Final Exam Flashcards
Tyrone Hayes
Studied the effects of Atrazine on frogs. paper: Hermaphroditic, demasculinized frogs after exposure to the herbicide atrazine at low ecologically relevant doses.
Louis Guillette
Studied the effects of endocrine disruptors on alligators in Lake Apopka, florida.
High levels of DDT caused skewed sex hormone ratios (low testosterone, high estrogen), and small phallus size in alligators.
a polarizing figure, big communicator. spoke to congress about the fact that if we are seeing this in alligators, then we should be looking at humans. Will people have reduced sperm count and phallus size as well?
What is toxicology and how would your definition expand to encompass environmental toxicology?
The study of adverse chemical effects on living organisms. The definition of environmental toxicology would expand to include populations, communities, and ecosystems (adverse effects over the entire biological hierarchy).
List the four processes collectively referred to as chemical disposition
Absorption
Distribution
Excretion
Metabolism
Who was Paracelsus and what contribution did he make to the field of toxicology?
Paracelsus is considered to be “the father of modern toxicology.” His important contribution was to state that “the dose determines the poison,” meaning that anything can be toxic, it just depends on the dose.
potency vs efficacy
see midterm, question 4.
A toxicant has to cross a biological membrane to produce damage. List the different ways in which entry can be achieved.
diffusion filtration active transport secondary active transport facilitated diffusion
for which sex are reproductive effects of toxic agents more damaging?
women. reproductive effects are much more damaging long-term because females are born with a set number of eggs, whereas males replenish sperm.
Dr Theo Colborn
studied endocrine disruptors in the great lakes… effects on birds
Her 1988 research on the state of the environment of the Great Lakes revealed that persistent, man-made chemicals were being transferred from top predator females to their offspring and undermining the construction and programming of their youngsters’ organs before they were born.
examples of endocrine disruptors
PCB, DDT, atrazine, DES
trenbolone
used as a growth promotor for beef production… anabolic steroid, makes cattle produce muscle.
effects on fish: females exhibit characteristics of male fish when exposed. this can have negative effects for the population… decreased number of eggs.
Kidd et al. paper
Collapse of a fish population after exposure to a synthetic estrogen.
Atrazine
an herbicide. banned in europe, but made by a european company
endocrine disrupting compounds
binds to nuclear receptor for a hormone
- can deactivate receptor : anti-estrogenic
- can mimic function: estrogenic.
definition of pesticide and 4 types
any substance intended for destroying, repelling, or mitigating any pest.
- insecticides
- fungicides
- herbicides
- rodenticides
historical background of pesticides
1st gen: natural products, ex. tobacco, sulfur
2nd gen: modern synthetic chemicals. ex DDT, dieldrin, aldrin
3rd gen. OP and carbamate insecticides, herbicide 2,4 D
4th gen: gene engineering. either plant secretes own pesticide or plant is made resistant to herbicide (ex, roundup-ready corn and soybeans)
organochlorine pesticides
aldrin, dieldrin, DDT, lindane. used extensively in the 40s, 50s, 60s
DDT
acts on the central nervous system by interfering with the movement of ions through neuronal membranes, delays the closing of the sodium ion channel and prevents the full opening of the potassium gates.
targets a specific ATPase that controls the rate of sodium, potassium, and calcium fluxes , plays a vital role in neuronal repolarization
Na+ gate leaking/open, causes “DDT jitters”
DDT controversy
banned in US in 1972 by Ruckelhaus, administrator of the FDA.
still used in other countries, ex south africa. very low toxicity for humans.
persistent in environment, interference with the inability of birds to mobilize sufficient for stabile egg shell formation
organophosphorous and carbamate compounds
used in chemical warfare. increased use since organochlorine compounds banned in the 70s.
degrade rapidly in the environment, less bioaccumulation, less chronic effects. greater potential toxicity for humans. greater potential for insect resistance.
inhibit enzymes like acetylcholinesterase, causing accumulation of acetylcholine
lifestyle choices as cancer causing agents
tobacco (30%)
alcohol (3%)
diet (35%)
neoplasia
new growth or autonomous growth of tissue
neoplasm
the lesion resulting from the neoplasia
benign
lesions characterized by expansive growth, frequently exhibiting slow rates of proliferation that do not invade surrounding tissues
malignant
lesions demonstrating invasive growth, capable of metastases to other tissues and organs
metastases
secondary growths derived from a primary malignant neoplasm
tumor
lesion characterized by swelling or increase in size, may or may not be neoplastic
cancer
malignant neoplasm
carcinogen
a physical or chemical agent that causes or induces neoplasia
genotoxic
carcinogens that interact with DNA resulting in mutation
nongenotoxic
carcinogens that modify gene expression but do not damage DNA
eight hallmarks of cancer
- sustaining cell proliferation
- resisting cell death (apoptosis)
- inducing angiogenesis
- enabling replicative immortality
- activating invasion and metastasis
- evading growth suppressors
- reprogramming of energy metabolism
- evading immune destruction
stages of the carcinogenesis process
- initiation: DNA modification, mutation, genotoxic. nonreversible.
- promotion: no direct DNA modification nongenotoxic. expansion of the initiated cell population. increase in proliferation or decrease in apoptosis. reversible.
- progression. DNA modification, genotoxic. mutation, chromosome disarrangement. changes from preneoplasia to neoplasia benign/malignant. irreversible.
carcinogenic factors associated with lifestyle
alcoholic beverage- esophagus, liver, oropharynx, and larynx
aflatoxins- liver
betel chewing- mouth
dietary intake (fat, protein, calories)- breast, colon, endometrium, gallbladder
tobacco smoking- mouth, pharynx, larynx, lung, esophagus, bladder
functions of the liver
filters nasties, nitrogenous waste destruction, glucose metabolism, break down insulin etc.
acetaminophen
most common cause of pharmaceutical poisoning/death and acute liver failure
anaglesia: pain reliever
antipyresis: fever reducer
absorption, distribution of acetaminophen
absorption: rapidly absorbed from the GI tract
distribution: 20% plasma protein bound, may increase to 50% in overdose, can cross placenta
metabolism of acetaminophen
occurs via several pathways:
sulfation, glucuronidation: phase 1, type II reactive conjugating ligand
2% excreted unchanged in the urine
4% biotransformed by CYP450 MFO system
excretion of acetaminophen
metabolic products are excreted by the kidneys
minimal excretion into breast milk
CYP450 and acetaminophen
most is metabolized through glucuronidation and sulfating, but a small amount is transformed via Cytochrome p450 2E1, which forms a reactive intermediate that can lead to toxicity.
ethanol
amphiphile (has both hydrophobic and hydrophilic characteristics) readily passes through biological membranes.
distributes from the blood into all tissues and fluids in proportion to their relative content of water
90% removed by ethanol oxidation, which occurs in the liver
general scheme for alcohol metabolism
alcohol-> aldehyde via alcohol dehydrogenase
aldehyde-> aldehyde hydrate-> carboxylic acid
aldehyde dehydrogenase
to alleviate effects of alcohol
hydrate beforehand
coffee 4 hrs afterwards
vitamin B
cortisol
stress hormone
normal gene activation
hormone enters cell, hormone binds to and activates receptor, receptor enters through nuclear pores and activates genes
interfering with transcription
toxicants acting on ligand-activated transcription factors can interfere with the signal getting to transcription
two ways to communicate a signal across distance
1) phosphorylation/dephosphorylation
2) put a molecule such as ubiquitin onto a protein that signals the protein for degradation
apoptosis
cell death that is programmed.. signal for the cell to retire.
reasons:
-kill mutated cells before they replicate
-limit cell growth before it gets out of hand
-defends against cancer
phosphorylation and ubiquitin
can work together to increase transcription
transcription
initiated by signal from membrane to nucleus
molecules that can affect cellular maintenance
calcium levels
ATP (mitochondria)
mitochondrial ATP synthase
this is an important form of maintenance. there are different ways to interfere, including cyanide.
calcium
stored in the ER, mitochondria, leave the cell via Na/Ca exchanger, or leave the cell via Ca ATP-ase
effects of toxicants on target molecules
1) dysfunction
2) destruction
3) neoantigen formation
4) globalized change in environment ex. chlorine has-> general tissue breakdown
dysfunction
dysfunction of target molecules. some toxicants activate protein target molecules, mimicking endogenous ligands. protein function is impaired when conformation or structure is altered by interaction with the toxicant. toxicants may interfere with the template function of DNA by binding to the DNA and causing nucleotide misfiring during replication.
destruction
destruction of target molecules. toxicants can alter the primary structure of endogenous molecules by means of cross-linking and fragmentation. several forms of DNA fragmentation are caused by toxicants
neoantigen formation
when the altered proteins evoke an immune response. T cell mediated immune response
toxicant-induced cellular dysregulation
cells are regulated by signaling molecules that activate specific cellular receptors linked to signal transuding networks that transmit the signals to the regulatory regions of genes and/or functional proteins. receptor activation may lead to:
1. altered gene expression that increases or decreases the quantity of specific proteins
2.a chemical modification of specific proteins
dysregulation of transcription
types of signaling pathways
- nuclear receptor. “normal gene activation”-> block or activate
- phosphorylation/dephosphorylation
- ubiquitination..usually signals degradation, interfere with transcription
- take advantage of voltage gated ion channels, in a polarized membrane. what we use when we run, jump. fast process, fast signal generators
disorders that chemicals inflicting cell death may initiate
ATP depletion, sustained rise in intracellular Ca2+
interference with cell maintenance
- ATP generation in the mitochondria- Krebs cycle, oxidative phosphorylation. can interfere, take away O2, ATP synthase, etc
- Ca2+ levels- inducing influx into cytoplasm, inhibiting export from cytoplasm. (should be stored in mitochondria)
DNA structure
wound/supercoiled: double helix-> chromosomes
nucleotides. guanine, cytosine. thymine, adenine.
types of DNA variation
- base pair substitutions
- structural mutations (copy number variation, section deleted, inserted, inverted). largest source of different between species.
synonymous
does not alter amino acid sequence
chemical carcinogenesis
- initiation
- promotion
after this point, cancer is growing without checks and balances
DNA repair types
- mismatch repair: tricky determining which is template and which is new strand. determine by methylated bases.
- base excision repair
- nucleotide excision repair
- non-homologous end joining ( if double strand break)
basic timeline of the genome
key: rapid progression of DNA research
watson and crick and rosalind franklin: double helix structure(50s)
fred singer: developed methods for sequencing DNA 70s-80s
next gen: pyrosequencing, single molecule sequencing
chemical modifications of DNA
direct and indirect genotoxic chemical carcinogens covalently modify DNA (adduct formation)
- almost all DNA damage is reversed by very effective and efficient cellular DNA repair mechanisms
- cells w unrepairable DNA damage usually undergo apoptosis
- errors in DNA repair lead to mutations that can result in cancer initiation
- mutations passed on to daughter cells by mitosis and clonal expansion
- damage of these types is much easier to repair than base substitution errors
