Li Yating, Huang Jing, Ge Caiyun, Zhu Sen, Wang Hui, Zhang Yuanzhen
Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Department of Otorhinolaryngology Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
Biomed Pharmacother. 2024 Mar;172:116246. doi: 10.1016/j.biopha.2024.116246. Epub 2024 Feb 14.
Azithromycin, a commonly used macrolide antibiotic for treating chlamydial infections during pregnancy, has sparked investigations into its potential effects on offspring development. Despite these inquiries, there remains uncertainty about the specific impact of prenatal azithromycin exposure (PAzE) on offspring ovarian development and the precise "effect window". Pregnant mice, following clinical guidelines for azithromycin dosing, were orally administered azithromycin at different gestational stages [(gestational day, GD) 10-12 or GD 15-17], doses (50, 100, or 200 mg/kg·d), and courses (single or multiple). On GD 18, we collected offspring blood and ovaries to examine changes in fetal serum estradiol (E2) levels, fetal ovarian morphology, pre-granulosa cell function, and oocyte development. Multiple courses of PAzE resulted in abnormal fetal ovarian morphological development, disorganized germ cell nests, enhanced ovarian cell proliferation, and reduced apoptosis. Simultaneously, multiple courses of PAzE significantly increased fetal serum E2 levels, elevated ovarian steroidogenic function (indicated by Star, 3β-hsd, and Cyp19 expression), disrupted oocyte development (indicated by Figlα and Nobox expression), and led to alterations in the MAPK signal pathway in fetal ovaries, particularly in the high-dose treatment group. In contrast, a single course of PAzE reduced fetal ovarian cell proliferation, decreased steroidogenic function, and inhibited oocyte development, particularly through the downregulation of Mek2 expression in the MAPK signal pathway. These findings suggest that PAzE can influence various aspects of fetal mouse ovarian cell development. Multiple courses enhance pre-granulosa cell estrogen synthesis function and advance germ cell development, while a single terminal gestation dose inhibits germ cell development. These differential effects may be associated with changes in the MAPK signal pathway.
阿奇霉素是孕期治疗衣原体感染常用的大环内酯类抗生素，已引发对其对后代发育潜在影响的调查。尽管有这些研究，但产前阿奇霉素暴露（PAzE）对后代卵巢发育的具体影响以及确切的“效应窗”仍不明确。按照阿奇霉素给药的临床指南，对怀孕小鼠在不同孕期阶段[妊娠日（GD）10 - 12或GD 15 - 17]、不同剂量（50、100或200 mg/kg·d）和不同疗程（单次或多次）口服阿奇霉素。在GD 18时，我们收集后代的血液和卵巢，以检查胎儿血清雌二醇（E2）水平、胎儿卵巢形态、前颗粒细胞功能和卵母细胞发育的变化。多次PAzE疗程导致胎儿卵巢形态发育异常、生殖细胞巢紊乱、卵巢细胞增殖增强和凋亡减少。同时，多次PAzE疗程显著提高胎儿血清E2水平，增强卵巢类固醇生成功能（以Star、3β - hsd和Cyp19表达表示），破坏卵母细胞发育（以Figlα和Nobox表达表示），并导致胎儿卵巢中MAPK信号通路发生改变，尤其是在高剂量治疗组。相比之下，单次PAzE疗程减少胎儿卵巢细胞增殖，降低类固醇生成功能，并抑制卵母细胞发育，特别是通过下调MAPK信号通路中Mek2的表达。这些发现表明，PAzE可影响胎儿小鼠卵巢细胞发育的各个方面。多次疗程增强前颗粒细胞雌激素合成功能并促进生殖细胞发育，而妊娠末期单次剂量则抑制生殖细胞发育。这些不同的影响可能与MAPK信号通路的变化有关。
