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PHA 315 > Teratology/Genetic Toxicology > Flashcards

Teratology/Genetic Toxicology Flashcards

1
Q

Specific mechanisms of actions of teratogens

A
  • Altered nucleic acid integrity/function
  • Excessive or reduced apoptosis
  • Reduced biosynthesis
  • Impeded morphogenetic movements
  • Mechanical disruption of tissues
  • Disruption of enzymatic function
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2
Q

US FDA categories of teratogens

A

Categories A, B, C, D, X

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3
Q

Category A teratogens

A

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).

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4
Q

Examples of Category A teratogens

A

levothyroxine
folic acid
liothyronine

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5
Q

Category B teratogens

A

Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

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6
Q

Examples of Category B teratogens

A

Metformin
Hydrochlorothiazide
Cyclobenzaprine
Amoxicillin
Pantoprazole

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7
Q

Category C teratogens

A

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.

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8
Q

Examples of category C teratogens

A

Tramadol
Gabapentin
Amlodipine
Trazodone

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9
Q

Category D teratogens

A

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.

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10
Q

Examples of Category D teratogens

A

Lisinopril
Alprazolam
Losartan
Clonazepam
Lorazepam

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11
Q

Category X

A

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.

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12
Q

Examples of Category X teratogens

A

Atorvastatin
Simvastatin
Warfarin
Methotrexate
Finasteride

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13
Q

Groups of teratogenic agents

A
  • 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
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14
Q

Teratogenic effects of radiation

A

Kills rapidly proliferating cells and acts as mutagenic agents

Effects include spina bifida, cleft palate, limb defects

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15
Q

Teratogenic effects of hyperthermia

A

Anencephaly
Spina bifida
Mental retardation
Cleft palate
Cleft lip
Limb defects

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16
Q

Known teratogenic drugs

A
  • ACE inhibitors
  • Anti epileptic drugs like phenytoin, carbamazepine, Valproic acid
  • Cocaine
  • Thalidomide
  • Tetracycline
  • Ethanol
  • Lithium
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17
Q

Possible teratogens

A

Primidone
Zidovudine
Cigarette smoking
Ergotamine
Streptomycin
Disulfiram

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18
Q

Critical periods for thalidomide with effects

A

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

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19
Q

Teratogenic effects of anti-epileptics

A

Trimethadione and Fetal Hydantoin Syndrome:

  • Xtic dysmorphogenesis
  • Facial clefts
  • Microencephaly
  • Nail dysplasia
  • Delayed devt
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20
Q

Teratogenic effects of valproic acid

A

Neural tube defects

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21
Q

Teratogenic effects of anticoagulants

A

Hypoplasia of nasal cartilage
Stippled epiphyses
CNS defects

22
Q

Teratogenic effects of tetracyclines

A
  • Acute fatty liver
  • Hepatotoxicity
  • Stained decidual teeth
  • Under developed enamel
  • Heart defects, club foot
23
Q

Teratogenic effects of ACE inhibitors

A
  • Oligohydramnios
  • Hypoplasia of the skull bones
  • Intrauterine growth restriction(IUGR)
  • Renal dysfunction
  • Fetal death
24
Q

Teratogenic effects of retinoic acid

A

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.
25
Q

Teratogenic effects of alcohol

A
  • Microcephaly
  • Mental retardation (leading cause)
  • Cardiac and renal abnormalities
  • Maxillary hypoplasia

Mild:
- Growth retardation
- Attention deficits with normal intelligence

26
Q

Teratogenic effects of cocaine

A
  • Spontaneous abortion
  • Prematurity
  • IUGR
  • Microcephaly
  • Cerebral infarction
  • Urogenital anomalies
  • Neurobehavioral disturbances, and neurologic abnormalities.
27
Q

Teratogenic effects of nicotine

A

Associated with IUGR; behavioral disturbances

28
Q

Teratogenic effects of androgenic agents

A

Synthetic Progestins (ethisterone, norethisterone) to prevent abortion, have androgenic action - masculinization of female genitalia.

29
Q

Teratogenic effects of DES

A

Caused carcinomas in cervical and vagina of women exposed in utero

30
Q

Teratogenic effects of cortisone

A

Cleft lip palate in susceptible rat and rabbit strains

31
Q

Teratogenic effects of heavy metals

A

Organic Mercury —- multiple neurological symptoms

Lead —- increased abortions, growth retardation, neurological disorders.

32
Q

Male-mediated teratogenesis causes

A

Mutations
LBW
Birth defects

33
Q

Drugs that double as genotoxicants

A

Carboplatin
Melphalan
Topotecan
Busulfan

34
Q

Non-genotoxic agents examples

A

Phenobarbital
CCl4
DES
Cyclosporine
Hexachloroethane
Clofibrate

35
Q

Mechanisms of actions of non-genotoxic agents

A

Cytotoxicity
Oxidative stress
Hormone modifiers
Immunosuppression
Inflammation
DNA methylation

36
Q

Polycyclic aromatic hydrocarbons; damage caused and mechanism of action

A

Damage caused:
a. Adducts formation
b. oxidative damage

Mechanism:
a. Metabolic activation
b. Induction of CYP450
c. Formation and redox cycling of quinones.

37
Q

Alkylating agents, nitrosamines; damage caused and mechanism of action

A

Damage caused: Methylated or ethylated bases
Mechanism: Metabolic activation

38
Q

Halogenated organics (PCBs, dioxins, chlorinated solvents, perfluorocarbons, BAHs); damage caused, MOA

A

Damage caused:
a. Oxidative damage
b. Adducts formation

Mechanism:
a. Induction of CYP450
b. Interference with mitochondrial function
c. Modification of peroxisome function

39
Q

Pesticides; damages caused, MOA

A

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

40
Q

Transition metals and heavy metals; damage caused, MOA

A

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

41
Q

Ionizing radiation; damage caused, MOA

A

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

42
Q

Ultraviolet light: damage caused, MOA

A

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

43
Q

Assays for detecting genetic alteration

A

Ames
Comet assay
SCE
Chromatid aberration assay
Micronucleus assay
Molecular analysis of mutations and gene expression

44
Q

Polycyclic aromatic hydrocarbons sources

A

Combustion of organic matter and fossil fuels
Crude oil and coal spills
Copier toner
Cartridges
Asphalt
Lubricants
Used oils

45
Q

Alkylating agents sources

A

Rubber industry, dyes

46
Q

Halogenated organically like PCB and chlorinated solvents

A

Paper processing
Combustion and manufacture of plastics
Industrial manufacturing

47
Q

Aziridine quinone sources

A

Chemotherapy

48
Q

Chlorinated hydrocarbons sources

A

Environmental

49
Q

Metals and metal compounds (cisplatin)

A

Chemotherapy

50
Q

Nitrogen mustard (cyclophosphamide)

A

Chemotherapy

51
Q

Transition/heavy metals

A

Metallurgical industries
Building materials and paint
Agric chemicals
Photographic emulsions

52
Q

Ionizing radiation sources

A

Nuclear weapons
Uranium ore mining
Sunlight

PHA 315 (6 decks)

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