Susceptibility of proliferating cells to benzo[a]pyrene-induced homologous recombination in mice

• Published in: Carcinogenesis (New York) Vol. 22; no. 4; pp. 641 - 649
• Main Authors: Bishop, A.J.R., Kosaras, B., Carls, N., Sidman, R.L., Schiestl, R.H.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-04-2001; Oxford Publishing Limited (England)
• Subjects: Animals; Animals, Newborn; B[a]P; Benzo(a)pyrene - pharmacology; Benzo(a)pyrene - toxicity; benzo[a]pyrene; Biological and medical sciences; Biological effects of radiation; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens; Cell Division - drug effects; Chemical agents; days post-coitum; days post-partum; dpc; dpp; Eye Color - drug effects; Eye Color - genetics; Fundamental and applied biological sciences. Psychology; Gene Deletion; Ionizing radiations; Medical sciences; Mice; Mice, Inbred C57BL; Neoplasms - etiology; Neoplasms - genetics; Optic Nerve - metabolism; Phenotype; Pigment Epithelium of Eye - drug effects; Pigment Epithelium of Eye - metabolism; Recombination, Genetic - drug effects; retinal pigment epithelium; RPE; Time Factors; Tissues, organs and organisms biophysics; Tumors; X-Rays; Cell proliferation; Toxicity; Homologous recombination; Retina; Postnatal development; Eye; Gamma irradiation; Ionizing irradiation; Reversion; Deletion; Biological effect; Teratogen; Rodentia; Pigment epithelium; Pigmentation; Pregnancy; Carcinogen; Vertebrata; Fetal development; Phenotype; Mammalia; Mouse; Newborn animal; Animal; DNA; Lesion; Mutation
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/22.4.641

The pink-eyed unstable mutation, pun, is the result of a 70 kb tandem duplication within the murine pink-eyed, p, gene. Deletion of one copy of the duplicated region by homologous deletion/recombination occurs spontaneously in embryos and results in pigmented spots in the fur and eye. Such deletion events are inducible by a variety of DNA damaging agents, as we have observed previously with both fur- and eye-spot assays. Here we describe a study of the effect of exposure to benzo[a]pyrene (B[a]P) at different times of development on reversion induction in the eye. Previously we, among others, have reported that the retinal pigment epithelium (RPE) displays a position effect variegation phenotype in the pattern of pink-eyed unstable reversions. Following an acute exposure to B[a]P or X-rays on the tenth day of gestation an increased frequency of reversion events was detected in a distinct region of the adult RPE. Examining exposure at different times of eye development reveals that both B[a]P and X-rays result in an increased frequency of reversion events, though the increase was only significant following B[a]P exposure, similar to our previous report limited to exposure on the tenth day of gestation. Examination of B[a]P-exposed RPE in the present study revealed distinct regions where the induced events lie and that the positions of these regions are found at increasing distances from the optic nerve the later the time of exposure. This position effect directly reflects the previously observed developmental pattern of the RPE, namely that cells in the regions most distal from the optic nerve are proliferating most vigorously. The numbers and positions of RPE cells displaying the transformed (pigmented) phenotype strongly advocate the proposal that dividing cells are at highest risk to deletions induced by carcinogens.