Anophthalmia in litters of pregnant rats treated with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a food-derived carcinogen, was incidentally encountered in a risk-assessment study with 2-generation exposure to PhIP Female Fischer 344 animals were given 200 ppm PhIP in the diet for 4 wk before mating with nontreated males and also during gestation and lactation periods. Mean numbers of newborn rats per litter in control and PhIP-treated groups were 7.9 ± 2.9 and 7.1 ± 1.6 in trial 1 and 8.3 ± 1.9 and 6.1 ± 2.4 in trial 2. Among 49 (trial 1) and 63 (trial 2) offspring from PhIP-treated dams, 9 (18.4%) and 32 (50.8%) demonstrated anophthalmia, and 1 (2.0%) and 8 (12.7%) demonstrated hydrocephaly. Five of 7 (71.4%) and 13 of 14 (92.9%) dams delivered pups with malformations in trials 1 and 2, respectively. Also, in a previous study that was carried out with the same protocol and that used the Sprague-Dawley strain of rats, anophthalmia and hydrocephaly were observed in 2 and 1 out of 175 pups, respectively, from 100 ppm PhIP-treated dams. No congenital malformations were found in control groups of the same size in either experiment. In addition to having been previously identified as a cause of carcinogenic activity, our findings suggest that PhIP is capable of causing anophthalmia in rats when administered during the gestational period.
Berg BN (1965). Dietary restriction and reproduction in the rat . J. Nutr.87: 344-348.
2.
De Pass LR and Weaver EV (1982). Comparison of teratogenic effects of aspirin and hydroxyurea in the Fischer 344 and Wistar strains. J. Toxicol. Environ. Health10: 297-305.
3.
Esumi H., Ohgaki H., Kohzen E., Takayama S., and Sugimura T. (1989). Induction of lymphoma in CDF1 mice by the food mutagen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Jpn. J. Cancer Res.80: 1176-1178.
4.
Felton JS, Knize MG, Shen NH, Lewis PR, Andresen BD, Happe J., and Hatch FT (1986). The isolation and identification of a new mutagen from fried ground beef: 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) . Carcinogenesis7: 1081-1086.
5.
Gerhardsson de Verdier M., Hagman U., Peters RK, Steineck G., and Overvik E. (1991). Meat, cooking methods and colorectal cancer: A case-referent study in Stockholm . Int. J. Cancer49: 520-525.
6.
Hasegawa R., Kimura J., Yaono M., Takahashi S., Kato T., Futakuchi M., Fukutake M., Fukutome K., Wakabayashi K., Sugimura T., Ito N., and Shirai T. (1995). Increased risk of mammary carcinoma development following transplacental and trans-breast milk exposure to a food-derived carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), in Sprague-Dawley rats. Cancer Res.55: 4333-4338.
7.
Hayes WC, Cobel-Geard SR, Hanley TR Jr, Murray JS, Freshour NL, Rao KS, and John JA ( 1981). Teratogenic effects of vitamin A palmitate in Fischer 344 rats. Drug Chem. Toxicol.4: 283-295.
8.
Holme JA, Wallin H., Brunborg G., Soderlund EJ, Hongslo JK, and Alexander J. (1989). Genotoxicity of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP): Formation of 2-hydroxyamino-PhIP, a directly acting genotoxic metabolite . Carcinogenesis10: 1389-1396.
9.
Ito N., Hasegawa R., Sano M., Tamano S., Esumi H., Takayama S., and Sugimura T. (1991). A new colon and mammary carcinogen in cooked food, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Carcinogenesis12: 1503-1506.
10.
Keen CL, Uriu-Hare JY, Swan SH, and Neutra RR (1992). The effects of water source on reproductive outcome in Fischer-344 rats. Epidemiology3: 130-133.
11.
Kurishita A. , Negishi R., and Ihara T. (1987). Incidence of spontaneous abnormalities in the rat and rabbit used in teratological study during 1981-1986 . J. Takeda Res. Lab.46: 69-79.
12.
Majima A. (1961). Eye-abnormalities in mice embryos caused by X-irradiation of mothers. On changes in the initial stage of development by irradiation on the 8th day of pregnancy. Jpn. J. Ophthalmol.5: 104-114.
13.
Manabe S., Suzuki H., Wada O., and Ueki A. (1993). Detection of the carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in beer and wine. Carcinogenesis14: 899-901.
14.
Manabe S., Tohyama K., Wada O., and Aramaki T. (1991). Detection of a carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), in cigarette smoke condensate. Carcinogenesis12: 1945-1947.
15.
Miller RW (1977). Relationship between human teratogens and carcinogens . J. Natl. Cancer Inst.58: 471-474.
16.
Nakatsu T., Ooshima Y., Takatani O., Matsukawa J., and Ihara T. (1981). Observation on spontaneous abnormalities in the mouse, rat and rabbit. J. Takeda Res. Lab.40: 67-76.
17.
Ozeki H. and Shirai S. (1998). Developmental eye abnormalities in mouse fetuses induced by retinoic acid. Jpn. J. Ophthalmol.42: 162-167.
18.
Padmanabhan R., Singh G., and Singh S. (1981). Malformations of the eye resulting from maternal hypervitaminosis A during gestation in the rat . Acta Anat.110: 291-298.
19.
Peluso M. Castegnaro M., Malaveille C., Friesen M. Garren L., Hautefeuille A., Vineis P., Kadlubar E. and Bartsch H. (1991). 32Postlabelling analysis of urinary mutagens from smokers of black tobacco implicates 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) as a major DNA-damaging agent. Carcinogenesis12: 713-717.
20.
Perraud J. (1976). Levels of spontaneous malformations in the CD rat and the CD-1 mouse. Lab. Anim. Sci.26: 293-300.
21.
Rose DP, Boyer AP, and Wynder EL (1986). International comparisons of mortality rates for cancer of the breast, ovary, prostate, and colon, and per capita food consumption . Cancer58: 2363-2371.
22.
Rothman KJ, Moore LL, Singer MR, Nguyen US, Mannino S., and Milunsky A. (1995). Teratogenicity of high vitamin A intake. N. Engl. J. Med.333: 1369-1373.
23.
Shirai S. (1991). Developmental mechanisms of congenital eye abnormalities . Acta Soc. Ophthalmol. Jpn.95: 1206-1237.
24.
Shirai T., Sano M., Tamano S., Takahashi S., Hirose M., Futakuchi M., Hasegawa R., Imaida K., Matsumoto K., Wakabayashi K., Sugimura T., and Ito N. (1997). The prostate: A target for carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) derived from cooked foods. Cancer Res.57: 195-198.
25.
Sunderman Fwj , Allpass PR, Mitchell JM, Baselt RC, and Albert DM (1979). Eye malformations in rats: Induction by prenatal exposure to nickel carbonyl . Science203: 550-553.
26.
Thompson LM , Tucker JD, Stewart SA, Christensen ML, Salazar EP, Carrano AV, and Felton JS (1987). Genotoxicity of compounds from cooked beef in repair-deficient CHO cells versus Salmonella mutagenicity . Mutagenesis2: 483-487.
27.
Ushiyama H. , Wakabayashi K., Hirose M., Itoh H., Sugimura T., and Nagao M. (1991). Presence of carcinogenic heterocyclic amines in urine of healthy volunteers eating normal diet, but not of inpatients receiving parenteral alimentation . Carcinogenesis12: 1417-1422.
28.
Wakabayashi K., Ushijima T., Takahashi M., Nukaya H., Kim S-B., Hirose M., Ochiai M., Sugimura T., and Nagao M. (1993). Exposure to heterocyclic amines. Environ. Health Perspect.99: 129-133.
29.
Wiley MJ, Cauwenbergs P., and Taylor IM (1983). Effects of retinoic acid on the development of the facial skeleton in hamsters: Early changes involving cranial neural crest cells. Acta Anat.116: 180-192.
30.
Yoshitomi K. and Boorman GA (1990). Eye and associated glands . In: Pathology of the Fischer Rat, GA Boorman, SL Eustis, MR Elwell, CA Montgomery Jr, and WF MacKenzie (eds). Academic Press, San Diego, California, pp. 239-259.
