Jelks K B, Miller M G
Department of Environmental Toxicology, University of California, One Shields Avenue, Davis, California 95616, USA.
Toxicol Sci. 2001 Jul;62(1):115-23. doi: 10.1093/toxsci/62.1.115.
Numerous studies have documented inhibitory effects of alpha-chlorohydrin (ACH) on glyceraldehyde-3-phosphate dehydrogenase (G3PDH) activity in spermatozoa. A sperm-specific G3PDH isoform has been described. The possibility that ACH may inhibit G3PDH in cell types other than sperm was investigated in this work. In addition, the onset of ACH-induced epididymal toxicity was described. Changes to epididymal histology occurred 6 h following a single dose of ACH (50 mg/kg po) and were confined to the proximal initial segment. By 24 h, no epithelial cells lined the basement membrane of that region. Three h after ACH administration (50 mg/kg po), G3PDH activity was significantly decreased in sperm (85%) as well as in kidney (31%), liver (49%), and epididymis (35%). Enzyme activity remained inhibited at 6 and 24 h. G3PDH was immunolocalized in the epididymis and staining was highest in the efferent ducts and initial segment as well as in smooth muscle. Since G3PDH is a microtubule-associated protein and microtubule-dependent endocytosis occurs in the epididymis, beta-tubulin was also immunolocalized. beta-tubulin densely stained the apical region of initial segment and caput epithelial cells. Disruption of beta-tubulin immunostaining correlated with the localization and onset of the lesion. Co-localization of G3PDH and beta-tubulin immunostaining was not observed although both antibodies most densely stained the initial segment. Our data indicate that histologic changes to the proximal initial segment of the epididymis occur rapidly, but subsequent to G3PDH inhibition. Moreover, ACH inhibition of G3PDH is not confined to sperm, although the sperm enzyme is most sensitive to inhibition.
众多研究已证明，α-氯醇（ACH）对精子中的甘油醛-3-磷酸脱氢酶（G3PDH）活性具有抑制作用。已描述了一种精子特异性的G3PDH同工型。本研究调查了ACH是否可能抑制精子以外的其他细胞类型中的G3PDH。此外，还描述了ACH诱导的附睾毒性的起始情况。单次给予ACH（50mg/kg口服）后6小时，附睾组织学发生变化，且局限于近端起始段。到24小时时，该区域的基底膜上没有上皮细胞衬里。给予ACH（50mg/kg口服）3小时后，精子（85%）以及肾脏（31%）、肝脏（49%）和附睾（35%）中的G3PDH活性显著降低。酶活性在6小时和24小时时仍受到抑制。G3PDH在附睾中进行了免疫定位，输出小管、起始段和平滑肌中的染色最高。由于G3PDH是一种微管相关蛋白，且附睾中发生微管依赖性内吞作用，因此也对β-微管蛋白进行了免疫定位。β-微管蛋白在起始段和附睾头上皮细胞的顶端区域密集染色。β-微管蛋白免疫染色的破坏与病变的定位和起始相关。尽管两种抗体在起始段的染色最密集，但未观察到G3PDH和β-微管蛋白免疫染色的共定位。我们的数据表明，附睾近端起始段的组织学变化迅速发生，但在G3PDH抑制之后。此外，ACH对G3PDH的抑制并不局限于精子，尽管精子中的该酶对抑制最为敏感。
