Gen Path L19

  1. Climate is the most striking factor related to Environmental Diseases
    • Directly by taxing body’s physiological reserves
    • Indirectly through influence on plants and insects
    • - Cardiovascular, cerebrovascular, and respiratory diseases, worsened by heat waves and air pollution.
    • - Malnutrition, local climate change disrupts crop production.
  2. How “human” affected by environmental factor?
    • Source of harm: persistent or transportable (volatile, water soluble)
    • Medium for transport: Air, water, soil
    • Receptor population: within the exposure pathway Routes of exposure: Inhalation, ingestion, and dermal absorption.
    • Dose - adequate amount to result in human harm.
  3. Xenobiotic metabolism
    • Xenobiotics can be metabolized to nontoxic metabolites (via phase I, hydrolysis, red-ox, and phase II, glucuronidation, sulfation, methylation, conjugation, reactions) and eliminated from the body (via urine, bile, feces; detoxification).
    • Xenobiotic metabolism may also result in the formation of a toxic reactive metabolite with effects on cellular molecules. If repair is not effective, short- and long-term effects (toxicity) develop.
  4. Dose-response curve for chemical toxicity
    • DOSAGES EFFECTS (concentration and duration of exposure)
    • Subthreshold, threshold, ..., ceiling effect
  5. Factors influence cause and effect associations
    • LATENCY PERIODS - exposure <-> clinical disease
    • 1. Genetic predisposition
    • eg. Xeroderma Pigmentosa: Defective DNA repair, + risk of skin cancers when exposed to direct sunlight.
    • 2. Ethnicity
    • 3. Age
    • 4. Gender
  6. Establish cause and effect associations
    • Via retrospective epidemiological analyses
    • Many environmental diseases are multifactorial and
    • several different foreign substances can contribute - increase in the risk of laryngeal cancer from the synergistic interaction between cigarette smoking and alcohol consumption.
  7. Common Environmental and Occupational Exposures
    • Personal Exposure - Tobacco; Alcohol; Drug abuse
    • Air Pollution (Indoor and Outdoor) - NO2, SO2, CO, …
    • Metals -occupation and non-occupational - Lead
  8. Cigarette smoking
    • Pleasant feelings
    • Mood enhancer
    • Social rejection
    • Withdrawal symptoms
    • Cost - 3.5hr of life per pack; or average 7.5yr difference in life expectancy.
  9. Tobacco smoke components
    • Gases - by-products of combustion intermixed with components of the air (for instance, CO, hydrogen chloride, acetone, formaldehyde)
    • Particles - tars (carcinogen), nicotine (addiction inducing), and a variety of organics.
  10. Tars - Polycyclic hydrocarbons
    • Direct-acting carcinogens in the skin,
    • Procarcinogens in producing lung and bladder cancer.
    • Inhaled polycyclic hydrocarbons are converted in the liver to an epoxide by aryl hydrocarbon hydroxylase (significantly higher levels in smokers who develop lung cancer)
  11. Toxic effects of tobacco smoke through various routes
    • Inhalation - toxic effects in the upper respiratory tract and lungs, mucous membranes.
    • Blood circulation - distant organ damages, eg myocardial infarction
    • Excretion/elimination - urine - bladder cancer
  12. Smoking as a cause of death and disability
    • Direct cause of chronic bronchitis and emphysema, which constitute chronic obstructive pulmonary disease (COPD).
    • The single largest cause of lung cancer and an important factor in other cancers, notably those of the bladder, oral cavity, larynx, and esophagus.
    • Increases the risk of heart disease, heart attack, stroke and several other causes of death. - Increased CO2, decreased HDL.
    • Interacts other environmental exposure in additive or synergistic fashion, eg, asbestos, alcohol.
  13. How Tobacco Smoking predispose to Emphysema?
    • Contains abundant reactive oxygen species (ROS)
    • Increases number of neutrophils and macrophages in lung
    • Slows transit of these cells
    • Promotes neutrophil degranulation
    • Inhibits α1–AT (α1-antitrypsin, which protects the lungs from enlargement)
  14. Microscopic view of normal lung and lung with emphysema
    • disrupted alveolar walls
    • enlarged airspaces of emphysema
    • color change, with black spots
  15. Histological view of squamous cell carcinoma of lung
    • highest frequency of p53 mutations, Rb, and CDK inhibitor p16.
    • blocks the main bronchus and causes bronchitis
    • coughing, Shortness of breath
    • Wall is broken -> coughing up blood
    • firm and has a pale white to tan cut surface.
  16. Annual Deaths Attributable to Cigarette Smoking in US
    • 480,000 in total
    • 29% lung cancer (also the no. 1 cause)
    • 28% ischemic heart disease
  17. Alcohol Abuse
    • A major worldwide health problem
    • the legal Blood Alcohol Concentration (BAC) limit for Driving Under the Influence: 0.08%
  18. Factors that influence BAC
    • Type of Alcoholic Beverage
    • Rate of Ingestion
    • Rate of Absorption
    • Rate of Tissue Distribution
    • Rate of Metabolism
    • Rate of Excretion
  19. Effects of Blood Alcohol Levels
    • 20mg/dL -> Decreased inhibitions, a slight feeling of intoxication
    • 80 -> Decrease in complex cognitive functions and motor performance
    • 200 -> Obvious slurred speech, motor incoordination, irritability, and poor judgment
    • 300 -> Light coma and depressed vital signs
    • 400 -> Death
  20. Alcohol Metabolism pathways in hepatocytes
    • Metabolism of ethanol: oxidation of ethanol to acetaldehyde by three different routes and the generation of acetic acid.
    • Oxidation by ADH (alcohol dehydrogenase) - takes place in the cytosol, the most important route;
    • CYP2E1 (cytochrome P-450 xenobiotic-metabolizing enzyme) - located in the ER (microsomes) and may also generate ROS
    • Catalase - located in peroxisomes (5% of ethanol metabolism)
    • Oxidation of acetaldehyde by aldehyde dehydrogenase (ALDH) - occurs in mitochondria
    • Both steps with ADH and ALDH also convert NAD+ to NADH and H+ at the same time
    • Liver is the major organ that metabolizes alcohol
    • The metabolic tolerance of alcohol is partially explained by a fivefold to tenfold induction of CYP2E1 -> increase the metabolism of ethanol and other drugs and chemicals.
  21. Mechanism of liver fatty change in alcoholism
    Excess of NADH over NAD (nicotinamide adenine dinucleotide) -> stims lipid biosynthesis -> Cytoplasmic accumulation of fat and hyaline, decreased oxidation of fatty acids
  22. Diseases Caused by Ethanol Abuse
    • Liver:
    • - Fatty change by Toxicity
    • - Acute hepatitis
    • - Alcoholic cirrhosis
    • Nervous system:
    • - Wernicke syndrome by Thiamine deficiency
    • - Korsakoff syndrome by Toxicity and thiamine deficiency
    • - Cerebellar degeneration by Nutritional deficiency
    • - Peripheral neuropathy by Thiamine deficiency
    • Cardiovascular system:
    • - Cardiomyopathy by Toxicity
    • - Hypertension by Vasopressor
    • GI tract:
    • - Gastritis by Toxicity
    • - Pancreatitis by Toxicity
    • Skeletal muscle:
    • - Rhabdomyolysis by Toxicity
    • Reproductive system:
    • - Testicular atrophy
    • - Spontaneous abortion
    • Fetus: Fetal alcohol syndrome
    • - Growth retardation by Toxicity: acetaldehyde
    • - Mental retardation
    • - Birth defects
  23. Drug injury
    • Therapeutic drugs -> adverse drug reactions
    • Nontherapeutic agents -> drug abuse
  24. Therapeutic Drugs (Medications) - Estrogens/NSAIDS
    • Oral Contraceptives (BCPs)
    • Hormone Replacement Therapy (HRT)
    • Acetaminophen (Tylenol)
    • Aspirin
  25. Acetaminophen (Tylenol)
    • Does not affect cyclooxygenase so bleeding associated with aspirin does not occur
    • Has analgesic and antipyretic actions but no anti-inflammatory action
    • Large doses may produce hepatic necrosis
  26. Acetaminophen metabolism and toxicity
    • 95% detoxified by Phase II enzymes -> excreted in urine as glucuronate or sulfate conjugates
    • 5% CYP2E1 activity -> NAPQI (N-acetyl-p-benzoquinone imine, toxic byproduct)
    • NAPQ is either conjugated with GSH (detoxified) in liver quickly, no toxicity, or (when overdose) involved with protein adducts or lipid peroxidation, which leads to hepatocyte necrosis and liver failure.
  27. Aspirin
    • Overdose - respiratory alkalosis followed by metabolic acidosis that may be fatal
    • Chronic aspirin toxicity (salicylism) - headache, dizziness, ringing in the ears (tinnitus), mental confusion, drowsiness, nausea, vomiting, and diarrhea
    • Inhibits cyclooxygenases (COX 1 & 2)
    • Erosive gastritis is a major cause of GI bleeding
    • May be implicated in Reye’s syndrome (swelling in liver and brain) in children < 15 years old, especially with influenza and chicken pox
  28. The common environmental pollutants
    • Outdoor air pollutants: sulfur dioxide, CO, ozone, nitrogen dioxide, lead, and particulate matter; Major target: Lungs
    • Indoor Air Pollution: CO, NO2 (from acid rain), Wood Smoke, Formaldehyde, Radon
  29. Carbon monoxide (CO)
    • car exhaust fumes
    • natural gas
    • Smoking
  30. Mechanisms of Carbon Monoxide Poisoning
    • combines with hemoglobin to form carboxyhemoglobin, 200x higher affinity than O2 - Tissue hypoxia
    • further damage by binding to myoglobin (60x higher affinity than O2)
  31. Clinical signs, Diagnosis & Treatment of CO poisoning
    • initial symptoms: headache, nausea, and dizziness.
    • more extensive exposures: symptoms of brain and heart hypoxia
    • recognized clinically: cherry-red color of the blood, skin, and mucous membranes due to the presence of carboxyhemoglobin.
    • Treatment: Immediate oxygen, maybe high pressure
  32. Radon
    • radioactive gas, alpha emitters, a decay product of uranium
    • widely distributed in soil and is prevalent in homes (especially in basements)
    • standard test in NJ houses
    • 10% of US homes have levels associated with an
    • increased risk of lung cancer.
    • second cause of lung cancer, next to smoking
    • spend less time in the basement & Proper venting
  33. Lead poisoning
    top environmental health hazard for young children-higher absorption
  34. SOURCES of Lead poisoning
    • Paint dust & flakes
    • House dust
    • Urban soil
    • Automotive exhaust
    • Spray painting
    • Mining & extracting lead
    • Battery burring
  35. Consequences of lead exposure
    • central and peripheral nervous systems - headache, dizziness, memory deficits, and decreased nerve conduction velocity
    • Blood - early and characteristic changes due to the interference of heme biosynthesis - microcytic hypochromic anemia; stiffening in the blood system; punctate basophilic stippling of RBC.
    • GI - abdominal pain due to severe contraction of smooth muscle; colicky and rigidity
    • Lead deposition in the gums
  36. Effects of lead poisoning in children related to blood levels
    • different level cause different symptoms
    • neural -> blood -> GI -> kidney, brain -> death
  37. Prominent Basophilic Stippling
    • Very fine, pinpoint cytoplasmic granules distributed evenly in the cytoplasm.
    • due to impaired RNA degradation.
    • Severe lead poisoning is treated with dimercaprol, an intramuscular heavy metal chelator
  38. Most cancer results from the interaction of genetics and the environment factors. Genetic factors—5-10% of cancer. External, "environmental" factors that act in conjunction with both genetic and acquired susceptibility responsible for the rest cases.
  39. The process of neoplasia begins with cell transformation when normal cells are exposed to radiation, chemical carcinogens, infectious agents, which causes DNA damage. The cell tries to repair, and if it’s not successful, it can cause point mutations, translocations, and/or amplifications, which transforms the cells, and leads to neoplasia
  40. Cancer Prevention
    • Modify hazardous lifestyles.
    • Reduction of involuntary exposure to carcinogens.
Card Set
Gen Path L19
Gen Path L19 Environmental Diseases