Embryotoxicity of benzo(a)pyrene and some of its synthetic derivatives in Swiss mice.
Embryotoxicity of benzo(a)pyrene and some of its synthetic derivatives in Swiss mice.
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发表时间：
1986
期刊：
影响因子：
11.2
通讯作者：
O. Barbieri;E. Ognio;O. Rossi;S. Astigiano;L. Rossi
中科院分区：
文献类型：
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作者：
O. Barbieri;E. Ognio;O. Rossi;S. Astigiano;L. Rossi
我们研究了苯并(a)芘（BP），苯并(a)芘-4,5-氧化物，以及7 β，8 α -二羟基-9 α，10 α -环氧-7,8,9,10-四氢苯并(a)芘的外消旋混合物，分别是BP的近端代谢物和最终致癌代谢物，6-甲基苯并(a)芘直接注射到胚胎瑞士小鼠后的致畸性。将化合物溶于丙酮和三辛烷酸（1:1）中，并在发育第10、12和14天以0.4 ~ 16.0 nmol/胚胎的剂量注射。在相同妊娠天数和相当剂量水平下给予BP的胎盘移植效应也进行了评估。对照组分别在妊娠第10、12、14天给予0.5、1.0、2.0微升/个胚胎的载体。这些胎儿在18天大时接受了检查。根据总的外部和内部畸形，7 β，8 α -二羟基-9 α，10 α -环氧-7,8,9,10-四氢苯并(a)芘似乎是最有效的胚胎毒性和致畸性化合物，导致85%的胚胎死亡率和100%的畸形胎儿在子宫内发育第10天治疗组。7 β、8 α -二羟基-9 α、10 α -环氧-7,8,9,10-四氢苯并(a)芘分别在妊娠第12天和第14天处理的畸形胎率分别为61%和27%。这种BP代谢物的作用是非常特殊的，可以发现畸形，如畸形、胸裂和胃裂、光秃和水肿。在考虑的任何发育阶段，BP（经胎盘和直接胚胎内注射）和苯并(a)芘-4,5-氧化物的使用均未导致畸形胎儿的显著增加。6-甲基苯并(a)芘分别在胎龄10、12和14天治疗的胎儿中诱发了50%、46%和31%的多种畸形（其中舌头突出的比例很高）。这些结果与先前有关15天龄瑞士小鼠胚胎中所测试化合物诱导肺肿瘤的数据相结合，强调了在小鼠中诱导致畸和致癌需要一种常见的BP代谢衍生物。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。
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.