双P通过直接准PTGS2并破坏类固醇激素合成来诱导卵巢功能障碍
Dingmei Qin1, Zijian Ma1, Zhipeng Lin1
1Anhui Province Key Laboratory of Embryo Development and Reproductive Regulation, Anhui Province Key Laboratory of Pollution Damage and Biological Control for Huaihe River Basin, Fuyang Normal University, Fuyang, Anhui 236037, China.
双P (BPP) 通过向PTGS2并破坏类固醇激素合成,导致卵巢毒性. 这项研究揭示了BPP的一种新机制.
科学领域:
- 环境毒理学环境毒理学
- 生殖毒理学 生殖毒理学
- 分子毒理学分子毒理学
背景情况:
- 双A (BPA) 的结构类似物,如双P (BPP),被怀疑是生殖毒素.
- BPP的特定卵巢毒性在很大程度上仍未被描述.
- 了解BPP的影响至关重要,因为它越来越多地被用作BPA的替代品.
研究的目的:
- 为了阐明BPP诱导的卵巢损伤在周围青春期雌性小鼠背后的机制.
- 研究BPP对卵巢结构,功能和分子通路的影响.
- 确定受BPP暴露影响的关键分子标和途径.
主要方法:
- 在体内小鼠模型 (近青春期雌性) 经过8周的BPP暴露.
- 综合网络毒理学和转录组学分析.
- 分子对接,微尺度热泳 (MST) 和表面等离子体共振 (SPR) 用于相互作用验证.
- 分析卵巢形态,DNA损伤,细胞亡和血清激素水平 (雌激素,LH).
主要成果:
- 暴露于BPP诱导了显著的卵巢损伤,包括卵泡缩,粒粉细胞失调,DNA损伤和亡.
- 血清激素分析显示雌激素的降低和氨化激素的增加.
- 前列腺素-内氧化物合成酶2 (PTGS2) 被确定为直接的BPP标,通过分子对接和生物物理方法 (MST,SPR) 确认结合.
- 通过降低关键基因 (Lhcgr,Fshr,Nr5a1,Foxl2,Star,Cyp11a1,Hsd3b,Cyp19a1) 的调节,BPP抑制了类固醇生成途径.
结论:
- 双P (BPP) 是一种强烈的卵巢毒素.
- BPP直接针对PTGS2,导致综合性转录阻断类固醇激素合成.
- 这项研究建立了BPP诱导的卵巢毒性和新出现的环境污染物的评估框架的新机制.
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