Di (2-ethylhexyl) phthalate impairs primordial follicle assembly by increasing PDE3A expression in oocytes
Di (2-ethylhexyl) phthalate impairs primordial follicle assembly by increasing PDE3A expression in oocytes
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DOI：
10.1016/j.envpol.2020.116088
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发表时间：
2021-01-12
影响因子：
8.9
通讯作者：
Shen, Wei
中科院分区：
文献类型：
--
作者：
Liu, Jing-Cai;Yan, Zi-Hui;Shen, Wei
已知邻苯二甲酸二（2-乙基己基）酯（DEHP）可能影响哺乳动物的生殖，在雌性动物中，药物作用的一个靶点是卵泡组装。在这里，我们重新审视了邻苯二甲酸酯对卵巢的作用，并从对体外暴露于DEHP的新生小鼠卵巢进行的转录组的生物信息学分析中，确定了PDE 3A的上调，这是DEHP对早期卵泡发育造成的最重要的改变之一。我们获得的一些证据表明，卵母细胞中cAMP水平的降低和由于PDE 3A增加而导致的PKA表达的平行降低是DEHP暴露卵巢中卵泡组装减少的主要原因。事实上，在培养的卵巢上的Pde 3a RNAi减少cAMP和PKA的减少抵消了由该化合物引起的原始卵泡组装损伤。此外，RNAi使卵母细胞中Kit、Nobox、Figla mRNA和GDF 9、BMP 15、CX 37、gH 2AX蛋白的水平和颗粒细胞中KitL转录物的水平以及DEHP暴露改变的增殖率正常化。综上所述，这些结果将PDE 3A确定为DEHP对哺乳动物早期卵子发生有害影响的新关键靶点，并强调cAMP依赖性途径是卵泡组装关键的卵母细胞和颗粒细胞活动的主要调节因子。此外，我们认为卵母细胞内cAMP的水平可能是其修复DNA损伤化合物（包括DEHP）引起的DNA损伤的能力的重要决定因素。(C)2020爱思唯尔有限公司保留所有权利。
It is known that Di (2-ethylhexyl) phthalate (DEHP) may impact mammalian reproduction and that in females one target of the drug's action is follicle assembly. Here we revisited the phthalate's action on the ovary and from bioinformatics analyses of the transcriptome performed on newborn mouse ovaries exposed in vitro to DEHP, up-regulation of PDE3A, as one of the most important alterations caused by DEHP on early folliculogenesis, was identified. We obtained some evidence suggesting that the decrease of cAMP level in oocytes and the parallel decrease of PKA expression, consequent on the PDE3A increase, were a major cause of the reduction of follicle assembly in the DEHP-exposed ovaries. In fact, Pde3a RNAi on cultured ovaries reducing cAMP and PKA decrease counteracted the primordial follicle assembly impairment caused by the compound. Moreover, RNAi normalized the level of Kit, Nobox, Figla mRNA and GDF9, BMP15, CX37, gH2AX proteins in oocytes, and KitL transcripts in granulosa cells as well as their proliferation rate altered by DEHP exposure. Taken together, these results identify PDE3A as a new critical target of the deleterious effects of DEHP on early oogenesis in mammals and highlight cAMP-dependent pathways as major regulators of oocyte and granulosa cell activities crucial for follicle assembly. Moreover, we suggest that the level of intracellular cAMP in the oocytes may be an important determinant for their capability to repair DNA lesions caused by DNA damaging compounds including DEHP. (C) 2020 Elsevier Ltd. All rights reserved.