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Embryotoxicity of Benzo(a)pyrene and Some of Its Synthetic Derivatives in Swiss Mice¹

Laboratory of in vivo Carcinogenesis, Institute of Clinical and Experimental Oncology, School of Medicine, University of Genova, and Istituto Nazionale per la Ricerca sul Cancro di Genova, Viale Benedetto XV, 10, 16132 Genova, Italy

We have studied the teratogenicity of benzo(a)pyrene (BP), benzo(a)pyrene-4,5-oxide, and a racemic mixture of 7ß,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, a proximal metabolite and ultimate carcinogenic metabolite of BP, respectively, and of 6-methylbenzo(a)pyrene after direct injection into embryonal Swiss mice. The compounds were dissolved in acetone and trioctanoin (1:1) and injected at doses ranging from 0.4 to 16.0 nmol/embryo on days 10, 12, and 14 of development. The transplacental effects of BP given at the same gestational days and at comparable dose levels were also evaluated. The control groups received 0.5, 1.0, or 2.0 µl/embryo of vehicle on days 10, 12, or 14 of pregnancy, respectively. The fetuses were examined when they were 18 days old. On the basis of gross external and internal malformations, 7ß,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene appeared to be the most potent embryotoxic and teratogenic compound tested, causing 85% of embryolethality and 100% of malformed fetuses in the group treated on day 10 of intrauterine development. There were 61 and 27% of malformed fetuses following 7ß,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene treatment on days 12 and 14 of gestation, respectively. The effects of this BP metabolite were very specific and malformations such as exencephaly, thoraco- and gastroschisis, phocomelia, and edema were found. The administration of BP (both transplacental and direct intraembryonal injection) and benzo(a)pyrene-4,5-oxide caused no significant increase of malformed fetuses in any of the developmental stages considered. 6-Methylbenzo(a)pyrene induced multiple malformations (among these a high percentage of protruding tongue) in 50, 46 and 31% of the fetuses treated on days 10, 12, and 14 of gestational age, respectively. These results combined with previous data concerning the induction of lung tumors by the tested compounds in 15-day-old Swiss mouse embryos, emphasize the requirement of a common metabolic derivative of BP to induce both teratogenesis and carcinogenesis in mice. Furthermore present data show that midgestation Swiss embryos are also highly sensitive to the 6-methyl derivative of BP.

¹ Supported by CNR Grant 83.02850.56 to Medicina Preventiva e Riabilitativa, Sottoprogetto Rischio Tossicologico.

² Present address: Laboratory of Comperative Carcinogenesis, National Cancer Institute, Frederick Cancer Research Facility, Frederick, MD 21701.

Received 6/17/85. Revised 9/20/85. Accepted 9/24/85.

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