Inorganic
arsenic (As) is a human
carcinogen but has not been unequivocally proven carcinogenic in rodents. For instance, one older study indicates that repeated iv
injections of
sodium arsenate might induce
lymphomas in Swiss mice (58% incidence) (Osswald and Goerttler, Verh. Dtsch. Ges. Pathol. 55, 289-293, 1971), but it was considered inadequate for critical evaluation of carcinogenic potential largely because of issues in experimental design. Therefore, we studied repeated iv
sodium arsenate injection and neoplastic response in male and female Swiss mice. Groups (n = 25) of mice received
sodium arsenate (0.5 mg/kg, iv) or saline (control) once/week for 20 weeks and were observed for a total of 96 weeks when the study ended. Differences in survival and
body weights were unremarkable. In females,
arsenate induced marked increases in the incidence and severity of cystic
hyperplasia of the uterus compared against controls.
Arsenate also was associated with a rare
adenocarcinoma of the uterus. Hyperplastic uterine epithelium from
arsenate-exposed animals showed strong positive immunostaining for the
proliferating cell nuclear antigen (
PCNA). There was also an upregulation of
estrogen receptor (ER) immunoreactive
protein in the early lesions of uterine
luminal and glandular
hyperplasia, although a progressive decrease in its expression was seen in the severe hyperplastic or neoplastic epithelium. In common with the preneoplastic and neoplastic gynecological lesions in humans, the levels of immunoreactive
inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine-containing
proteins were greater in the uterine hyperplastic epidermis and their intensity was positively correlated with the severity of the lesions.
Arsenate-induced uterine hyperplastic lesions also showed a strong upregulation of
cyclin D1, an
estrogen-associated gene product essential for progression through the G1 phase of the cell cycle. In other tissues,
arsenate increased testicular interstitial cell
hyperplasia incidence and severity over control but without affecting the incidence of tubular degeneration.
Arsenate also induced increases in hepatic proliferative lesions (HPL; foci of alteration +
neoplasia), but only in females. Significant skin changes (incidence of hyperkeratotic lesions) and renal lesions (severity of nephropathy) also occurred in
arsenate-treated females. Thus, repeated
arsenate exposure, though not outright tumorigenic in the present study, was associated with proliferative, preneoplastic lesions of the uterus, testes, and liver.
Estrogen treatment has been associated with proliferative lesions and
tumors of the uterus, female liver, and testes in other studies, supporting a hypothesis that
arsenate might somehow act through an estrogenic mode of action.