Lee Grace S, Liao Xiaoyan, Cantor Rita M, Collins Michael D
Molecular Toxicology Interdepartmental Program, University of California, Los Angeles School of Public Health, Los Angeles, California 90095, USA.
Birth Defects Res A Clin Mol Teratol. 2006 Jan;76(1):19-28. doi: 10.1002/bdra.20201.
Most toxicological studies have tested single chemical agents at relatively high doses, and fewer studies have addressed the toxic effects of chemical interactions. It is important to understand the toxicity of chemical mixtures in order to assess the more realistic risks of environmental and occupational exposures. A number of chemicals are known to induce a predominantly postaxial forelimb ectrodactyly in C57BL/6 mice, including acetazolamide, ethanol, cadmium, valproic acid, carbon dioxide, dimethadione, phenytoin, and 13-cis-retinoic acid and all-trans-retinoic acid (RA). In the present study, the interactive effects of coadministration of cadmium and RA on developing limbs were investigated.
Pregnant C57BL/6 mice were treated with different intraperitoneal (IP) doses of cadmium chloride (CdCl2) and/or RA on gestational day (GD) 9.5, and fetuses were collected on GD 18 and double stained for examination of skeletal defects.
When RA was given simultaneously with cadmium, a significant increase in the incidence and severity of forelimb ectrodactyly (predominantly postaxial) was observed compared to the results with corresponding doses of cadmium or RA alone. When mice were exposed to subthreshold doses of both cadmium (0.5 mg/kg) and RA (1 mg/kg), the combined treatment exceeded the threshold, resulting in forelimb ectrodactyly in 19% of the fetuses. Moreover, coadministration of cadmium and RA at doses exceeding the respective thresholds showed a synergistic effect, that is, 92% of fetuses were found with the forelimb defect as opposed to 10% if the response were additive.
The findings demonstrate that concurrent exposure to these teratogens can have a synergistic effect and that subteratogenic doses may combine to exceed a threshold.
大多数毒理学研究都在相对高剂量下测试单一化学物质，而涉及化学物质相互作用毒性影响的研究较少。了解化学混合物的毒性对于评估环境和职业暴露更现实的风险很重要。已知多种化学物质会在C57BL/6小鼠中诱发主要为轴后型前肢缺指畸形，包括乙酰唑胺、乙醇、镉、丙戊酸、二氧化碳、二甲双酮、苯妥英以及13-顺式维甲酸和全反式维甲酸（RA）。在本研究中，研究了镉和RA共同给药对发育中肢体的相互作用影响。
在妊娠第9.5天，对怀孕的C57BL/6小鼠腹腔内（IP）注射不同剂量的氯化镉（CdCl2）和/或RA，在妊娠第18天收集胎儿并进行双重染色以检查骨骼缺陷。
当RA与镉同时给药时，与相应剂量的镉或RA单独给药的结果相比，观察到前肢缺指畸形（主要为轴后型）的发生率和严重程度显著增加。当小鼠暴露于镉（0.5mg/kg）和RA（1mg/kg）的亚阈值剂量时，联合治疗超过阈值，导致19%的胎儿出现前肢缺指畸形。此外，镉和RA以超过各自阈值的剂量共同给药显示出协同作用，即92%的胎儿出现前肢缺陷，而如果反应是相加的，则为10%。
研究结果表明，同时接触这些致畸物可产生协同作用，亚致畸剂量可能会叠加超过阈值。
