Apoptosis (programmed cell death) as an indicator of xenobiotic toxicity
Xenobiotics alter the frequency and pattern of apoptosis (programmed cell death). Preliminary studies identified the mouse liver, with normally low levels of apoptosis, as a preferable test system to the chicken embryo limb, with normally high levels of apoptosis. The major purposes of these investigations, using the apoptogen and necrogen 1,1-dichloroethylene (DCE), were to determine if increases in apoptosis, (1) could be quantified as a direct result of treatment, (2) were dose- and time-dependent, (3) were independent of necrosis, (4) were associated with mitosis in the control of cell numbers and (5) were limited to specific areas of the liver. To these ends, food-deprived female, CF-1 mice were administered DCE ip under varying experimental conditions. Increased apoptosis occurred in a dose- and time-dependent manner after treatment with 12.5, 40, and 125 mg/kg for 0.5, 1, 2, 4 and 8 hr. Peak effects were observed at 4 hr. Apoptosis occurred only in the midzonal/pericentral areas of the liver. At 12.5 mg/kg, there were no effects on biochemical (alanine transaminase) and morphological indices of necrosis, establishing apoptosis as a separate phenomenon from necrosis. Increased {sup 3}H-thymidine incorporation (DNA synthesis), mitosis and the percentage of octaploid hepatocytes occurred from 24-48 hr after treatment with the apoptotic but non-necrotic dose of 40 mg/kg. Apoptosis only occurred in the midzonal/pericentral areas of the liver after multiple doses with DCE, indicating the zonal selectivity of the response. In conclusion, apoptosis, a normally occurring homeostatic process associated with mitosis in the control of cell numbers, is affected by selected xenobiotics in a dose-dependent manner. Xenobiotic-induced apoptosis in the liver occurs at low doses of xenobiotics which cause no other effects on tissue structure or function.
- Research Organization:
- Kansas Univ., Lawrence, KS (USA)
- OSTI ID:
- 5524395
- Resource Relation:
- Other Information: Thesis (Ph. D.)
- Country of Publication:
- United States
- Language:
- English
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59 BASIC BIOLOGICAL SCIENCES
LIVER
NECROSIS
XENOBIOTICS
TOXICITY
BIOLOGICAL INDICATORS
CHICKENS
DNA REPLICATION
DOSE-RESPONSE RELATIONSHIPS
MICE
THYMIDINE
TIME DEPENDENCE
TRACER TECHNIQUES
TRITIUM COMPOUNDS
ANIMALS
AZINES
BIRDS
BODY
DIGESTIVE SYSTEM
FOWL
GLANDS
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
ISOTOPE APPLICATIONS
MAMMALS
NUCLEIC ACID REPLICATION
NUCLEOSIDES
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PATHOLOGICAL CHANGES
PYRIMIDINES
RIBOSIDES
RODENTS
VERTEBRATES
560300* - Chemicals Metabolism & Toxicology
550501 - Metabolism- Tracer Techniques