PLH 419 General Principles of Toxicology Defination of

PLH - 419

General Principles of Toxicology Ø Defination of toxicology. Ø Purposes of toxicology. Ø Terms of toxicology ( Toxin and toxicant). Ø Classification of toxic agents (Target organs, use, source, effects, physical state, chemical stability, chemical structure, poisoning potential, biochemical mechanisms of action). Ø Development of toxicology (especially after the widespread use of anaesthetics, disinfectants, radioactivity, vitamins). Ø The tragic of thalidomide incident.

Branches of Toxicology A toxicologist is trained to examine the nature of toxic agents effects including their cellular, biochemical and molecular mechanisms of action and assess the probability of their occurrence. Categories Ø Descriptive toxicologist. Ø Mechanistic toxicologist. Ø Regulatory toxicologist. Ø Occupational (Industrial) toxicology. Ø Environmental toxicology. Ø Ecotoxicology. Ø Forensic toxicology. Ø Analytical toxicology. Ø Clinical toxicology.

Exposure and Toxic Responses Ø Exposure classes (toxicants in food, air, water, and soil as well as toxicants characteristic of domestic and occupational settings). Ø Toxic effects may be systemic or local at the site of exposure. Ø The target organs that are affected may vary depending on dosage and route of exposure. Ø Sings and symptoms are the effects produced by the action of a particular poison on the physiological function of the body. Ø Certain general symptoms suggested the possibility of a number of poisons; 1. Sudden death (aconitine, cyanide and barium compounds). 2. Eyes (ergot, morphine, pilocarpine, atropine and cocaine). 3. Breath (acetic acid, ammonia, phenol, ether and iodine). 4. Mouth (atropine, pilocarpine and ammonia).

Exposure and Toxic Responses (cont. ) 5. Skin (atropine, pilocarpine, strong acids and alkalies, cyanosis produced by aniline, acetanilide). 6. GIT (metals, ergot and food poisons). 7. Cardiovascular system (quinidine, digitalis, ephedrine and reserpine). 8. Liver (carbone tetrachloride and chloroform). 9. Kidney (phenol and sulphonamides). 10. Nerves (peripheral neuritis due to antimony and arsenic). 11. Skeletal muscle (curare and flaxedil). 12. Blood changes (anaemia by benzene, haemolysis due to saponins, leukopenia by benzene). 13. CNS (strychnine, picrotoxin, barbiturates, ether, alcohol).

Factors That Influence Toxicity There are numerous factors which may modify the patient's responses to the toxic agent. For examples; Ø Physicochemical composition of the toxicant (solids, liquids, particle size, p. H), Ø Dose and concentration (aspirin tablets, dilution), Ø Routes of administration (inhalation > IV > IP > SC > IM > ID > oral > topical), Ø Metabolism of the toxic agent (more polar or more toxic), Ø State of health (person with severe hepatic or renal disease, hypertension, head injuries), Ø Age and maturity (gray-baby syndrome, reduced pharmacokinetics in elderly people), Ø Nutritional state and dietary factors (stomach contents, types of food, proteins), Ø Pharmacogenetics or idiosyncrasy (succinyl-choline, aspirin, fava beans), Ø Sex (erythromycin, lipid sol. , larger BV and tissue mass in men which dilute the chemical), Ø Environmental (temperature, occupation (liver-metab), living conditions), Ø Chemical interactions (the increase or decrease of toxicity by simultaneous or

Evaluation of Safety of Chemicals and drugs Sources of information on safety 1. Experimental studies 2. Controlled clinical studies 3. Epidemiological studies Experimental studies Ø Goals of toxicity studies. Ø Adv. & disadv. of toxicity tests using experimental animals. Ø Characteristics of ideal animal species. Ø Examples. Ø Strains of rats 1. Specific pathogen free animals, 2. Germ free animals, 3. Dirty animals, 4. Rats for specific purposes.

Experimental toxicity tests Toxicity tests General toxicity studies Specific studies Acute toxicity tests Prolonged toxicity tests a. Toxicometric studies a. Subacute toxicity tests (2 -4 Weeks) a. Reproductive toxicity b. Skin & eye studies b. Subchronic toxicity tests (≈3 months) b. Teratogenic studies c. Pyramidal test c. Chronic toxicity studies (>3 months) c. Carcinogenic studies d. Life span toxicity studies d. Mutagenic studies

Acute toxicity tests: Toxicometric studies LD 50: Median lethal dose (the dose that causes 50% mortality in a population). LC 50: Median lethal concentration (inhaled drugs). LD 0: Represents the dose at which no individuals are expected to die. This is just below the threshold for lethality. LD 10: Refers to the dose at which 10% of the individuals will die. EDs: Effective Doses that are used to indicate the effectiveness or harmful effect (paralysis) of substances. TI: Therapeutic Index (is used to compare therapeutically effective dose to the toxic dose = LD 50 / ED 50).

Acute toxicity tests: Toxicometric studies (cont. ) Factors affecting LD 50. Ø Species, age, sex, body weight, general health condition, strain, diet, nutritional status & number of animals used in the test Ø Route of administration (oral route differ from parental route) Ø Environmental conditions (lab conditions) i. e. intra & inter laboratory conditions Ø Experimental procedure, stress, dosage formulation. Importance of LD 50: Classification of chemicals according to LD 50 of drugs given orally to rats into; Ø Super toxic chemicals: LD 50 < 5 mg/kg Ø Extremely toxic chemicals: LD 50 = 5 – 50 mg/kg Ø Very toxic chemicals: LD 50 = 50 – 500 mg/kg Ø Moderately toxic chemicals: LD 50 = 0. 5 – 5 g/kg Ø Slightly toxic chemical: LD 50 = 5 – 15 g/kg Ø Practically non- toxic compound: LD 50 > 15 g/kg

Acute toxicity tests: Toxicometric studies (cont. ) Ø The use of ED 50 and LD 50 doses to derive the TI may be misleading as to safety, depending on the slope of the dose-response curves for therapeutic & lethal effects. Ø Knowledge of the slope is important in comparing the toxicity of various substances. Ø For some toxicants a small increase in dose causes a large increase in response (toxicant A, steep slope). For other toxicants a much larger increase in dose is required to cause the same increase in response (toxicant B, shallow slope). Ø To overcome this deficiency, toxicologists often use another term to denote the safety of a drug - the Margin of Safety (MOS). Ø The MOS is usually calculated as the ratio of the dose that is just within the lethal range (LD 01) to the dose that is 99% effective (ED 99). The MOS = LD 01/ED 99.

Acute toxicity tests: Toxicometric studies (cont. ) Ø NOAEL is the highest data point at which there was not an observed toxic or adverse effect. Ø LOAEL is the lowest data point at which there was an observed toxic or adverse effect. Ø The terms NOELs and LOELs do not necessarily imply toxic or harmful effects and may be used to describe beneficial effects of chemicals as well.

Acute toxicity tests: Skin & eye studies (Dermal) Ø Such testing may provide information on the adverse effects resulting from a dermal application of a single dose of a test substance. Ø The acute dermal test also provides the initial toxicity data for regulatory purposes, labelling, classification & subsequent subchronic & chronic dermal toxicity studies. Ø Comparison of acute toxicity by the oral & dermal route may provide evidence of the relative penetration of a test material. Ø Draize test 1. It is a simple and generalized test developed to study eye irritation in rabbits. 2. It is used as the animal test to identify human eye irritants. 3. The Draize test can adequately identify most of the moderate to severe human eye irritants

Acute toxicity tests: Pyramidal single dose test Ø Large number of dogs ≈ 100 are given a single daily X dose of a compound under test. Ø At the end of the day, the number of dogs which died & those which survived is observed. Ø The procedure is continued, till all dogs die, then plotting is done. Ø It helps in studying the mechanism of drug toxicity. Ø It can be used to determine any pathological changes by examination of the animal after death. Ø The effect of the drug on all body organs can be examined. Ø Clinical chemical tests can be performed on living animals (hematology, and detection of different biotransformation and excretion product (metabolites), and determination of t½ of the compound).

Prolonged toxicity studies Ø They predict any cumulative effect of the drug. Ø Compound under test is given daily in 3 dose levels for 2 – 4 weeks (Subacute), for 90 days (Subchronic) or more than 90 days (Chronic). Ø Animals are observed for different parameters: physiological, clinical and chemical tests, behaviour, CNS & autonomic profiles. Ø At the end of the test, animals are subjected to the following tests & then are killed. 1. Hematological studies: hemoglobin, RBCs, WBCs, platelets. 2. Clinical chemistry studies: serum creatinine, ALT, AST. 3. Histopathological studies: for different organs (spinal cord, heart, kidney). Ø Life – Span Toxicity Test 1. The same previous procedures are applied but treatment with chemicals starts after weaning of offsprings (litters). 2. Administration of the chemical is continued till death of animals. 3. When animals die spontaneously, the same previous parameters are determined.

Specific Toxicity Studies: Reproductive toxicity (toxicity on male or female reproductive system) Ø Toxic effects may cause: Decreased libido and impotence, Infertility, Interrupted pregnancy (abortion, fetal death, or premature delivery), Infant death or childhood morbidity, Altered sex ratio and multiple births, Chromosome abnormalities and Childhood cancer. Ø Developmental Toxicity (toxicity on developing embryo or fetus) Embryolethality (Failure to conceive, spontaneous abortion), Embryotoxicity (Growth retardation or delayed growth of specific organ systems), Teratogenicity (Irreversible conditions that leave permanent birth defects in live offspring). Ø Carcinogenic studies Carcinogenicity is a complex multistage process of abnormal cell growth and differentiation which can lead to cancer. The initial neoplastic transformation results from the mutation of the cellular genes that control normal cell functions. Mutation may lead to abnormal cell growth. It may involve loss of suppresser genes that usually restrict abnormal cell growth. Many other factors are involved (e. g. , growth

Necessary measures to prevent further deterioration of the patient; 1. Stabilization of the patient, 2. Diagnosis of the poison, 3. Prevention and treatment of poisoning, 4. Administration of antidotes (specific antidotes or using the antidote cocktail), 5. Continuing care. Principles in management of Poisoned Patient 1. Stabilization of the patient (ABCDEs measures) A. Evaluation of Airway obstruction Causes (Mucosal swelling, Secretions, Posterior displacement of the tongue and Foreign bodies). Signs and Symptoms (Dyspnea, Dysphoria, Air hunger, Cyanosis, Diaphoresis and Tachypnea). Measures (Clearing the airway, use of nose-pharyngeal tube, Intubation or Cricothyroidotomy). B. Evaluation of Breathing (by ventilation and oxygenation) Causes (Respiratory depressant drugs, Pneumonia, Pulmonary edema, Lung abscess, Pulmonary emboli, Bronchospasm from numerous environmental & occupational sources and Tetanus). Signs and Symptoms (Tachypnea, Cyanosis, Hypoventilation and altered mental state). Evaluated by measuring of blood gases (Pa. CO 2, Pa. O 2), Chest X-ray, or Tidal volume.

Principles in management of Poisoned Patient (cont. ) C. Evaluation of (C) Circulation Signs and Symptoms of inadequate tissue perfusion is shock (Depressed consciousness, Decreased blood pressure, Peripheral vasoconstriction, Metabolic acidosis and Oliguria) Treatment (Position change, Vasopressors as Dopamine and Norepinephrine, and Fluids). D. Evaluation of Depression (D) or Excitation (E) Depression is evaluated by (measuring the pupillary size, pupillary light reflex, motor responses to pain, and /or spontaneous eye movements). Treatment of depressed patient (coma cocktail: Glucose, Thiamine & Naloxone ) Excitation is manifested as seizures. Treatment of generalized seizures secondary to toxins (Diazepam, Phenytoin, Phenobarbital, General anaesthesia, Enhancement of drug elimination by Hemodialysis). Treatment of violent patient (Benzodiazepines with Haloperidol and stabilization of blood glucose level).

Principles in management of Poisoned Patient (cont. ) 2. The diagnosis of poisons Once the patient has been stabilized, the potential poison has to be identified. The diagnosis of poisoning involves the following; 1. History given by the patient himself or relatives. 2. Physical examination of the patient. 3. Laboratory investigations. I. History Adults (Conscious or unconscious patients). Children (presence of traces, disintegrated tablets, abnormal behaviour or GIT disturbances). II. Physical examination of the patient (Blood pressure, pulse, respiration, temperature, eyes, mouth, skin, abdomen, nervous system). III. Laboratory investigations (Toxicant extraction from Urine, Blood, Hair, Meconium, Saliva or Sweat samples, screening by TLC, GLC, Enzyme-mediated immunoassay techniques.

Principles in management of Poisoned Patient (cont. ) 3. Prevention and treatment of poisoning A- Non ingested poison 1. Inhalation exposures Ø Immediate, cautious removal of the patient from the hazardous environment. Ø Administration of 100% humidified O 2, assisted ventilation, and bronchodilators. Ø Observe for edema of the respiratory tract and later non-cardiogenic pulmonary edema. Ø Arterial blood gas assays, chest examination, and blood tests for the criminal substance (e. g. , cyanide) should be performed. Ø Treatment should not await laboratory results. 2. Dermal exposures Ø Attendees should wear protective gear (gloves, gown, shoe covers). Ø Remove the patient’s contaminated clothes, contact lenses, and jewelry immediately. Ø Gently rinse and wash the skin with copious amounts of water for at least 30 minutes. Ø Do not use forceful flushing in a shower. Use slightly cold water and soap of oily substances. Ø Toxic substances such as organophosphorous compounds, metal compounds, phenol, may penetrate the intact skin and must be handled with proper protective equipment. 3. Ocular exposures Ø Ocular decontamination consists of at least 15 minutes of immediate irrigation of eyes with normal saline or water. Alkaline or acid irrigating solutions should be avoided. Ø Continue to irrigate the eye for as long as the p. H is abnormal. Ø Alkaline corneal burns are requiring ophthalmic consultation.

Principles in management of Poisoned Patient (cont. ) B- Ingested poison 1 - Dilution of the poison with water. 2 - Prevention of further absorption of poison. Ø Induction of Emesis (Syrup of ipecac and Apomorphine). Ø Gastric lavage (noso-gastric or an oro-gastric tube). Ø Adsorption by activated charcoal (exceptions poisonings with heavy metals). Ø Cathartics (hyper-osmotic saline, bulk-forming stimulant, and lubricant laxatives). 3. Enhancement of elimination of absorbed poison. A. Forced diuresis (mannitol or furosemide) and p. H alteration (Na. HCO 3). B. Extracorporeal techniques: Ø Peritoneal dialysis (Diffusion of toxins from mesenteric capillaries across the peritoneal membrane into dialysate dwelling in the peritoneal cavity). Ø Hemodialysis (Two catheters are inserted into the patient’s femoral vein. Blood is pumped from one catheter through the dialysis unit (a cellophane bag) and returned through the other catheter. Ø Hemofiltration (Similar to hemodialysis, except that the blood is pumped through a hemifilter, where waste products and water are removed by hydrostatic pressure. Replacement fluid is added and the blood is returned to the patient). Ø Hemoperfusion (The blood is withdrawn from the patient and passed directly over the adsorbing material contained in sterile columns to remove toxic materials). Ø Plasmapheresis and Plasma exchange (separation of cellular blood components from plasma then cells are resuspended in fresh frozen plasma and reinfused again). Ø Exchange transfusion (removal of the patient’s blood, replacement with fresh whole blood). Ø Plasma perfusion (combination of plasmapheresis and hemoperfusion).

Principles in management of Poisoned Patient Hemodialysis Semipermeable membrane Peritoneal dialysis (cont. )

Principles in management of Poisoned Patient (cont. ) 4. Inactivation of the absorbed poison (Antidotes). 1. Chelators as Deferoxamine, Dimercaprol, EDTA, Penicillamine, DMSA for HMs. 2. Cyanide antidote as Dicobalt Edetate, Cyanide antidote kit (Amylnitrite, Na nitrite, and Na thiosulphate) and Hydroxocobolamin. 3. Calcium salts as Calcium gluconate and calcium chloride (hydrofluoric acid skin burns, neuromuscular paralysis, ingestion of fluoride salts, calcium channel blocker overdose, Bblocker overdose). I. V. Ca 2+ gluconate should be given slowly. 4. Antivenins against spiders and snake bites. 5. Antidotes to methyl alcohol (10% ethanol), & ethylene glycol (4 -methylpyrazole: 4 -MP). Ø 4 -aminopyridine (4 -AP), an antagonist of non-depolarizing neuromuscular blocking agents. Ø Benztropine and diphenhydramine, reverse drug induced dystonias (sustained M. C. ). Ø Atropine, antagonizes cholinergic stimuli at muscarinic receptors. Ø Dantrolene, decreases the release of Ca 2+ from the S. R. of skeletal muscle cells. Ø Flumazenil, competitive inhibitor to benzodiazepine at the GABA-BDZ receptor complex. Ø Folinic acid (leucovorin) and folic acid, precursor of the active form tetrahydrofolic acid. Ø Glucagon, increasing cardiac c. AMP, chronotropic and inotropic activity of the heart, release of glucose from liver stores, and the release of catecholamines. Ø Hyperbaric oxygen, displaces CO from HB, myoglobin and cytochrome oxidase enzyme. Ø Methylene blue, an electron carrier, reduces methemoglobin to hemoglobin. Ø Pyridoxine is essential in the synthesis of GABA within the CNS. Ø Sodium bicarbonate, neutralizes hydrogen ions and raises p. H.

Teratogenesis is a prenatal toxicity characterized by structural or functional defects in the developing embryo or fetus. It also includes intrauterine growth retardation, death of the embryo or fetus, and transplacental carcinogenesis. Stages of intrauterine human development: Ø pre-implantation and post-implantation stages (0 8 weeks), teratogens may produce abortion, no effect at all, an anatomic defect (teratogenesis), or a metabolic or functional defect that may not be detected until later in life. Ø fetal development (9 weeks birth), influence neurologic development, growth, physiologic and biochemical functioning, mental development, and reproduction or death of the fetus. Teratology education: Anencephalic newborn Cleft lip and palate Microtia Congenital abnormalities (birth defects) comprise > 1/5 of all fatalities among newborns/infants. Ø Of these, the largest portion consists of cardiac abnormalities followed by lung abnormalities and chromosomal aberrations.

Teratogenesis (cont. ) Dose-effect relationship Ø Teratogens may demonstrate a dose-effect relationship. Ø With most agents, a dose threshold for teratogenic effects has not been determined. Ø Teratogens must reach the developing conceptus in sufficient amounts to cause their effects it depends on its m. wt. , polarity, lipid solubility and the existence of a specific protein carrier. FDA Classifications of Drug Risk A. No fetal risk shown in controlled human studies in all trimesters. B. Animal studies show a risk that is not confirmed in human studies during all trimesters. C. Fetal risk shown in controlled animal studies but no controlled human studies are available or studies in humans and animals are not available. D. Studies show fetal risk in humans (use of drug may be acceptable even with risks). X. Risk to fetus clearly outweighs any benefits from these drugs. Examples of teratogenic agents Ø Thalidomide (X). Limb defects and other congenital anomalies Ø Warfarin (D). Skeletal abnormalities (curvature of the spine) and Limb abnormalities. Ø Aminoglycosides (C) at high dose. VIII cranial nerve damage. Ø ACE inhibitors (D). Renal tubular dysplasia, skull and pulmonary hypoplasia. Ø Antineoplastics (D). Growth retardation, cleft palate, eyes, kidney, cardiac, limbs, skull defects. Ø Retinoids (X). H eart defect, spontaneous abortion, microtia or cognitive defects. Ø Other teratogenic agents as Ionizing radiation, infections (virus, syphilis, toxoplasmosis), metabolic imbalance (alcoholism, diabetes, folic acid deficiency, iodine deficiency,

One of the mechanisms of teratogenesis is Mutations Ø Mutations are heritable changes in the genome of a cell or an organism. Ø There are three different levels at which mutation takes place, namely at the DNA sequence level (gene mutations), at the chromatin structure level (structural chromosome aberrations) and at the chromosome number level (numerical chromosome aberrations). Ø Induced somatic cell mutations the development of secondary tumours. Ø Induced germ cell mutations abnormal reproductive outcomes. 1. Gene Mutations Ø Gene mutations are changes in base pair sequence within a gene. Ø Polymorphism; are variation in the DNA sequences. Ø Gene mutations can alter the amino acid sequence of the protein encoded by the gene. Ø Gene mutations arise either through the base substitutions, or the deletion or insertion of one or more bases from one or more codons, leading to a mispairing in the replication and transcription. Ø Gene defects can be diagnosed using DNA analyses by DNA sequencing and Micoarrays. The consequences of gene mutations can be: Ø Missense mutation : the code of an amino acid is altered into the code of another amino acid (expressed as decreases in function rather than by total loss). Ø Nonsense mutation : the code of an amino acid is changed into a termination code (causing a

Mutations: Gene Mutations (cont. ) Ø Most of these mutations lead to missing gene products or products that are unable to function. In rare cases, however, a mutation can also bring about the synthesis of a "better" protein, i. e. , one that is better suited for the environmental conditions. Ø Eero Mantyranta, a Finnish cross-country skier who won two gold medals in the 1964 Olympics, was born with a mutation in the erythropoietin receptor gene that allows his blood to carry significantly more oxygen than the average person's. Eero Mantyranta

Mutations: Examples Gene Mutations The inheritance of monogenetic diseases occurs in accordance with Mendel's laws. In this, one distinguishes among dominant and recessive genes. 1. Autosomal dominant inheritance D = dominant trait. Dd = children with trait "Dominant" means that having a mutation in just one of the two copies of a particular gene is all it takes for a person to have a trait. Examples of such diseases are: 1. Marfan's syndrome (abnormalities in connective tissues) due to mutations in the fibrillin-1 gene on 15 q 21. 1. 2. Aniridia (incomplete formation of the iris). 3. von Recklinghausen's disease (Neurofibromatosis: changes in skin coloring and the growth of tumors along nerves in the skin, brain, and other parts of the body).

Mutations: Examples Gene Mutations (cont. ) 2. Autosomal recessive inheritance d = recessive gene, dd = children with disease "Recessive" means that both copies of the gene must have a mutation in order for a person to have the trait. Examples for such diseases are: 1. Cystic fibrosis (disease of the mucus glands) due to mutations in the CFTR gene on 7 q 31. 2. 2. Familiar hemo-chromatosis (accumulates excess iron) due to mutations in the HFe gene. 3. Sickle cell anemia (atypical hemoglobin S). 4. Tay-Sachs disease (progressively destroys nerve cells in the brain and spinal cord) due to mutations in the HEXA gene. .

Mutations: Examples Gene Mutations (cont. ) 3. X chromosomal inheritance All male descendents are ill. Among the female descendents there are healthy and carriers. Both are phenotypically healthy. Examples for X chromosome-linked recessive diseases are: 1. Duchenne's muscular dystrophy due to mutations in the gene DMD, in Xp 21. 2. Hemophilia A and B (deficiencies of clotting factor VIII and factor IX, respectively). 3. Red-green blindness.

Mutations: Examples Gene Mutations (cont. ) 3. X chromosomal inheritance (cont. ) Ø Ø Ø 74 (normal color vision) 21 (dichromacy or anomalous trichromacy) No numbers (achromatopsia) Ø Ø 49 (normal color vision) No numbers (deuteranopic) Ø Ø 37 (normal color vision) No numbers (protanopic) Ø Ø 56 (normal color vision) No numbers (tritanopic)

Mutations: Structural Chromosome 2. Structural Chromosome Aberrations Ø Structural Chromosome Aberrations are changes in chromosome structure and involve gross alteration of the genetic material and are detected by light microscopy. Ø Structural aberrations are the result of chromosomal breaks that occur during cell division. Here deletion, rings and duplication (unstable) lead to an abnormal phenotype, while inversion, insertion as well as translocation (stable) can be balanced. This means that the carrier of this structural aberration can escape notice phenotypically, because the entire genetic material is present. Examples of structural chromosome aberrations are 1. Cri du chat syndrome (cry of the cat) due to the deletion of part of the short arm of chromosome 5. 2. Wolf-Hirshchhorn syndrome (mental and growth retardation) is due to the partial deletion of part of the short arm of chromosome 4. 3. CATCH 22 syndrome (cardiac, abnomal faces, thymic hypoplasia, cleft palate, hypocalcemia) is due to the deletion of the q 11. 13 region on chromosome 22.

Mutations: Structural Chromosome Aberrations (cont. ) Many of Structural Chromosome Aberrations can be detected with staining techniques such as Ø Giemsa staining techniques G= gaps, A= acentric fragments, B= breaks, R= centric rings Ø Banding techniques In this karyogram ring formations of chromosomes 1, 7 & 16 can be seen. This man can be phenotypically healthy. Problems occur when gametes are formed. Ø Fluorescence-in-situ-hybridization (FISH) techniques 40 XY t(14; 17; 19)

Mutations (cont. ) 3. Numerical Chromosome Aberrations Ø These are changes in the number of chromosomes in the genome. Ø When mutations change the number of whole chromosome sets present, polyploid cells result. Ø When mutations change parts of chromosome sets, aneuploid cells result. Ø The normal diploid genome is euploid, and contains a complete set of chromosomes from each parent, e. g. 2 n = 46 for humans. Thus, 45 or 47 chromosomes would be described as aneuploid, whereas cells with 69 chromosomes would be described as triploid (3 n). Ø Aneuploid nomenclature for autosomes in diploid organisms: The aneuploid condition 2 n-1 is called monosomic (meaning “one chromosome loss”), 2 n+1 is called trisomic, and 2 n -2 (where the -2 represents homologs) is nullisomic. Ø Aneuploid nomenclature for sex-chromosome in diploid organisms: The symbolism simply lists the copies of each sex chromosome, such as XXY, XYY, XXX, or XO. Mechanisms of Aneuploidy Induction Ø Non-disjunction of chromosomes at anaphase or Ø Chromosome loss during cell division.

Mutations: Numerical Chromosome Aberrations (cont. ) Aneuploidy due to non-disjunction in autosomes during spermatogenesis Ø Patau's syndrome (47, Y-13 -13: 90% lethality in the first year of life). Ø Edwards's syndrome (47, Y-18 -18: 90% lethality in the first year of life). Ø Down’s syndrome (47, Y-21 -21)

Mutations: Numerical Chromosome Aberrations (cont. ) Aneuploidy due to non-disjunction in sex chromosomes during spermatogenesis

Mutations: Numerical Chromosome Aberrations (cont. ) Examples of Aneuploidy due to non-disjunction in sex chromosomes during spermatogenesis Klinefelter’s syndrome (47, X-X-Y) Turner's syndrome (45, X-O)