Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis
Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis
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DOI：
10.1073/pnas.0406085102
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发表时间：
2005-03-01
影响因子：
11.1
通讯作者：
Nebert, DW
中科院分区：
文献类型：
--
作者：
Dalton, TP;He, L;Nebert, DW
睾丸坏死是所有试验种属中镉（Cd 2+，CA）毒性的敏感终点。对镉诱导的睾丸损伤的抗性是一种隐性性状，分配给小鼠3号染色体上的Cdm基因座。我们首先将含有Cdm基因的区域缩小到880 kb。两个敏感和两个抗性近交系的SNP分析表明，这一地区的400 kb的单倍型块与镉诱导的毒性表型一致，在这一地区是SIc 39 a8基因编码的溶质载体超家族的成员。SIc 39 a8编码SLC 39 A8（ZIP 8），其在植物和酵母中的同源物是推定的锌转运蛋白。我们在这里表明，ZRT，IRT样蛋白（ZIP）8在培养的小鼠胎儿成纤维细胞中的表达导致细胞内镉流入和积累的速率增加>10倍，对镉诱导的细胞死亡的敏感性增加30倍。完整的ZIP 8 mRNA和内含子-外显子剪接点在两个敏感品系和两个抗性品系的小鼠之间没有核苷酸差异;通过使用原位杂交，我们发现ZIP 8 mRNA在敏感品系的小鼠睾丸的血管内皮细胞中是突出的，而在这些细胞中没有抗性品系。因此，SIc 39 a8是Cdm基因，定义了睾丸血管内皮细胞对Cd毒性的敏感性。
Testicular necrosis is a sensitive endpoint for cadmium (Cd2+, CA) toxicity across all species tested. Resistance to Cd-induced testicular damage is a recessive trait assigned to the Cdm locus on mouse chromosome 3. We first narrowed the Cdm-gene-containing region to 880 kb. SNP analysis of this region from two sensitive and two resistant inbred strains demonstrated a 400-kb haplotype block consistent with the Cd-induced toxicity phenotype; in this region is the SIc39a8 gene encoding a member of the solute-carrier superfamily. SIc39a8 encodes SLC39A8 (ZIP8), whose homologs in plant and yeast are putative zinc transporters. We show here that ZRT-, IRT-like protein (ZIP)8 expression in cultured mouse fetal fibroblasts leads to a >10-fold increase in the rate of intracellular Cd influx and accumulation and 30-fold increase in sensitivity to Cd-induced cell death. The complete ZIP8 mRNA and intron-exon splice junctions have no nucleotide differences between two sensitive and two resistant strains of mice; by using situ hybridization, we found that ZIP8 mRNA is prominent in the vascular endothelial cells of the testis of the sensitive strains of mice but absent in these cells of resistant strains. SIc39a8 is therefore the Cdm gene, defining sensitivity to Cd toxicity specifically in vascular endothelial cells of the testis.