Abstract：
Phthalates are a class of environmental endocrine disrupting chemicals which can cause reproductive system damages. However, data about reproductive toxicity spectrum of phthalate metabolites among Chinese women undergoing in vitro fertilization (IVF) treatments are scarce yet. Previous studies regarding underlying embryo toxicities focused on oxidative stress and apoptosis, while energy metabolism abnormality might be another key cause for embryo developmental disruptions. Here, we found that among the measured eight phthalate metabolites, monomethyl phthalate (MMP) had the second highest urinary concentration in women receiving IVF. Compare to the lowest exposure level group, MMP in tertile 3 was associated with fewer counts of oocyte retrieved and good-quality embryos, and MMP in tertile 2 was correlated with reduced good-quality embryo rate. The direct embryo toxicities of MMP were studied using mouse 2-cell embryos. Consistent to results found in human populations, exposure to MMP induced mouse early embryo developmental delay. Furthermore, MMP exposure led to excessive reactive oxygen species production in early embryos, and antioxidant can partially rescue the early embryo development slow down. Embryo apoptosis could also be caused by oxidative stress. To be noted, elevated apoptosis level was not found in live \"slow\" embryos but dead embryos, which suggested that apoptosis was not related to early embryo developmental delay. Additionally, MMP exposure depleted adenosine triphosphate (ATP) synthesis of early embryos, which could be reversed by antioxidant. In conclusion, MMP, as the newly found embryonic toxicant in Chinese women, resulted in early embryo development delay, apoptosis, and energy metabolism disruptions via inducing redox imbalance.
摘要：
邻苯二甲酸盐是一类环境内分泌干扰化学物质，可引起生殖系统损害。然而,在接受体外受精（IVF）治疗的中国女性中，邻苯二甲酸酯代谢物生殖毒性谱的数据还很少。以前关于潜在胚胎毒性的研究集中在氧化应激和细胞凋亡，而能量代谢异常可能是胚胎发育中断的另一个关键原因。这里,我们发现在测量的八种邻苯二甲酸酯代谢物中，在接受IVF的女性中，邻苯二甲酸单甲酯（MMP）的尿浓度第二高。与最低暴露水平组相比，三元组3中的MMP与较少的卵母细胞回收和优质胚胎计数相关，三元组2中的MMP与优质胚胎率降低相关。使用小鼠2细胞胚胎研究了MMP的直接胚胎毒性。与在人群中发现的结果一致，暴露于MMP诱导小鼠早期胚胎发育延迟。此外，MMP暴露导致早期胚胎产生过量的活性氧，而抗氧化剂可以部分挽救早期胚胎发育减慢。胚胎凋亡也可能是由氧化应激引起的。值得注意的是,在活的“慢”胚胎中没有发现细胞凋亡水平升高，而是在死的胚胎中发现，提示细胞凋亡与早期胚胎发育延迟无关。此外,MMP暴露耗尽了早期胚胎的三磷酸腺苷（ATP）合成，这可以被抗氧化剂逆转。总之,MMP,作为中国女性新发现的胚胎毒物，导致早期胚胎发育延迟，凋亡，和能量代谢的破坏通过诱导氧化还原失衡。
