University of North Carolina, Chapel Hill, NC 27599, USA.
Toxicol In Vitro. 2010 Feb;24(1):327-34. doi: 10.1016/j.tiv.2009.08.003. Epub 2009 Aug 20.
Human phthalate exposure occurs as mixtures of diesters with varying activity towards testosterone-dependent development. Dibutyl (DBP), diethylhexyl (DEHP) and butylbenzyl (BBP) phthalate disrupt sexual development in the fetal rat. Dimethyl (DMP) and diethyl (DEP) phthalate do not. These differences in potency may result from differential delivery of the monophthalates to the testes or from variation in the abilities of the compounds to alter steroidogenesis. We tested five phthalates in pregnant rats (500mg/kg-d, GD12-19) and analyzed the fetal testes for corresponding monoesters (MMP, MEP, MBP, MEHP, MBeP). Testes MMP and MEP levels were 2-40-fold higher than the active monoesters, MBP and MEHP. BBP exposure led to low concentrations of MBeP, but similar MBP levels to DBP. An in vitro MA-10 cell assay measured the direct effect of monophthalates on testosterone production. MEHP inhibited LH-stimulated testosterone production at 1microM. RT-PCR confirmed down-regulation of genes associated with cholesterol transport and steroid synthesis and metabolism by MEHP. Five additional phthalates were tested for testosterone inhibition. MBP and mono-n-octyl phthalate were similar to MEHP; MMP, MEP and MBeP were poor inhibitors of testosterone production. Based on these results, differences in the phthalates' ability to interfere with sexual development in vivo appears to be more associated with differential potency for testosterone inhibition than differences in tissue doses.
人体邻苯二甲酸酯暴露是多种酯的混合物，其对睾酮依赖型发育的活性各不相同。邻苯二甲酸二丁酯（DBP）、邻苯二甲酸二（2-乙基）己酯（DEHP）和邻苯二甲酸丁基苄基酯（BBP）会破坏胎儿大鼠的性发育。邻苯二甲酸二甲酯（DMP）和邻苯二甲酸二乙酯（DEP）则不会。这种效力差异可能是由于单邻苯二甲酸酯向睾丸的不同传递，或者由于化合物改变类固醇生成的能力不同所致。我们在怀孕大鼠中测试了五种邻苯二甲酸酯（500mg/kg-d，GD12-19），并分析了胎儿睾丸中相应的单酯（MMP、MEP、MBP、MEHP、MBeP）。睾丸 MMP 和 MEP 水平比活性单酯 MBP 和 MEHP 高 2-40 倍。BBP 暴露导致 MBeP 浓度较低，但 MBP 水平与 DBP 相似。MA-10 细胞体外测定直接测量了单邻苯二甲酸酯对睾酮产生的影响。MEHP 在 1μM 时抑制 LH 刺激的睾酮产生。RT-PCR 证实 MEHP 下调了与胆固醇转运和类固醇合成与代谢相关的基因。另外五种邻苯二甲酸酯测试了对睾酮的抑制作用。MBP 和单正辛基邻苯二甲酸酯与 MEHP 相似；MMP、MEP 和 MBeP 对睾酮产生的抑制作用较差。基于这些结果，邻苯二甲酸酯在体内干扰性发育的能力差异似乎与其对睾酮抑制的效力差异更相关，而与组织剂量的差异无关。
