Quantitative relationship between arsenic exposure and AP-1 activity in mouse urinary bladder epithelium.
Because of the potential of arsenic for causing cancer in humans, and of the fact of widespread environmental and occupational exposure, deriving acceptable human-limit values has been of major concern to industry as well as to regulatory agencies. Based upon epidemiological evidence and mechanistic studies, it has been argued that a non-linear dose-response model at low-level exposures is more appropriate for calculating risk than the more commonly employed linear-response models. In the present studies, dose-response relationships and recovery studies employing a cancer precursor marker, i.e., activating protein (AP)-1 DNA-binding activity, were examined in bladders of mice exposed to arsenic in drinking water and compared to histopathological changes and arsenic tissue levels in the same tissue. While AP-1 is a functionally pleomorphic transcription factor regulating diverse gene activities, numerous studies have indicated that activation of the MAP kinase pathway and subsequently increased AP-1 binding activities, is a precursor for arsenic-induced cancers of internal organs as well as the skin. We observed previously that within 8 weeks of exposure AP-1 activation occurs in urinary bladder tissue of mice exposed to arsenic in the drinking water. In the present studies, C57BL/6 mice were exposed to sodium arsenite at various concentrations in the drinking water for 8 consecutive weeks. Minimal but observable AP-1 activity occurred in bladder tissue at exposure levels below which histopathological changes or arsenic tissue accumulation was detected. Marked AP-1 DNA-binding activity only occurred at exposure levels of sodium arsenite above 20 microg/ml, where histopathological changes and accumulation of arsenic in the urinary bladder epithelium occurred. Although the experimental design did not allow statistical modeling of the entire dose-response curve, the general shape of the dose-response curve is not inconsistent with the previously proposed hypothesis that arsenic-induced cancer follows a non-linear dose-response model.
Simeonova
P P
PP
Toxicology and Molecular Biology Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown West Virginia 26505-2888, USA.
Wang
S
S
Kashon
M L
ML
Kommineni
C
C
Crecelius
E
E
Luster
M I
MI
D000818:Animals; D001151:Arsenic / Q000493:pharmacokinetics / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000493:pharmacokinetics / Q000633:toxicity*; D004249:DNA Damage; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004326:Drinking; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018570:Risk Assessment; D014018:Tissue Distribution; D018808:Transcription Factor AP-1 / Q000096:biosynthesis*; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology
D002274:Carcinogens, Environmental; D004268:DNA-Binding Proteins; D018808:Transcription Factor AP-1; D001151:Arsenic