Teratology/Genetic Toxicology Flashcards
Specific mechanisms of actions of teratogens
- Altered nucleic acid integrity/function
- Excessive or reduced apoptosis
- Reduced biosynthesis
- Impeded morphogenetic movements
- Mechanical disruption of tissues
- Disruption of enzymatic function
US FDA categories of teratogens
Categories A, B, C, D, X
Category A teratogens
Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters).
Examples of Category A teratogens
levothyroxine
folic acid
liothyronine
Category B teratogens
Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.
Examples of Category B teratogens
Metformin
Hydrochlorothiazide
Cyclobenzaprine
Amoxicillin
Pantoprazole
Category C teratogens
Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
Examples of category C teratogens
Tramadol
Gabapentin
Amlodipine
Trazodone
Category D teratogens
There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
Examples of Category D teratogens
Lisinopril
Alprazolam
Losartan
Clonazepam
Lorazepam
Category X
Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.
Examples of Category X teratogens
Atorvastatin
Simvastatin
Warfarin
Methotrexate
Finasteride
Groups of teratogenic agents
- Infectious agents
- Physical agents: Radiation, hyperthermia
- Drugs and chemical agents
- Hormones
- Maternal metabolic imbalances: Diabetes/Alcoholism/Phenylketonuria
- Nutritional deficiencies: iodine deficiency- cretinism
- Obesity
- Male mediated teratogenesis
Teratogenic effects of radiation
Kills rapidly proliferating cells and acts as mutagenic agents
Effects include spina bifida, cleft palate, limb defects
Teratogenic effects of hyperthermia
Anencephaly
Spina bifida
Mental retardation
Cleft palate
Cleft lip
Limb defects
Known teratogenic drugs
- ACE inhibitors
- Anti epileptic drugs like phenytoin, carbamazepine, Valproic acid
- Cocaine
- Thalidomide
- Tetracycline
- Ethanol
- Lithium
Possible teratogens
Primidone
Zidovudine
Cigarette smoking
Ergotamine
Streptomycin
Disulfiram
Critical periods for thalidomide with effects
21-22 days: absent external ears, cranial nerve disorders
24-27 days: phocomelia (especially arms)
27-28 days: phocomelia (especially lower limbs)
34-36 days: hypoplastic thumbs, anorectal stenosis
Teratogenic effects of anti-epileptics
Trimethadione and Fetal Hydantoin Syndrome:
- Xtic dysmorphogenesis
- Facial clefts
- Microencephaly
- Nail dysplasia
- Delayed devt
Teratogenic effects of valproic acid
Neural tube defects
Teratogenic effects of anticoagulants
Hypoplasia of nasal cartilage
Stippled epiphyses
CNS defects
Teratogenic effects of tetracyclines
- Acute fatty liver
- Hepatotoxicity
- Stained decidual teeth
- Under developed enamel
- Heart defects, club foot
Teratogenic effects of ACE inhibitors
- Oligohydramnios
- Hypoplasia of the skull bones
- Intrauterine growth restriction(IUGR)
- Renal dysfunction
- Fetal death
Teratogenic effects of retinoic acid
Critical period: 5-7 weeks after LMP
- Spontaneous abortion and birth defects - High.
- Microtia
- Micrognathia
- Cleft palate and/or thymic aplasia, CVS anomalies, and NTDs.
Teratogenic effects of alcohol
- Microcephaly
- Mental retardation (leading cause)
- Cardiac and renal abnormalities
- Maxillary hypoplasia
Mild:
- Growth retardation
- Attention deficits with normal intelligence
Teratogenic effects of cocaine
- Spontaneous abortion
- Prematurity
- IUGR
- Microcephaly
- Cerebral infarction
- Urogenital anomalies
- Neurobehavioral disturbances, and neurologic abnormalities.
Teratogenic effects of nicotine
Associated with IUGR; behavioral disturbances
Teratogenic effects of androgenic agents
Synthetic Progestins (ethisterone, norethisterone) to prevent abortion, have androgenic action - masculinization of female genitalia.
Teratogenic effects of DES
Caused carcinomas in cervical and vagina of women exposed in utero
Teratogenic effects of cortisone
Cleft lip palate in susceptible rat and rabbit strains
Teratogenic effects of heavy metals
Organic Mercury —- multiple neurological symptoms
Lead —- increased abortions, growth retardation, neurological disorders.
Male-mediated teratogenesis causes
Mutations
LBW
Birth defects
Drugs that double as genotoxicants
Carboplatin
Melphalan
Topotecan
Busulfan
Non-genotoxic agents examples
Phenobarbital
CCl4
DES
Cyclosporine
Hexachloroethane
Clofibrate
Mechanisms of actions of non-genotoxic agents
Cytotoxicity
Oxidative stress
Hormone modifiers
Immunosuppression
Inflammation
DNA methylation
Polycyclic aromatic hydrocarbons; damage caused and mechanism of action
Damage caused:
a. Adducts formation
b. oxidative damage
Mechanism:
a. Metabolic activation
b. Induction of CYP450
c. Formation and redox cycling of quinones.
Alkylating agents, nitrosamines; damage caused and mechanism of action
Damage caused: Methylated or ethylated bases
Mechanism: Metabolic activation
Halogenated organics (PCBs, dioxins, chlorinated solvents, perfluorocarbons, BAHs); damage caused, MOA
Damage caused:
a. Oxidative damage
b. Adducts formation
Mechanism:
a. Induction of CYP450
b. Interference with mitochondrial function
c. Modification of peroxisome function
Pesticides; damages caused, MOA
Damage caused:
a. Oxidative damage
b. methylated or ethylated bases
Mechanism:
a. Induction of CYP450
b. Redox cycling (diquat)
c. Interference with mitochondrial function
d. Modification of peroxisome function
Transition metals and heavy metals; damage caused, MOA
Damage caused:
a. Oxidative damage
b. Adducts crosslinks (As, Cr, Pt)
Mechanism:
a. Reduction of O2 to form superoxides
b. Reduction of H2O2
c. Interference with mitochondrial metabolism d. Inhibition of DNA repair
e. Inhibition of antioxidant enzymes
f. Glutathione depletion
Ionizing radiation; damage caused, MOA
Damage caused:
a. Oxidative damage
b. Base loss and fragmentation
c. DNA-DNA cross links
Mechanism:
a. Formation of oxy radicals from H2O and O2 b. Excitation of O2 to singlet oxygen
c. Direct interaction of radioactive particle with DNA sugars and bases
Ultraviolet light: damage caused, MOA
Damage caused:
a. Oxidative damage
b. Formation of pyrimidine dimers photoproducts
Mechanism: a.
Excitation of O2 to singlet oxygen
b. Interaction of UV light with bases
Assays for detecting genetic alteration
Ames
Comet assay
SCE
Chromatid aberration assay
Micronucleus assay
Molecular analysis of mutations and gene expression
Polycyclic aromatic hydrocarbons sources
Combustion of organic matter and fossil fuels
Crude oil and coal spills
Copier toner
Cartridges
Asphalt
Lubricants
Used oils
Alkylating agents sources
Rubber industry, dyes
Halogenated organically like PCB and chlorinated solvents
Paper processing
Combustion and manufacture of plastics
Industrial manufacturing
Aziridine quinone sources
Chemotherapy
Chlorinated hydrocarbons sources
Environmental
Metals and metal compounds (cisplatin)
Chemotherapy
Nitrogen mustard (cyclophosphamide)
Chemotherapy
Transition/heavy metals
Metallurgical industries
Building materials and paint
Agric chemicals
Photographic emulsions
Ionizing radiation sources
Nuclear weapons
Uranium ore mining
Sunlight
