midterm 2 Flashcards
(249 cards)
1
Q
3 main genotoxicant effects
A
- mutagenesis
- aneugenesis
- clastogenesis
2
Q
what are mutations
A
inherited alterations in the DNA sequence
3
Q
what is the importance of mutations
A
- source of all genetic variation, which further provides the raw material for evolution
- source of many diseases and disorders
- useful for probing fundamental biological processes
4
Q
somatic cell mutations
A
- does not pass down to next generation
- limited to tissues
- tissue damage leads to loss of function and possibly apoptosis/necrosis
5
Q
germ cell mutations
A
- passed on to next generation
- mutation is present in all tissues/ the entire organism
6
Q
base substitutions, insertions, and deletions
A
- base substitution alters a single codon
- an insertion or a deletion alters the reading frame and may change many codons
7
Q
expanding nucleotide repeats
A
- hairpin forms on newly synthesized strand cause part of the template to be replicated twice increasing the number of repeats on the newly synthesized strand
8
Q
missense mutation
A
amino acid is replaced with a different amino acid
9
Q
nonsense mutation
A
sense codon is replaced with nonsense codon
10
Q
silent mutation
A
codon is replaced with a synonymous codon
11
Q
neutral mutation
A
no change in function
12
Q
suppressor mutation
A
hides the effect of another mutation- restores wild type
13
Q
intragenic suppressor mutation
A
mutation within the same gene
14
Q
intergenic suppressor
A
occurs in a gene other than the one bearing the original mutation that it suppresses
15
Q
chemically induced mutation
A
any environmental agent that significantly increase the rate of mutation above the spontaneous rate is called a mutagen
16
Q
5-bromouracil
A
base analog
- resembles thymine, except it has a bromine atom in place of a methyl group on the 5-carbon atom
- this can alter DNA bases because it may mispair with guanine
17
Q
chemically mutation inducing mutagens
A
- 5-bromouracil
- oxidative radicals
- intercalating agents
18
Q
radiation-induced mutation
A
- radiation greatly increases mutation rates in all organisms
- pyrimidine dimer
- SOS system in bacteria
19
Q
pyrimidine dimer
A
two thymine bases block replication
- result from UV light
20
Q
SOS system in bacteria
A
allows bacterial cells to bypass the replication block with a mutation-prone pathway
21
Q
aneugenesis
A
- aneuploidy/polyploidy
- metaphase interference in mitosis or meiosis
- partitioning of chromosomes
22
Q
causes of aneuploidy
A
- deletion of centromere during mitosis and meiosis
- robertson translocation
- nondisjunction during meiosis and mitosis
23
Q
effects of aneugenesis in humans
A
sex-chromosome aneuploids
- turner syndrome XO
- klinefelter syndrome XXY
autosomal aneuploids
- trisomy 21- primary or familial
24
Q
clastogenesis
A
- chromosomal breakage
- chromosomal aberrations
25
genotoxicity assays
DNA damage
Clastogenic/aneugenic
Mutagenicity assays
- ames test
- transgenic assays
Other mutations
- microsatellites
- SNPs
- sequencing
26
what is the ames test used for
used to identify chemical mutagens
27
what is the comet assay
- single gel electrophoresis, sensitive and rapid method for measuring DNA damage and repair in single eukaryotic cell
- basis for the assay is that loops of DNA containing a break lose their supercoiling and become free to extend toward the anode when exposed to current during electrophoresis at high pH
- the results appear as structures resembling comets observed by fluorescence microscopy
- comet contains distinct head and tail
28
what is the head and tail composed of in comet assay
head is composed of intact DNA and the tail consists of damaged or broken pieces of DNA
29
what is the intensity of comet tail relative to
intensity of tail relative to head reflects the number of DNA breaks
30
epigenetic changes
external modifications to DNA that alter gene expression
3 known mechanisms
- DNA methylation
- histone modification
- RNA interference
31
DNA methylation
- methyl groups almost always added to cytosine bases with the sequence ---CG--- ---GC---
- when DNA is replicates, each of the new DNA helices will have an old strand with methyl groups and a new strand without methyl groups
- DNA methyltransferase I will replace the missing methyl group
32
histone modification
during different stages of the cell cycle, the histone charge is modified by
- methylation
- acetylation
- phosphorylation
- ubiquitylation
33
RNAi
RNA interference or post-transcriptional gene silencing, PTGS, is a conserved bio response to double stranded RNA that mediates resistance to both endogenous parasitic and exogenous pathogenic nucleic acids and regulates the expression of protein-coding genes
34
epigenetic changes through miRNA
miRNAs involve translational repression or degradation of the target mRNA. miRNAs negatively regulate gene expression at the post-transcriptional level. They bind sequences in the target messenger RNA through complementarity and form RNA-RNA complex
35
how do inhaled xenobiotics impact humans
can affect lung tissues directly or distant organs after absorption. Water solubility is a decisive factor in determining how deeply a given gas penetrates into the lung
36
how does particle size impact the effects of inhalation
particle size is usually a critical factor determining the respiratory tract region in which a particle or an aerosol will deposit
37
the lung contains most of the enzymes involved in what that have been identified in other tissues
xenobiotic transformation
38
what is asthma
characterized by increased reactivity of the bronchial smooth muscle in response to exposure to irritants
39
what is emphysema
the destruction of the gas-exchanging surface area results in a distended, hyperinflated lung that no longer effectively exchanges oxygen and carbon dioxide
- enlargement of air spaces distal to the terminal bronchiole
40
4 main physiological features of the lung
1. gas exchange- provides O2 to the tissues and removes CO2
2. large surface area
3. branching structure, airway- entire blood volume passes through the lung multiple times every hour partly due to all the internal surface area
4. pocketed structure- alveolar, allows inflating and deflating action
41
2 zones of the lung
1. conducting zone- circulating the air
- air enters through nasal and oral cavity
- nasal passage warms/humidifies air; first barrier/filter
- nasal passages are lined by distinctive epithelial barriers, including olfactory cells
2. Respiratory zone
- trachea and bronchi
- mucus layer
- bifurcating structure
42
type 1 alveolar cells
- are squamous and can lay down flat
- cover up to 95 percent of the alveolar surface
- involved in gas exchange
- permeable
- cluster their organelles
- unable to replicate- this is one of the main problems pertaining to toxicity
- are susceptible to toxic insult
43
type 2 alveolar cells
- cover a small fraction of the alveolar surface area, about 5 percent, which is the surface layer
- secrete pulmonary surfactant, which decreases the surface tension
- can proliferate and differentiate into type 1 cells to compensate when lung tissue is damaged
- are granular and roughly cuboidal
- found at the blood-air barrier
- are relatively numerous- 60 percent of alveolar cells
44
a toxic effect on type 1 or type 2 alveolar cells will have a larger impact
type 2 because there are no other cells that can step in and replace them. type 2 cells can replace type 1 cells so it is not as dramatic of an impact
45
which two lung cells besides type 1 and 2 alveolar cells are important
- alveolar macrophages
- polymorph neutrophils
46
primary function of the lung
Ventilation
Diffusion
Perfusion
47
ventilation
- during inhalation thoracic cage expands via muscle contractions- brings fresh air into chest
- during exhalation, chest wall and diaphragm relaxation causes contraction, expelling CO2 rich air
48
Diffusion
- gas exchange occurs across a vast surface area of 140 m2 within the alveoli, but various abnormal processes, including fluid accumulation, surfactant disruption, and chronic toxicity-related changes, can significantly hinder oxygen diffusion to erythrocytes
49
perfusion
- the lung receives the entire cardiac output from the right ventricle, allowing for the exchange of gases and potential exposure to toxic chemicals as blood with high CO2 and low O2 enters via the pulmonary artery
- blood with high O2 and low CO2 leaves through the pulmonary vein
- chemicals entering the peripheral venous system pass through the pulmonary capillaries before reaching other organs or tissues
50
why does the ling posses significant biotransformation capabilities
cytochrome P450 uses oxygen/oxidating and the lungs have highly concentrated/large oxygen content
51
balance between activation and inactivation processes in the lungs
balance between activation and inactivation processes are crucial for protecting the lung from injury, especially given the high oxygen levels in the respiratory tract. Various phase 1 enzymes are found in the lung but exhibit non-uniform expression across different cell types and regions
52
role of phase 2 enzymes in respiratory system
phase II enzymes such as gluthatione-S-transferases, glucuronosyl transferases, and sulfotransferases play a significant role in modulating chemical toxicity in the lung, with their combine action and localization determining toxicity
53
what coordinates the regulation of phase II enzymes
transcription factor NRF2, and the potential for detoxification also depends on the cellular localization and synthesis of glutathione, which varies by lung region and isoform
54
particle deposition
1. particle size is a critical factor in determining where in the respiratory tract particles are deposited
2. aerosols include a range of particle types including dusts, fumes, smoke, mists, fog, and smog, with smaller particles classified as submicrometer or nanoparticles
3. atmospheric particles can be primary- directly emitted, or secondary- formed in the atmosphere. typically categorized into two modes- accumulation and coarse, which dominate particle volume and mass distributions
55
particle clearance
- lung defense relies on particle clearance
- clearance from the respiratory tract DOES NOT equate to removal from the body
- PM10- coarse particles- includes pollen and desert dust, stays on the top part of the respiratory system and is expelled by the mucus layer
- PM2.5- fine particles- includes bacteria, fungal and mold spores, pollen, and toner dust- these go deep into the lungs
- PM1- inhalable particles- viruses and exhaust gases, these particles are small enough to transfer to the blood/plasma
56
nasal clearance
- particles deposited in the nose are cleared based on location and solubility in mucus
- anterior deposits removed through wiping and blowing
- posterior deposits are trapped in mucus and cleared via mucociliary transport toward glottis where they are eventually swallowed
57
tracheobronchial clearance
particles in tracheobronchial tree are cleared through mucociliary transport and particle-laden macrophages are transported to the oropharynx for swallowing
58
alveolar clearance
- alveolar macrophages clear particles deposited in the alveolar region
- involves innate and adaptive immune systems, with macrophage phagocytosis requiring specific recognition and receptor interactions, leading to particle ingestion
- most macrophages eventually move to the airways for removal via mucociliary clearance
- some insoluble particles may be removed through lymphatic drainage, and long, narrow fibers can be sequestered in the lung for extended periods
59
3 important anatomical components of the lung
Bronchial smooth muscles
- maintain airway tone
- regulated by nervous system
Mucus
- changes in production and/or composition
- excess can damage epithelial cell lining, epithelium
Irritation
- constrict airways cause asphyxiation
- examples- sulfur dioxide, ozone, cigarette smoke, particulate matter
60
pulmonary toxicology
- during manufacture or use of industrial products such as pigments or fibers
- to miners of minerals from disturbing the earth's crust
- from anthropogenic sources
- from nanomaterials that have been specifically engineered for special purposes
- the pulmonary health effects of fibers are severe
61
silicosis
- caused by silica dust, which causes a fibrous reaction in tissues
- the pathophysiology involves the uptake of silica by macrophages and eventual lysosomal degradation
- the lysosomal membrane ruptures, beginning a repetitive, destructive cycle that culminates in fibrosis
62
asbestosis
- due to inhalation of asbestos, a fibrous mineral composed of silicates. asbestos goes deeper in the lung than silica dust
- health effects include- diffuse interstitial fibrosis, bronchial carcinoma, a cancer in the pleural space- mesothelioma
63
Chronic Obstructive Pulmonary Disease -COPD
- encompasses both airway and alveolar pathology- bronchitis and emphysema- persistent sputum production and cough, excessive mucus production and decreased mucociliary clearance
- respiratory infections influence COPD-associated chronic cough. Involves various receptors and stimuli, clearing mucus in smaller bronchial generations but become less effective in larger airways due to diminished airflow acceleration
64
4 D's of pulmonary toxicology
Dose
Dimension
Distribution
Durability
65
dose
- exposure concentration vs dose to target tissue
- characterization of the 'chemical' properties of the the molecules
- considerations must be made among gravimetric concentrations vs. number concentration vs. surface area concentration of the- complex mixture, the individual components within the mixture, and measured per animal weight or cell culture volume
66
dimension
- definitive size of a particle or fiber- diameter for particle, aspect ratio for fiber
- the toxicity of fibers vs. particles
- other physical properties of a particle or fiber
67
distribution
- deposition- in the upper airways, distal alveolar sites, or even deep sub-pleural region
- translocation- through the epithelium, into the interstitial spaces, into blood circulation, and accumulation in the lymph nodes
- clearance- macrophage mediated phagocytosis followed by mucociliary escalator clearance
68
durability
- usually not in reference to inhaled gases or vapors
- particles and fibers, which are most durable in the lung, also tend to be the most pathogenic
- lung clearance rates- shorter fibers usually clear first
- biodegradable is the opposite of biodurable or biopersistent
69
asbestos
1. comprises various silicate mineral fibers and is linked to three types of lung disease- asbestosis, lung cancer, and malignant mesothelioma
2. the development of these diseases depends on factors like fiber shape, length, and surface properties
3. once asbestos fibers deposit in the lung, they may trigger inflammation, macrophage activation, and production of reactive oxygen species, contributing to asbestos-related lung diseases and carcinogens
70
what is the most toxic type of asbestos and the most commonly found
chrysotile
71
silica
- silicosis is a lung disease caused by inhaled silicon dioxide particles, is primarily associated with crystalline forms of SiO2
2. the pathogenicity of silica depends on factors such as particle size, concentration, and surface properties, with particles around 1 micrometer in size being the most fibrogenic
3. acute silicosis occurs rapidly in individuals exposed to a high amount of silica in a short period of time
4. chronic silicosis, with a latency period of over 10 years is characterized by conglomerate nodules in lungs and involves macrophage phagocytosis, inflammation, and fibrotic changes
72
in vivo nose-only inhalation set up
1. inhalation studies involve animals placed in a ventilated chamber with a controlled test atmosphere. Works well for gases but challenging for particles or complex mixtures
2. Gases like SO2, O2, or NO2 can be easily generated and controlled for exposure through metering and dilution, while more complex substances need careful consideration due to their potential interactions
73
isolated perfused lung experimental set up
applicable to various lab species, involves perfusing the lungs with blood or substitute while actively or passively ventilating it, enabling the study of drug metabolism and lung metabolic activity through the introduction of toxic chemicals
74
regulation of the internal environment- hormones
animals maintain in their internal environment despite external fluctuations through the endocrine system, involving hormone secretion from endocrine glands to target tissues
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hormone production and transport
hormones are produced by ductless endocrine glands and are released into the bloodstream, which carries them to target organs. Hydrophilic and hydrophobic hormones are transported differently in the blood stream
76
hormone-receptor interaction
hormones exert their effects by binding to specific receptors in target tissues, either on the cell membrane or within the cellular nucleus. This interaction triggers a series of intracellular events that lead to physiological responses
77
pituitary gland
- anterior pituitary receives endocrine input from the hypothalamus in the form of peptide-releasing hormones- transported in portal vessels to stimulate the release of hormones in the anterior pituitary cells
78
adrenal glans
- located on the superior poles of each kidney
- the cortex synthesizes and secretes steroid hormones that regulate salt and fluid balance, glucose homeostasis, and a long term response to stress
- the medulla secretes the catecholamines, epinephrine, and norepinephrine
79
steroidogenesis
- adrenal steroids are synthesized from cholesterol by specific enzyme-catalyzed reactions that involve a complex shuttling of steroid intermediates between the mitochondria and endoplasmic reticulum
- the common biosynthetic pathway from cholesterol is the formation of pregnenolone, the basic precursor for the three major classes of adrenal steroids
80
glucocorticoids
physiological effects include
- hepatic glucose production, gluconeogenesis
- protein catabolism
- fat catabolism
- increased bone resorption
- altered mood
- increased gastric acidity
at the pharmacological doses, cortisol can prevent vascular collapse during overwhelming stress, provide an anti-inflammatory effect, and invoke immunosuppression
81
essential role of adrenals and mineralocorticoids
- loss of mineralocorticoid production can lead to a life-threatening condition characterized by potassium retention and hypovolemic shock, along with excessive urinary loss of sodium, chloride, and water
- aldosterone is produced by the adrenal cortex and is crucial in regulating electrolyte balance. It promotes sodium reabsorption while increasing the excretion of potassium and hydrogen ions by the kidney
- the renin-angiotensin system is the primary regulator of aldosterone production in the adrenal cortex. Renin initiates the cascade that produces and secretes aldosterone. Angiotensin II, acts as a vasoconstrictor and stimulates the zona glomerulosa cells to produce aldosterone
82
thyroid glands
parafollicular C cells within the thyroid produce calcitonin, a hormone involved in calcium regulation
- the thyroid secretes T4 and T3. These hormones are stored in thyroglobulin within follicles and play a crucial role in regulating metabolism affecting various target tissues
- impact of xenobiotics- can alter the thyroid gland's structure. These changes may reduce hormone storage capacity and impair the synthesis and storage of thyroid hormones
83
specific chemicals that affect thyroid hormones
- PCBs inhibit thyroid hormone synthesis
- PBDEs induce enzymes in the liver, downregulate transport proteins, and can bind to thyroid receptors
- perchlorate primarily inhibits thyroid hormone synthesis by reducing iodide uptake
- pesticides like DDT and HCB can increase thyroid volume, and induce antibodies that attack the thyroid
- PFOS and PFOA alter thyroid hormone levels by affecting metabolic enzymes in the liver and deiodinases in the thyroid gland
84
insulin
promotes energy storage by lowering blood glucose, fatty acids, and amino acids, and facilitating their conversion into glycogen, triglycerides, and protein. Its effects include increased cellular glucose uptake, reduced blood glucose levels, stimulated glycogen synthesis, glycerol production, amino acid uptake, inhibited lipolysis, and stimulated protein synthesis
85
glucagon
acts as a counter-regulatory hormone to insulin
- promotes catabolic processes and prevents hypoglycemia by stimulating glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis in the liver
- release triggered by epinephrine, norepi, and specific amino acids
- insulin and somatostatin inhibit its secretion
- can stimulate insulin secretion from pancreatic beta cells
86
what cells in the pancreas are the most vulnerable to chemical damage
beta cells are the most vulnerable compared to alpha and gamma cells
87
does insulin or glucagon deficiency have a more significant physiological impact
insulin deficiency due to counterregulatory hormones
88
what are alloxan and streptozotocin used for
commonly used chemicals to create diabetes animal models by selectively targeting and destroying pancreatic beta cells
89
STZ is used for what in humans
triggers immune response leading to beta cell destruction in rats, but does not induce diabetes in humans when used as chemotherapy
90
endocrine-disrupting chemicals
exogenous agent that interferes with the production, release, transport, metabolism, binding, action, or elimination of natural hormones responsible for the maintenance of homeostasis and the regulation of developmental processes
91
four modes of action of endocrine-disrupting chemicals
1. serving as steroid receptors ligands
2. modifying steroid hormone metabolizing enzymes
3. perturbing hypothalamic-pituitary release of trophic hormones
4. uncharacterized proximate modes of action
92
sexual differentiation
- male sexual differentiation is critically dependent on the physiological action of androgens
- imbalance in the androgen/estrogen ratio can affect sexual differentiation
- environmental xenoestrogens can mimic estrogens and xenoandrogens that perturb endocrine balance may cause demasculinization and feminization in a male fetus
93
hypothalamic-pituitary-gonadal axis
- FSH and LH are synthesized and released from the pituitary gland
- hypothalamic neuroendocrine neurons secrete specific releasing or release-inhibiting factors
- FSH acts primarily on sertoli cells- stimulates mitotic activity of spermatogonia
- hypothalamo-pituitary-gonadal feedback system is a very delicately modulated hormonal process
94
unique barriers in the reproductive system
- maternal-fetal interface- placenta
- blood-testis barrier- situated between the lumen of an interstitial capillary and the lumen of a seminiferous tubule
95
target for chemical toxicity- CNS
- drugs and chemicals can act directly on the hypothalamus and anterior pituitary, causing alterations in the secretion of hypothalamic-releasing hormones and/or gonadotropins
- synthetic hormones are very effective in suppressing gonadotropin secretion, and this blocks ovulation
96
targets for chemical toxicity- gonads
- gonads are targets for a host of drugs and chemicals, the majority of these are cancer chemotherapeutic agents. Alkylating agents are affective against rapidly dividing cells like cancer cells and dividing germ cells
- different cell populations of the mammalian testis exhibit somewhat different thresholds of sensitivity to different toxicants- sertoli cell intermediate sensitivity; leydig cells- resistant
97
targets for chemical toxicity- steroidogenesis
- several drugs, hormones and chemicals can affect steroidogenesis by interfering with or inhibiting specific enzymes
98
evaluating reproductive capacity
- endocrine system of the female is more complex and dynamic than that of the male
- there are many different chemicals/drugs that can perturb the reproductive system which adds another dimension of difficulty in assessing reproductive toxicity
99
hematoxicology
the study of the adverse effects of chemicals on the blood and blood-forming tissues
100
functions of the blood
- delivery of oxygen to tissues throughout the body
- maintenance of vascular integrity
- provision of the many effector immune functions and necessary for host defense
- requires a prodigious proliferative and regenerative capacity
101
hematopoiesis
- highly regulated sequence of events- blood cell precursors proliferate and differentiate to meet the needs of oxygen transport, host defense and repair, hemostasis, and other vital functions
- the bone marrow is the principal site of hematopoiesis in humans and most laboratory and domestic animals
- in the human fetus, hematopoiesis can be found in the liver, spleen, bone marrow, thymus, and lymph nodes
- the bone marrow is the dominant hematopoietic organ in the latter half of gestation and the major blood-cell-producing organ at birth
102
meaning of the suffix -emia
reference to the blood
103
meaning of the suffix -penia
decreased number of blood cells
104
meaning of the suffix -cytosis
increased number of blood cells
105
toxicology of the erythron
- erythrocytes compose 40 percent of the circulating blood volume and transport of oxygen from the lungs to the peripheral tissues and carbon dioxide from the tissues to the lung
- erythrocytes can also act as a carrier/ reservoir for drugs and toxicants
- xenobiotics may affect the production, function, and/or survival of erythrocytes
- two mechanisms that lead to anemia are either decreased production or increased destruction of erythrocytes
106
alterations in red cell production
- defects in the synthesis of porphyrin ring of heme can lead to sideroblastic anemia, with its characteristic accumulation of iron in bone marrow and erythroblasts
- xenobiotics that can interfere with the steps of in erythroblast heme synthesis
- characterized by the presence of ring sideroblasts in the bone marrow
107
alterations in the respiratory function of hemoglobin
- methemoglobinemia
- carboxyhemoglobinemia
108
methemeoglobinemia
- property of oxyhemoglobin is the oxidation of iron from the ferrous to ferric state to form methemoglobin, which is unable to transport oxygen
- normal erythrocyte has metabolic mechanisms for reducing heme iron back to the ferrous state. Failure if these control mechanisms leads to methemoglobinemia, in which arterial blood becomes a characteristic brown color
109
carboxyhemoglobinemia
- the resp. function in hemoglobin may be impaired by blockade of the ligand binding site following interaction with other substances, one being CO
- CO has a high affinity about 200 times that of oxygen
- binding of CO causes the oxygen dissociation curve to shift to the left, further compromising oxygen delivery to the tissues
110
alterations in erythrocyte survival
- erythrocytes are exposed to oxidative injuries and physical passages of the microcirculation and spleen
- nonimmune hemolytic anemia
- oxidative hemolysis
- nonoxidative chemical-induced hemolysis
111
nonimmune hemolytic anemia
intravascular fragmentation of erythrocytes gives rise to microangiopathic hemolytic anemia
112
oxidative hemolysis
molecular oxygen is reactive and potentially toxic. The normal respiratory function of erythrocytes generates oxidative stress on a continuous basis
113
nonoxidative chemical-induced hemolysis
some xenobiotics are associated with hemolysis without oxidative injury
arsenic hydride inhalation can result in severe hemolysis. Stibine may result in hemolytic anemia
114
toxicology of the leukon
the leukon consists of leukocytes including granulocytes, monocytes, and lymphocytes
- leukemia
115
human leukemia and other hematopoietic malignancies
- leukemias- hematopoietic stem of progenitor cells in bone marrow undergo uncontrolled proliferation and cannot differentiate normally into mature blood cells
- based on the stage of differentiation and rate of clonal expansion, they are characterized as acute or chronic
- four major types of leukemia- acute/chronic lymphoblastic, acute/chronic myeloid
116
toxicology of platelets
- multicomponent system is responsible for preventing the loss of blood from sites of vascular injury and maintaining circulating blood in a fluid state
- loss of blood is prevented by formation of stable hemostatic plugs. This response is normally limited to sites of vascular injury
- thombocytopenia
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thrombocytopenia
may be due to decreased production or increased destruction of platelets
118
cardiovascular toxicity
- adverse effects of extrinsic and intrinsic stresses on the heart and vascular system
119
cardiac structure
- myofibril, contractile element, consists of smaller filaments. Thick filaments are myosin and thin filaments are actin
- calcium, sodium, and potassium are important for proper function of cardiac myocytes
120
when does myocyte contraction occur
- action potential causes the release of Ca and the entry of extracellular Ca into the cell - excitation-contraction coupling
121
what does the increase of Ca in myocytes cause
Ca binds to troponin and tropomyosin leading to the interaction between action and myosin via crossbridge formation. ATP is hydrolyzed by ATPase and release of energy is cause
- ultimately causes contraction of the myocardium
122
what is the PR interval in ECG
measure of the time from onset of atrial activation to the onset of ventricular activation
123
what is the QRS segment in ECG
conduction pathway through the ventricles
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what is the ST segment in ECG
period the entire ventricular myocardium is depolarized
125
what is the QT interval in ECG
electrical systole
126
phosphocreatine and the heart
energy reserve system to maintain a high phosphorylation potential to drive ATPase reactions under highly demanding conditions
127
cardiac metabolic pathways
continuous synthesis of ATP via mitochondrial oxidative phosphorylation uses the oxidation of fatty acids providing about 65 percent of the total energy demand and oxidation of glucose provides about 30 percent of the total energy demand
128
what is the ultimate functional effect of cardiac toxic manifestations
decreased cardiac output and peripheral tissue hypoperfusion
- critical cellular event leading to toxicological cardiomyopathy is myocardial cell death, which leads the ECM remodeling and fibrotic scarring in the place of lost cells along with functional changes in response to reduced contractile function
129
acute cardiac toxicity
a single exposure to a high dose of cardiotoxic chemicals is manifested by cardiac arrhythmia or profound depression of pump function
130
chronic cardiac toxicity
results from long-term exposure to chemicals
often manifested by cardiac hypertrophy and the transition to heart failure
131
cardiac arrhythmia
- can arise from chronic remodeling of the heart
- arrhythmia often manifested as tachycardia or bradycardia
132
cardiac hypertrophy
- observed during pressure overload and is characterized by new contractile-protein units assembled in parallel- results in relative increase in the width of individual cardiac myocytes
133
heart failure
- inability of the heart to maintain cardiac output that is sufficient to meet to metabolic and oxygen demands of peripheral tissues
134
myocardial degenerative responses
- myocardial cell death, fibrosis, and contractile dysfunction
135
toxic effect on myocardial regeneration
- cardiac stem cells/cardiac progenitor cells are responsible for cardiac repair
136
myocardial cell death
- loss of cardiac myocytes is a fundamental component of myocardial injury
137
mitochondrial dynamics
- mitochondrial fusion and fission constitute a major response of cardiomyocytes to stresses
138
cardiac hypertrophy
- physiologic hypertrophy is considered an adaptive response in which cardiac function changes to meet an increased demand of cardiac output
- functionally, the increased mass is associated with enhanced contractility and cardiac output
139
arrhythmogenenic cardiomyopathy
compromise of electrical conduction can lead to sudden in an otherwise healthy individual
140
cardiac toxic chemicals
Alcohol
- inhibits protein synthesis and and Ca2 sequestration, alter mitochondrial respiration, and disturb actin and myosin interaction
- Reactive oxidative metabolites from ethanol biotransformation is a possible major contributing factor to ACM
Anti-inflammatory agents
- NSAIDs are selective inhibitors of COX-2
- cardiac events caused by this are often related to thrombotic events and other things related to downregulation of prostacyclin production
141
endothelial cells
- line all vessels of the circulatory system
- modulate blood flow, transport of circulating factors to end-target organs, and removal of waste products
- produce nitric oxide and prostacyclin
142
vascular smooth muscle cells
- surrounds arteries and veins
143
responses of vascular endothelial cells to toxic insults
nitric oxide rapidly interacts with superoxide to form peroxynitrite, which can form nitrotyrosine adducts
144
response of smooth muscle cells to toxic insults
damage to vascular smooth muscle cells involves changes in vascular tone and atherosclerosis. Toxic substances influence calcium homeostasis in multiple ways impacting contractility
145
oxidative stress and vascular injury
- many xenobiotics generate ROS during their biotransformation in endothelial and smooth muscle cells, producing oxidative injury
- an increased ROS in endothelial cells is related to stimulation by angiotensin II, as well as other neurohormonal factors and cytokines
146
effects of vascular toxicity
- hypertension and hypotension
- atherosclerosis
- edema
- hemorrhage
147
vascular system toxic chemicals
- cocaine
- analgesics and NSAIDs
- carbon monoxide
148
biomarkers for cardiovascular toxicity
- structural changes and functional alterations can be directly observed by echocardiography and electrocardiogram
149
what is risk assessment
- process of estimating the probability of occurrence of an event and the probable magnitude of adverse effects over a specified period of time
- process of determining the risk associated with an event, provides systematic framework, grounded in scientific principles to understand and manage diverse risks
150
what does risk assessment need to be effective
- benefits and costs
- technological alternatives
- societal values
151
what does risk assessment incorporate
- science
- economics
- public policy
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basis for measuring risk
- risk caused by a chemical, physical, or biological agent- intrinsic risk, presence factor, defense factor
- conceptual relationship risk = hazard/preventative measures
153
human health risk assessment end points
1. cancer
- drive regulators decision
- unambiguous endpoint; dreaded
2. Non-cancer
- temporary and reversible enzyme change
- immune suppression
- reproduction abnormalities
- developmental abnormalities
- resp. and allergic reactions
154
risk assessment process
1. data analysis/hazard identification
2. exposure assessment
3. dose-response or toxicity assessment
4. risk characterization
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data analysis/hazard identification
- quantities and concentration of chemical, physical, and biological agents in environmental media at a site or study area
156
exposure assessment
pathways and routes, receptors including sensitive subgroups, exposure rates, and timing
157
dose-response or toxicity assessment
- relationship between exposure or dose and adverse health effects
- carcinogens - slope factor
- non carcinogens- reference dose
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risk characterization
integration of toxicity and exposure data for qualitative or quantitative expression of health risks; uncertainty analysis
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hazard identification
- animal
- epidemiology
- cell/tissue culture
- clinical
- computational
- monitoring surveillance
160
what does LOAEL and NOAEL mean
- lowest observed adverse effect level
- no observed adverse effect level
161
what is an adverse effect
- a harmful or potentially harmful change in the physiologic state, or organ structure that may result in an observed deleterious health outcome
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general procedure for non-cancer dose-response assessment
- first step is to review database to identify most sensitive species
- second step is to determine the critical effect
- determine the NOAEL or LOAEL
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MRL
- an estimate of the daily human exposure to a substance that is likely to be without an appreciable risk of adverse, noncancer effects over a specified duration of exposure
- an estimate of daily exposure to the human population that is likely to be without appreciable risk or deleterious effects during lifetime
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RfD
- reference dose- threshold response
- idea that there is a safe dose at which there are no bad effects or the body can repair the damage done
- estimate of daily exposure level for humans without appreciable risk of deleterious effects furing a lifetime
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uncertainty factors
- to estimate an acceptable lifetime dose for humans
- NOAEL
- divide by uncertainty factors - 10 for average to sensitive human, 10 for animal to human
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threshold vs. nonthreshold effects
- noncancer effects traditionally considered to have threshold
- cancer traditionally been considered to have no threshold; that is any exposure poses some risk
- however, with better understanding of carcinogenesis, scientists have begun considering the potential for non-linear dose response curves, or even thresholds for cancer
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what is QSAR
quantitative structure-activity relationship
- prediction of chemical behavior and properties based on molecular structure and properties
- quantitative relationship in that a mathematical model is used to account for the observed activity
- structure- the structure of the molecule
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significance of QSAR
allow prediction of activity of compounds in the absence of experimental data
- allow prediction of activity of compounds that do not exist
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QSAR strategy, what two trends work in opposition
1. obtain sharpest possible correlation, sort out substituents that do not conform well
2. encompass widest possible variation in structure including hundreds of derivatives
- if the model is trained with more compounds so it should have broader applicability
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important QSAR considerations
- quality of Y- dependent variable or activity- strength of QSAR depends on the quality of the dependent variable
- choice of X- independent variables or descriptors- improper choice of independent variables results in poor QSAR
- overfitting- ideal ratio is 1 descriptor to 5 molecules of the training set
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steps in building a QSAR equation
1. entering the molecules in the training set
2. entering biological activity data
3. entering molecular descriptors
4. generating the equations
5. analyzing the QSAR equations
6. validating the QSAR equation
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what is the most metabolically active organ
liver
173
what is the relationship between the live and blood
- liver receives high blood flow
- liver CAN STORE BLOOD
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normal function of the liver
- extracts ingested nutrients, vitamins, metals, drugs, environmental toxicants, and waste products of bacteria FROM the blood for metabolism, storage, and/or excretion into BILE
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bile
alkaline fluid that aids digestion and is secreted by the liver and stored in the gallbladder
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gallbladder
the small sac-shaped organ beneath the liver where bile is stored after secretion and before release into the intestine
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bilirubin
orange-yellow pigment formed in the liver by the breakdown of hemoglobin and excreted in the bile
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bile formation in the liver
formation of bile is essential for uptake of lipid nutrients from the small intestine, protection of the small intestine, protection of the small intestine from oxidative insults, and excretion of endogenous and xenobiotic compounds
179
hepatocytes
- cells that compose the liver
- contain a rich supply of phase I enzymes that convert xenobiotics to reactive electrophilic metabolites
- also has phase II enzymes that add a polar group to the molecule
- balance between phase I and phase II reactions determines whether a reactive metabolite will initiate liver cell injury or be safely detoxified
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fat metabolism in the liver
1. oxidizes fatty acids to supply energy
2. synthesizes large amounts of cholesterol and lipids
3. synthesizes fat from carbohydrates
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protein metabolism in the liver
1. de-aminates amino acids
2. makes urea for fluid removal
3. makes plasma proteins- albumin
4. converts amino acids
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carbohydrate metabolism in the liver
1. stores glycogen
2. produces glucose
3. forms many carbohydrates from intermediate products
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four basic cells that reside in the liver
1. hepatocytes
2. kupffer cells - important macrophages
3. hepatic stellate cell
4. sinusoidal endothelial cells
184
hepatitis
- inflammatory condition of the liver often caused by viral infection
- also caused by autoimmune disorders or exposure to some medications, drugs, toxins, or alochols
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fatty liver
occurs from most toxicants when lipid accumulates in hepatocytes
186
hepatocyte death
usually necrosis
187
cholestasis
obstruction of canaliculi between plates leads to cell swelling, death, inflammation, 2 types- decreased bile flow or decreased bile salt formation
188
bile duct damage
- obstruction/blockage of the bile ducts
189
sinusoidal disorders
obstruction caused by drug or toxic substance abuse- something blocking the blood flow into the liver
190
liver fibrosis
- the scarring process that represents livers response to injury
191
cirrhosis
accumulation of collagen fibers
- collagen secreted by activated ITO cells following injury or inflamation
- accumulates around portal veins or within the space of disse
Occurs when normal repair mechanisms are overloaded- limits flow of blood, NOT REVERSIBLE, increased with CCl4, increased with chronic alcoholism
192
normal function of the kidney
- excrete waste products
- regulate fluid volume
- maintain acid-base balance
1. Cortex constitutes the major portion of the kidney and receives a disproportionately higher precentage of the blood flow
193
formation of urine involves what 3 basic processes
1. ultrafiltration of plasma
2. reabsorption of water and solutes from the ultrafiltrate
3. secretion of selected solutes into the tubular fluid
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renal failure
Acute Kidney Injury
- characterized by an abrupt decline in filtration rate
- associated with increased renal vascular resistance and tubular damage
Chronic Kidney disease
- progressive deterioration of renal function
- associated with nephropathy
- progression to renal failure is related to other failures triggered by the initial injury
195
creatinine
- waste product formed in muscle from a high energy storage compound- you should have a much higher concentration in urine than you have in plasma
- ATP is the immediate source of energy for muscular contraction as it is hydrolyzed to ADP
- creatine phosphate can be stored in muscle at 4 times the concentration of ATP
- small amounts are ingested as constituent of meat
- best indicator of renal function as it is a function of muscle mass and not affected by diet, age, and sex
196
blood urea nitrogen
- indicator of renal function that can be done in a common blood test
- main reason for dialysis is to remove urea out of the blood
197
environmental nephrotoxicity
Metals
- mercury
- cadmium
- chromium, lead, platinum, uranium
Halogenated Hydrocarbons
- chloroform
- terafluoroethylene
198
breakdown of the causes of human birth defects
- 15-25 percent genetic cause
- 4 percent maternal conditions
- 3 percent maternal infections
- 1-2 percent deformation
- less than 1 percent chemical and environmental influences
- 65 percent unknown etiology
199
thalidomide
- cause limb malformations in newborns
- most susceptible 20-36 days after fertilization
- proposed mechanism is embryonal DNA oxidation and misregulation of the expression of genes critical for outgrowth of limb
200
Diethylstilbestrol
- prescribed between 1940 and 1970 to prevent miscarriages in high risk pregnancies
- increases estrogen and progesterone synthesis by the placenta
- female children- vaginal and cervical carcinomas, uterine anomalies
- males children- epididymal cyst, hypotrophic testes, decreased semen volume and poor semen quality
201
alcohol
Fetal Alcohol Syndrome
- craniofacial dysmorphism
- intrauterine and postnatal growth restriction
- disabled pyschomotor and intellectual development
- IQ 68
202
tobacco smoke
- lower birth weight
- increased risk of - sudden infant death syndrome, behavioral attention disorders, orofacial cleft, gastroschisis, branching morphogensis and maturation of the lung, nicotine-related adverse neurodevelopmental outcomes
203
impact of cocaine on fetal development
- at risk of premature labor, spontaneous abortion, increased perinatal mortality, and fetal death
- intrauterine growth restriction, microcephaly, altered presencephalic development, decreased birth weight, irritability, and occasional seizures
- genitourinary tract malformation
- impaired auditory process
204
retinoic acid
- active ingredient in accutane
- carries a pregnancy category X warning, meaning it is a known human teratogen
205
Wilson's general principles of teratology
I. susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which this interacts with adverse environmental factors
II. susceptibility to teratogenesis varies with the developmental stage at the time of exposure to an adverse influence
III. teratogenic agents act in specific ways on developing cells and tissues to initiate sequences of abnormal developmental evnets
IV. the access of adverse influences to developing tissues depends on the nature of the influence
V. the four manifestations of deviant development are death, malformation, growth restriction, and functional deficit
VI. manifestations of deviant development increase in frequency and degree as dosage increases, from the no effect to the totally lethal
206
innate immune system vs adaptive immune system
1. innate immune system
- non specific
- present at birth
2. adaptive immune system
- acquired
- developed during the lifetime of an individual as an adaptation to the exposure of a given pathogen
207
innate immune system
- evolutionarily older
- germline-encoded recognition
- non-specific
- cellular responses- mediated by leukocytes
- humoral responses- mediated by macromolecules, as opposed to cells, found in extracellular fluids
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cellular responses of the innate immune system
1. macrophages
2. dendritic cells
3. mast cells
4. neutrophils
5. eosinophils
6. natural killer cells
209
Macrophages
large cells that recognize, engulf and destroy target cells via phagocytosis and are found in stationary form in the tissues or as mobile white blood cells at sites of infection
210
dendritic cells
a type of antigen-presenting cell that form an important role in the adaptive immune system. The main function of dendritic cells is to present antigens to T-cells
211
mast cells
contain secretory granules, each containing powerful biologically active molecules called mediators
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neutrophils
polymorphonuclear cells that recognize, engulf and destroy target cells via phagocytosis and are found in the blood. Most abundant of leukocytes
213
eosinophils
polymorphonuclear phagocytic cells important in defense against parasites
214
natural killer cells
bind to virus-infected cells or tumor cells and kill them by the insertion of granules containing perforin
215
humoral responses in innate immunity
1. complement proteins
2. lysozyme
3. antimicrobial peptides
4. cytokines
216
complement proteins
- part of the complement system
- complement system is made up of a large number of distinct plasma proteins that react with one another to opsonize pathogens and induce a series of inflammatory responses that help to fight infection
217
lysozyme
- catalyzes the hydrolysis of certain bacterial cell walls by breaking peptidoglycan and glycosidic linkages
- present in tears, mucus, egg albumin, and some plants
218
antimicrobial peptides
- small molecular weight proteins with broad spectrum antimicrobial activity against bacteria, viruses, and fungi
- evolutionarily conserved
- target microbial membrane killing the pathogen
219
cytokines
small secreted proteins released by cells to communicate. There are both pro-inflammatory cytokines and anti-inflammatory cytokines
- monokines- cytokines made by monocytes
- chemokines- cytokines with chemotactic activities
- lymphokines- cytokines secreted by lymphocytes
- chemokines- cytokines with chemotactic activities
- interleukins- cytokines created by one leukocyte and acting on other leukocytes
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adaptive immune system
- evolved 500 million years ago - vertebrates only
- rearrangement of gene segments
- specific and memory
- cellular responses mediated by lymphocytes
- humoral responses mediated by macromolecules- antibodies
221
cellular responses from the adaptive immune system
1. B lymphocytes- born and mature in the bone marrow. Produce antibodies
2. T lymphocytes- born in the bone marrow but mature in the thymus
- helper T-cells- work with B-cells to induce the production of antibodies by B-cells
- cytotoxic t-cells directly target cells infected with a virus
222
antibodies
immunoglobins secreted by plasma B-cells
- IgG, IgM, IgD, IgD, IgA, IgE
223
what percentage of total antibodies are IgG
80 percent
224
innate immunity vs. adaptive immunity
Innate immunity
- invertebrates and vertebrates
- germline-encoded
- non-specific
- immediate activation
- cellular responses
- humoral responses
- no memory
Adaptive immunity
- vertebrates only
- acquired through life
- specific - gene rearrangement
- delayed activation
- cellular responses
- humoral responses
- memory
225
relevance of immunotoxicology to human health
- drug safety
- immunotoxicity of transplant anti-rejection drugs
- failure of immune response
- autoimmune disease
- hypersensitivity to disease
- immunosuppression
226
hypersensitivity reactions
- cause cell damage through excessive immune response to antigens
- hypersensitivity- overreaction to infectious agents
- allergy- overreaction to environmental substances
- autoimmunity- overreaction to self
227
type I hypersensitivity
- IgE-mediated; quick onset after exposure
- allergic reactions
- examples- bee stings, latex, certain medications
228
Type II hypersensitivity
- cytotoxic/antibody-mediated
- cytotoxic
- hemolytic reactions, goodpasture syndrome, hyperacute graft rejection
229
Type III hypersensitivity
- immune complex/IgG/IgM mediated
- immune complex deposition
- hypersensitivity pneumonitis, systemic lupus erythematosus, polyarteritis nodosa, serum sickness
230
Type IV hypersensitivity response
- delayed or cell-mediated
- chronic graft rejections, PPD, latex, Nickel, poison ivy
231
immunodeficiency
- loss or inadequate function of various components of the immune system
- can occur in any part or state of the immune system- physical barrier, phagocytes, B lymphocytes, complement, natural killer cells
- the immunocompromised host has an impaired function of immune system and is at high risk of infection
232
congenital immunodeficiency
- primary
- genetic abnormality
233
acquired immunodeficiency
- secondary
- results from infections, nutritional deficiencies or treatments
234
immunoecotoxicology
- fish represent the largest vertebrate group on the planet
- they have significant economic and ecological value
- in 1980s, immunotoxic studies were reported in fish for the first time
235
what are the causes of inconsistencies in immunotoxic findings
- different chemical attributes eliciting different responses
- differences in chemical concentrations, frequency and duration of exposure
- species-specific alterations in immune function
- age-dependent immune responses
- sex-dependent immunocompetence
236
What is the main mechanism of pyrethoid ester toxicity
causing hyperexcitability of the membrane by interfering with sodium transport
237
true or false, pyrethrins, are composed of two primary structural moieties, an acid, and an alcohol, and can be of type 1 (with a-cyano substituent) or type II (no a-cyano substituent)
false
- type one does NOT have an a-cyano substituent but type II does
238
true or false, in the kidney, the papilla receives a higher precentage of blood flow while the cortex only recieves 1-2%
false the blood flow is flipped
239
true or false, lipophilicity and toxicity are strongly related to the amount of chlorine atoms in pesticides
false
240
true or false, an endocrine disruptor is an exogenous agent that interferes with the production, release, transport, metabolism, binding, action, or elimination of natural hormones responsible for the maintenance of homeostasis and the regulation of developmental processes
true
241
what is characterized by the long-term accumulation of extensive amounts of collagen fibers in response to direct injury or inflammation of the liver, resulting in permanently reduced liver function
cirrhosis
242
true or false, in the endocrine pancreas, beta cells are highly vulnerable to chemical damage compared to alpha and gamma cells
true
243
the toxic effect that causes the death of a neuron is called
neuronopathy
244
true or false, cardiac arrhythmias may arise from chronic remodeling of the heart, and are often manifested as tachycardia or bradycardia
true
245
_____ are important macrophages in the liver and release cytotoxins in response to signals from damaged endothelial cells
kupffer cells
246
true or false, in renal failure, serum creatine levels and blood urea nitrogen levels (BUN) are high
true
247
true or false, defects in the synthesis of porphyrin ring of heme can lead to sideroblastic anemia, with its characteristic accumulation of iron in bone marrow erythroblasts
true
248
the process that leads to the loss or gain of entire chromosomes is called what
aneugenesis
249
the condition when a hematopoietic stem or progenitor cell in bone marrow undergo uncontrolled proliferation and cannot differentiate normally into mature blood cells is known as
leukemia
