CdSe/ZnS量子点对亲代雌鼠的生殖毒性及向子代传递机制

In vivo toxicity of quantum dots (QDs) in animals has been broadly studied. However, its reproductive toxicity toward pregnancy animals has not yet been systematically investigated. Previous research showed that QDs can accumulate in vivo and pass through placenta barrier and cause fetus death, but it is still not clear with the mechanism of acute reproductive toxicity toward uterus, yolk sac, placenta, and fetal formation and development after exposure in QDs. Researches on chronic QDs reproductive toxicity are even rare. In this proposal, mice will be chose as target, systematical evaluation of the acute and chronic reproductive toxicity of QDs exposed in different pregnancy stages will be performed, and DGE, RT-qPCR, and Western blotting will be employed to investigate key mediating molecules that caused the QDs reproductive toxicity, and further characterize the biomarkers that realize the toxic effect. ICP-MS and TEM will be also used to characterize the mechanism of QDs in vivo biodistribution, degradation, and transfer to their offspring through the placenta barrier, in comparison with CdCl2 solution. In summary, the proposed research intends to investigate the mechanism of reproductive toxicity and offspring transmission of QDs, and will provide the theoretical basis for the exposure assessment of QDs in pregnant animals, as well as for the application or prohibition of QDs in mammals, especially in pregnant mammals.

量子点（QDs）在活体动物的毒性研究已逐步开展，然而其对妊娠动物的生殖毒性研究相对缺乏。研究显示QDs可长期留存于体内，且可穿越胎盘屏障致胎鼠死亡，但其在妊娠期暴露对子宫、卵黄囊、胎盘及胎鼠形成和发育的急性毒性的分子机制并不明确，其引起慢性毒性的相关研究更加匮乏。本项目拟以小鼠为研究对象，深入探讨QDs在不同妊娠时期暴露对雌鼠和胎鼠（或子鼠）急性和慢性毒性效应，进一步应用DGE、RT-qPCR和Western blotting发掘QDs引起生殖毒性的关键效应分子（生物标志物），初步阐明QDs引发生殖毒性的分子机制。同时，拟采用ICP-MS和TEM探讨CdSe/ZnS QDs与镉盐溶液在体内分布、传递、降解的特征差异，阐明QDs穿越胎盘屏障向子代传递的机制。本项目通过探讨QDs生殖毒性的作用机制及向子代传递机制，为其在妊娠动物暴露评价及在哺乳动物特别是妊娠期哺乳动物的应用或禁用提供理论依据。

量子点因其优越的荧光特性，在生物医学研究等领域被广泛应用。妊娠期是哺乳动物最敏感的时期，妊娠期暴露量子点可能会影响胚胎形成和发育进而影响动物的生长繁殖。本研究通过对小鼠妊娠期早期、中期、晚期暴露量子点，发现量子点会抑制母鼠体重增长，影响胚胎发育（胚胎植入、胚胎重量、胎鼠重量、胎鼠数目、畸形数目）。通过对孕鼠和子代体内量子点含量测定，发现量子点可通过鼠奶传递至子鼠，但并不能在子鼠体内蓄积，且量子点未通过胎盘屏障进入胚胎。在不同妊娠时期对孕鼠暴露量子点可对胚胎的植入、子宫蜕膜、胎盘发育、胎盘营养物质转运、胎盘激素分泌等产生影响。通过肝素的干预，发现其对量子点引起的生殖毒性可起到保护作用。对妊娠中期暴露量子点后的孕鼠胎盘进行转录组学和RT-qPCR分析，结果显示细胞凋亡、内质网应激、激素表达、胚胎发育等通路基因表达异常，并进一步推测量子点可通过胎盘细胞凋亡诱导生殖毒性，其中ATF6、bax可作为量子点引起的生殖毒性的潜在生物标志物。