[CANCER RESEARCH 47, 6294-6296, December 1. 1987) Inheritance of Susceptibility to Phototumorigenesis and Persistent Hyperplasia in F, Hybrids between SENCAR Mice and BALB/c or C57BL/6 Mice1 Paul T. Strickland2 and Rodney P. Swartz Department of Environmental Health Sciences, The Johns Hopkins University, School of Hygiene and Public Health, Baltimore, Maryland 21205 fP. T. S.J, and Pulmonary Disease Division, Georgetown University Hospital, Washington, DC 20007 [R. P. S.J ABSTRACT SENCAR mice are selectively bred for hypersusceptibility to two- stage chemical skin carcinogenesis. They are also hypersusceptible to UV radiation tumorigenesis with single high-dose, but not chronic low- dose, exposures. In addition, SENCAR mice exhibit an exaggerated and persistent epidermal hyperplasia (due to sustained proliferation of the basal cells) in response to UV-induced tissue damage. In the present study, we have examined the inheritance of susceptibility to both photo- tumorigenesis and persistent hyperplasia in the l;, offspring of SENCAR mice crossed with either of two inbred strains (BALB/c or C57BL/6) which are relatively resistant to phototumorigenesis. A total of 428 mice from the parental strains and reciprocal I-, crosses were given a single high dose (8.64 x IO4 .l/iir) of UV radiation (FS40 sunlamps) which causes persistent hyperplasia and tumorigenesis in many SENCAR, but no BALB/c or C57BL/6, mice. F, hybrids between SENCAR and C57BL/6 mice did not develop persistent hyperplasia or skin tumors, which indicates that susceptibility to both traits is completely recessive to the C57BL/6 genotype. In contrast, F, hybrids between SENCAR and BALB/c mice developed both persistent hyperplasia and skin tumors, although at a much lower incidence than the SENCAR mice, indicating that susceptibility to both traits is only partially (incompletely) recessive to the BALB/c genotype. Thus, in either I , cross, susceptibility to phototumorigenesis decreased in parallel with persistent hyperplasia. These results are consistent with the hypothesis that the two character istics are mechanistically related. INTRODUCTION Exposure to exogenous carcinogens is believed to cause the majority of human cancers. However, the considerable variation within the human population for susceptibility to genotoxic agents and carcinogenesis suggests that certain host factors mediate this response (1, 2). Abnormalities in DNA repair or oxidative metabolism have been associated with increased sus ceptibility to carcinogenesis in some cases (3-5). One approach directed toward understanding the mechanisms responsible for susceptibility has been the study of animal strains unusually susceptible to carcinogenesis. SENCAR mice are selectively bred for hypersusceptibility to two-stage chemical skin carci nogenesis (6-8) and are also hypersusceptible to UV radiation carcinogenesis (9) with certain exposure protocols. While the biological basis for this sensitivity is unclear, it probably does not involve abnormalities in carcinogen metabolism (7, 8), DNA repair (10, 11), epidermal growth factor receptors (12), phorbol ester receptors ( 13), or systemic immunological factors (14). On the other hand, two anomalous properties of SENCAR skin have been reported, (a) Cultured keratinocytes from SEN- Received 5/13/87; revised 8/17/87; accepted 8/31/87. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1Research supported in part by funds from the Mellon Foundation and Department of Health and Human Services Grants ES03841 and ES03819 and in part by the National Cancer Institute. Department of Health and Human Services, under Contract N01-CO-23909 with Litton Bionetics, Inc. 2To whom requests for reprints should be addressed, at Division of Occupa tional Medicine, The Johns Hopkins University, 3100 Wyman Park Drive, Building 6, Baltimore, MD 21211. CAR skin are resistant to forced terminal differentiation by modulation of Ca2+ concentration in the medium (15), whereas keratinocytes from other (resistant) mouse strains are suscep tible to forced differentiation, (b) SENCAR mice exhibit an exaggerated and persistent epidermal hyperplasia (which is due to sustained proliferation of epithelial basal cells) in response to tissue damage caused by UV radiation (16). It is not known whether these two properties are causally related to each other, or to the hypersusceptibility of SENCAR mice to skin carci nogenesis. In the present study, the inheritance of susceptibility to phototumorigenesis and persistent hyperplasia has been exam ined in the F, offspring of SENCAR mice crossed with either of two inbred strains (BALB/c or C57BL/6) which are relatively resistant to phototumorigenesis. In addition, the distribution of skin tumors and persistent hyperplasma among individual SENCAR mice exposed to UV radiation was analyzed. MATERIALS AND METHODS Animals. Parental strains of mice [CnORL SENCAR, BALB/cAnNCr, and C57BL/6NCr] were obtained from the National Cancer Institute-Frederick Cancer Cancer Research Facility Animal Resources Program and maintained as previously described (9). Five breeding pairs of each of the following crosses were initiated: BALB/c x SENCAR F, (hereafter called CSF,); SENCAR x BALB/c F, (here after called SCF,); C57BL/6 x SENCAR F, (hereafter called B6SF,); and SENCAR x C57BL/6 F, (hereafter called SB6F,). All breeding pairs produced offspring with the exception of 3 of the 5 pairs in the C57BL/6 x SENCAR cross. The mean size of 36 litters produced was 10.1 ±3.9 with a range of 3 to 19offspring. Coat colors of the offspring were white for CSFi and SCFi mice and black or gray for B6SF, and SB6Fi mice. FI offspring were used for experiments at 8 to 10 wk of age, and dorsal hair was removed with electric clippers prior to irradia tion. The appearance of the skin of the mice with pigmented hair was similar to that of the albino mice. The small amount of residual hair left after clipping was more visible in the pigmented mice. The hair growth cycle was in the resting phase at treatment (8 to 10 wk), and the growing phase began 1 to 2 wk later. Animals were routinely monitored and found to be free of murine viruses, parasites, Myco- plasma, and pathogenic bacteria. UV Radiation. Mice were exposed to a bank of six FS40 sunlamps (Westinghouse, Bloomfïeld,NJ) situated 20 cm above the animals. During irradiation the animals were housed in wire-topped cages par titioned into compartments for individual animals. The average fluence rate at the position of the animals was 8.0 J/m2/s as measured by a IL700 photometer with PT171C detector. Persistent Hyperplasia and Tumor Induction. A total of 428 mice from the parental strains and FI crosses (Table 1) were given a single high dose (8.64 x IO4J/m2) of UV radiation which is known to cause ulcération, persistent hyperplasia, and tumorigenesis in SENCAR mice (16). All animals were inspected weekly, and gross skin reactions and tumors were recorded. The incidence of persistent hyperplasia was determined from the weekly observations at 4, 5, and 6 wk after treatment, since the response was most prominent during this period. Twenty-eight wk after irradiation the animals were sacrificed, and samples of all skin tumors were taken for histopathological examina tion. The probability of tumor development was determined by a life- table analysis (17), and differences in tumor development between 6294 on July 24, 2021. © 1987 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from