Epidemiology studies have indicated that many human
cancers are influenced by environmental factors. Genetically altered mouse model systems offer us the opportunity to study the interaction of chemicals with
genetic predisposition to
cancer. Using the heterozygous p53-deficient (+/-) mouse, an animal model carrying one wild type p53 gene and one p53 null allele, we studied the effects of
phenolphthalein on
tumor induction and p53 gene alterations. Earlier studies showed that
phenolphthalein caused carcinogenic effects in Fisher 344 rats and B6C3F1 mice after a 2-yr dosing period (Dunnick and Hailey,
Cancer Res. 56: 4922-4926, 1996). The p53 (+/-) mice received
phenolphthalein in the feed at concentrations of 200, 375, 750, 3,000, or 12,000 ppm (approximately 43, 84, 174, 689, or 2,375 mg/kg
body weight/day or 129, 252, 522, 2,867, or 7,128 mg/m2 body surface area/day) for up to 6 mo. A target organ
cancer site that accumulated p53
protein in the B6C3F1 mouse (i.e., thymic
lymphoma) was also a target site for
cancer in the p53 (+/-) mouse. In the p53 (+/-) mouse, treatment-related atypical
hyperplasia and
malignant lymphoma of thymic origin were seen in the control and dosed groups at a combined incidence of 0, 5, 5, 25, 100, and 95%, respectively. Twenty-one of the thymic
lymphomas were examined for p53 gene changes, and all showed loss of the p53 wild type allele. Chemical-induced ovarian
tumors in the B6C3F1 mouse showed no evidence for p53
protein accumulation and did not occur in the p53 (+/-) mouse. The p53-deficient (+/-) mouse model responded to
phenolphthalein treatment with a carcinogenic response in the thymus after only 4 mo of dosing. This carcinogenic response took 2 yr to develop in the conventional B6C3F1 mouse bioassay. The p53-deficient (+/-) mouse is an important model for identifying a carcinogenic response after short-term (< 6 mo) exposures. Our studies show that exposure to
phenolphthalein combined with a
genetic predisposition to
cancer can potentiate the carcinogenic process and cause p53 gene alterations, a gene alteration found in many human
cancers.