsenic
Define the dose-response curve.
A visual representation of the response rate of an individual/group/population through a range of doses of a particular substance (a toxin or therapeutic drug)
Define ED-50 and TD-50. What should the relationship between them look like?
ED-50: effective dose 50%; the dose that causes an effect in 50% of the population of observed subjects
ED-50 of aspirin would be the dose that relieves headaches in 50% of the people
TD-50: toxic dose 50%; the dose that is toxic to 50% of the population
Often used to indicate responses such as reduced enzyme activity, decreased reproductive success, or onset of specific symptoms
ED-50 should be much smaller than LD-50 or TD-50 and LD-50 and TD-50 should be as high as possible
Give 3 details about the dose-response curve.
How individuals will respond to a chemical is not known
Instead predictions made about
how a percentage of the population will respond to a specific dose
Dose at which 50% of the population dies is LD-50 (lethal dose 50)
Give 4 details about the dose-response curve regarding a particular chemical.
For a particular chemical, there may be a whole family of dose–response curves
Which dose is of interest depends on what is being evaluated
Overlap between the therapeutic dose (ED) and the toxic dose (TD); a slight increase in dose can have adverse effects
The greater the therapeutic index, the safer the drug
Define the therapeutic index.
The ratio of the toxic dose 50% to the efficacy dose 50%
The larger the therapeutic index, the safer the drug
Describe how timing and exposure can affect the dose-response relationship.
Can be influenced by timing and exposure route (adults vs fetus, oral vs dermal) and window of susceptibility
For a fetus, the primary exposure route is the placenta, which makes a fetus much more sensitive to toxic effects
For the route of administration, the pesticide chlorpyrifos, an organophosphate is ten times more toxic via oral administration than via dermal application
What is BPA? Why is it important?
BPA: organic chemical compound used as a building block for polycarbonate plastics, which are used in products like medical devices, reusable water bottles, and eyeglasses
People are exposed to BPA via 3 routes: oral, inhalation, and dermal
Oral is the most predominant route due to leaking into ingestible substances from containers
BPA levels in blood have been associated with a variety of conditions in women including obesity, endometrial hyperplasia, recurrent miscarriages, abnormal karyotypes, and polycystic ovarian syndrome
What are the 3 classifications of toxicants?
Chemical class (heavy metals, alcohols, solvents)
Source of exposure (industrial pollutants, waterborne toxicants, and pesticides)
Effects on human health (hepatoxic and neurotoxic)
Define environmental toxicology.
Studies toxicants that come from or are discharged into the environment, and health effects on humans, animals, and ecosystems
List the 6 types of toxicants and give examples of them.
Carcinogens: cause cancer
Examples: radiation, benzene, nitrosamaine
Mutagens: cause mutations in DNA
Examples: radiation, bromine, benzene, ROS
Teratogens: cause birth defects Examples: alcohol, phenytoin
Allergens: cause unnecessary immune response
Neurotoxins: damage nervous system
Endocrine disruptors: interfere with hormones
Examples: DDT, dioxin, PCBs
Why are animals studied in environmental toxicology?
Animals are studied for their own welfare and they act as “canaries in a coal mine” to warn of effects on humans
Give an example of a teratogen. What mechanism does it use to affect the body?
The drug thalidomide, used to relieve nausea during pregnancy, turned out to be a potent teratogen, and caused
thousands of birth defects before being banned in the 1960s
It binds to guanine-rich sites in DNA
Explain how chemicals can disrupt the endocrine system.
Some chemicals, once inside the bloodstream, can “mimic” hormones
If molecules of the chemical bind to the sites intended for hormone binding, they cause an inappropriate response
Thus these chemicals disrupt the endocrine (hormone) system
Examples: DDT and the bird population; thyroid and PCB
What routes can toxicants take through the environment?
Surface water and groundwater can accumulate toxicants
Runoff from large areas of land drains into water bodies, becoming concentrated
Toxicants in groundwater or surface water reservoirs used for drinking water pose potential risks to human health
Volatile chemicals can travel long distances on atmospheric currents
PCBs are carried thousands of miles from developed nations of the temperate zone up to the Arctic, where they are found in tissues of polar bears and seals
Give 3 details about persistence in chemicals.
Some chemicals are more stable than others, persisting for longer in the environment
Examples: DDT and PCBs
Temperature, moisture, sun exposure, etc., affect rate of degradation
Most toxicants degrade into simpler breakdown products; some of these are also toxic
Define and list the steps in toxicokinetics.
Toxicokinetics: the study of how a chemical is absorbed, distributed, metabolized, and excreted by the body
Absorption: chemicals gaining access to the inside of the body
Distribution: chemicals moving within your body to various organs
Metabolism: chemical processing facilitate elimination
Excretion: elimination from the body via urine, feces, and exhaled breath
Give 5 details about absorption and distribution.
Solubility of a toxicant affects its absorption:
hydrophilic (water loving, polar) compounds are easily excreted in urine
hydrophobic (water hating, nonpolar) compounds can easily cross lipid-containing barriers (e.g., skin)
Hydrophobic (i.e., fat soluble) toxicants usually carried in blood attached to proteins
Toxicants generally follow the laws of diffusion (move from higher to lower areas of concentration)
Chemicals absorbed in the intestine may undergo first-pass metabolism in the liver
A few chemicals are excreted unchanged
Give 4 details about metabolism.
Most biotransformation occurs in liver, rich in cytochrome p450 and other metabolic enzymes, but all cells have some capacity to metabolize xenobiotics
Biotransformations increase a molecule’s water solubility/polarity, for easy excretion in urine
Four categories of metabolic transformations:
Oxidation (phase I reaction)
Reduction (phase I reaction)
Hydrolysis (phase I reaction)
Conjugation (phase II reaction; polar groups added to phase I products)
Genetic polymorphisms and enzyme induction can both help explain why people react differently
How can diet influence the condition of a disease?
The microbes in the intestine influence the uptake of chemicals and nutrients in the food and the chemicals to which we are exposed
They can alter the composition of the microbe’s stem cells and create a complex series of feedforward and feedback mechanisms that can have major effects
Give 2 details about the factors that affect toxicity. What are the 2 types of toxicity?
Not all people are equal; sensitivity to toxicant can vary with sex, age, weight, etc.
Babies, older people, or those in poor health are more sensitive
Type of exposure:
Acute = high exposure in short period of time
Chronic = lower amounts over long period of time
Give 3 details about mixtures of toxicants.
Substances may interact when combined together
Mix of toxicants may cause effects greater than the sum of their individual effects
These are called synergistic effects
Give 4 details about the basic components of a gene and a genome.
DNA: 2 strings of bases (thymine, guanine, cytosine, adenine), with sugar (deoxyribose) attached to each, combined in double helix
Gene: specific sequence of nucleotides (base + its sugar) controlling a cell function, e.g., make proteins
Human genome: ~3 billion base pairs/~24,000 genes; every cell has exact copy
Genes packaged in 46 chromosomes (each a matched set of 2; 22 x 2 autosomes, plus 2 sex specific)
What is the most common genetic variability? What are less common ones?
Most common: SNPs (single nucleotide polymorphisms): differences in single nucleotides in the same position of a gene
Less common: disease causing mutations, deletion polymorphism, gene duplication
Give 4 details about excretion.
Major route is through kidneys/urine
Liver/bile also important for some chemicals
Volatile gases and vapors excreted primarily by lungs, even if chemical originally absorbed by skin or ingested
Basic (e.g., high pH) and hydrophobic chemicals can be excreted through breast milk, posing unique risk for infants
Give 2 details about liver cancer from moldy corn and peanuts.
In parts of Jiangsu province in China, liver cancer (hepatocellular carcinoma, or HCC) was for many years the leading cause of death in males under the age of 50, yet in many other parts of the world, liver cancer in men is relatively rare
This population has a large number of hepatitis B cases and are constantly exposed to Aflatoxin B (occurs in moldy or contaminated foods)
GSTM1 deletion polymorphism is associated with about a twofold increase in risk of liver cancer
List 4 details about gene expression regulation.
To initiate transcription, transcription factors (proteins) bind to a gene’s promoter region
Ligand-activated nuclear transcription factors need other molecules, such as hormones, to bind first
Example: estrogen binds to the estrogen receptor, moves to nucleus, and binds to binding sites on the gene, turning it “on”
Endocrine disruptors are environmental chemicals that interfere with this signaling
List 6 details about epigenetic regulation.
DNA methylation; in general:
Genes with more methylated bases in regulatory region (hypermethylation) are underexpressed (switched off) while hypomethylated genes are over-expressed (turned on)
Interference during development can have lasting effects; methylation changes also common in neoplasms
Other epigenetic mechanisms: histone
acetylation/deacetylation,
Epigenome responds to food, drugs, stress, toxicants
Epigenetic mechanisms likely responsible for most environmental disease
Epigenetic information can be transmitted to offspring (fetal origins of adult disease hypothesis)
What are real world GxE examples?
Differences in drug responses between individuals (e.g., primaquine and hemolytic anemia in people
with G6PDH allele variant)
Black soldiers with the G6PDH allele variant contracted hemolytic anemia after using prophylactic cream
Acetylcholine, pseudocholinesterase and succinylcholine
Differences in alcohol responses (ALDH2*2 polymorphism = reduced ALDH2 enzyme function
and acetaldehyde buildup [flushing, hangover])
Explain methylation and phenotype-importance of maternal diet.
All mammals have Agouti gene; gene product is a dual amino acid peptide that causes the pigment cells in hair follicles to produce a yellow pigment instead of brown/black
Agouti gene can also bind to certain receptors in the brain to change metabolism leading to obesity
When the Agouti gene has been demethylated (removal of methyl groups), the mouse is yellow, obese, and has a higher risk of diabetes and cancer
When the Agouti gene is methylated, the mouse is brown and healthy
