邻苯二甲酸二乙基己基酯对胎鼠肺发育的抑制作用

目的探讨孕大鼠染毒邻苯二甲酸二乙基己基酯(DEHP)对胎鼠肺发育的抑制作用及其可能机制。方法 Sprague-Dawley大鼠受孕后第12天每天ig给予DEHP0,10,100和750mg.kg-1,至自然分娩。第1天每窝随机取自然分娩仔鼠3只,测定体质量;光镜观察肺组织病理学改变及测定辐射状肺泡计数(RAC)和肺间质比例,免疫组化法检测基质金属蛋白酶-2(MMP-2)、基质金属蛋白酶组织抑制剂-2(TIMP-2)和血管内皮生长因子(VEGF)的表达。结果与正常对照组相比,DEHP组仔鼠体质量明显下降(P<0.01)。光镜下仅DEHP750mg.kg-1组可见肺间质增厚,间质细胞增多,肺泡数目减少,RAC减小,肺间质比例增大(P<0.05)。与正常对照组比较,DEHP组VEGF表达差异无统计学意义;DEHP10,100和750mg.kg-1组MMP-2表达和MMP-2/TIMP-2值明显高于正常对照组〔MMP-2分别为0.099±0.009,0.124±0.008,0.140±0.010vs0.091±0.011(P<0.01);MMP-2/TIMP-2分别为1.079±0.074,1.447±0.077,1.704±0.084vs0.994±0.079(P<0.01)〕。结论孕鼠染毒DEHP后对胚胎生长和肺发育有抑制作用。DEHP抑制胎鼠肺发育的机制可能与MMP-2的过度表达以及MMP-2/TIMP-2平衡失调有关。

Inhibition of di-(2-ethylhexyl) phthalate on fetal lung development in rats

OBJECTIVE To explore the effects of di-(2-ethylhexyl) phthalate (DEHP) on fetal lung development in rats pups and its underlying mechanisms. METHODS Pregnant Sprague-Dawley rats were ig given DEHP 0 ,10 ,100 and 750 mg·kg^-1 from gestational twelveth day to the day of spontaneous delivery. Then rat pups from each litter were randomly selected on the first day of life. Body mass was measured and the lung was processed for histology and computerized calculation of the interstitial tissue proportion of the lung and radical alveolar counting (RAC), as well as immunohistochemical determination of the expression of matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2) and vascular endothelial growth factor (VEGF). RESULTS Compared with normal control group, body mass of pups from DEHP groups was significantly lower (P<0.01). The lung histological examination revealed that the alveolar septa were thicker, and the number of alveolars decreased only in DEHP 750 mg·kg^-1 group. RAC was significantly lower and the lung interstitial tissue proportion was significantly higher in DEHP 750 mg·kg^-1 group (P<0.05). The expression of VEGF in DEHP groups was similar to that in normal control group. The expression of MMP-2 and MMP-2/TIMP-2 in DEHP 10, 100 and 750 mg·kg^-1 groups were significantly higher than that in normal control group 〔MMP- 2: 0.099±0.009，0.124±0.008，0.140±0.010 vs 0.091±0.011, (P<0.01)；MMP-2/TIMP-2: 1.079±0.074，1.447±0.077，1.704±0.084 vs 0.994±0.079, (P<0.01)〕. CONCLUSION Prenatal DEHP exposure leads to intra uterus growth restriction and impairs lung development in rats. Over expression of MMP-2 and the imbalance of MMP-2/TIMP-2 may be part of the mechanism underlying the impaired lung development.