Barbieri O, Ognio E, Rossi O, Astigiano S, Rossi L
Cancer Res. 1986 Jan;46(1):94-8.
We have studied the teratogenicity of benzo(a)pyrene (BP), benzo(a)pyrene-4,5-oxide, and a racemic mixture of 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-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 microliter/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, 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-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 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-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.
我们研究了苯并(a)芘（BP）、苯并(a)芘-4,5-氧化物以及7β,8α-二羟基-9α,10α-环氧-7,8,9,10-四氢苯并(a)芘（一种BP的近端代谢物和最终致癌代谢物）的外消旋混合物，以及6-甲基苯并(a)芘直接注射到瑞士胚胎小鼠体内后的致畸性。将这些化合物溶解于丙酮和三辛酸甘油酯（1:1）中，并在发育的第10、12和14天以0.4至16.0 nmol/胚胎的剂量进行注射。还评估了在相同妊娠天数和相当剂量水平下给予BP的经胎盘效应。对照组在妊娠的第10、12或14天分别接受0.5、1.0或2.0微升/胚胎的赋形剂。当胎儿18天大时进行检查。基于明显的外部和内部畸形，7β,8α-二羟基-9α,10α-环氧-7,8,9,10-四氢苯并(a)芘似乎是所测试的最具胚胎毒性和致畸性的化合物，在子宫内发育第10天接受治疗的组中导致85%的胚胎致死率和100%的畸形胎儿。在妊娠第12天和第14天接受7β,8α-二羟基-9α,10α-环氧-7,8,9,10-四氢苯并(a)芘治疗后，畸形胎儿分别为61%和27%。这种BP代谢物的作用非常特异，发现有诸如无脑儿、胸腹壁裂、短肢畸形和水肿等畸形。给予BP（经胎盘和直接胚胎内注射）以及苯并(a)芘-4,5-氧化物在任何所考虑的发育阶段均未导致畸形胎儿显著增加。6-甲基苯并(a)芘在妊娠第10、12和14天接受治疗的胎儿中分别诱导出50%、46%和31%的多种畸形（其中高比例为伸舌）。这些结果与先前关于所测试化合物在15日龄瑞士小鼠胚胎中诱导肺肿瘤的数据相结合，强调了BP的一种共同代谢衍生物在小鼠中诱导致畸和致癌作用的必要性。此外，目前的数据表明妊娠中期的瑞士胚胎对BP的6-甲基衍生物也高度敏感。
