Quantitative relationship between arsenic exposure and AP-1 activity in mouse urinary bladder epithelium

Pp. Simeonova et al., Quantitative relationship between arsenic exposure and AP-1 activity in mouse urinary bladder epithelium, TOXICOL SCI, 60(2), 2001, pp. 279-284
Citations number
Categorie Soggetti
Pharmacology & Toxicology
Journal title
ISSN journal
1096-6080 → ACNP
Year of publication
279 - 284
SICI code
Because of the potential of arsenic for causing cancer in humans, and of th e fact of widespread environmental and occupational exposure, deriving acce ptable 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-l evel exposures is more appropriate for calculating risk than the more commo nly 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 bladder s of mice exposed to arsenic in drinking water and compared to histopatholo gical changes and arsenic tissue levels in the same tissue. While AP-I is a functionally pleomorphic transcription factor regulating diverse gene acti vities, numerous studies have indicated that activation of the MAP kinase p athway and subsequently increased AP-1 binding activities, is a precursor f or arsenic-induced cancers of internal organs as well as the skin. We obser ved previously that within 8 weeks of exposure AP-I activation occurs in ur inary bladder tissue of mice exposed to arsenic in the drinking water. In t he 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-I activity occurred in bladder tissue at exposure levels belo w which histopathological changes or arsenic tissue accumulation was detect ed. Marked AP-1 DNA-binding activity only occurred at exposure levels of so dium arsenite above 20 mug/ml, where histopathological changes and accumula tion of arsenic in the urinary bladder epithelium occurred. Although the ex perimental design did not allow statistical modeling of the entire dose-res ponse curve, the general shape of the dose-response curve is not inconsiste nt with the previously proposed hypothesis that arsenic-induced cancer foll ows a non-linear dose-response model.