Exogenous gonadotropin-controlled ovarian stimulation is the critical step in animal reproductive management, such as pig, sheep, bovine and other species. It helps synchronize ovulation or stimulate multiple ovulations. However, a number of evidence indicated an unexpected decrease in pregnancy outcomes following ovarian stimulation. This study aimed to explore the underlying mechanism of the pregnancy defect and develop a practical rescue strategy. Compared with those in the control group, gilts that underwent ovarian stimulation showed a decrease in pregnancy rate, farrowing rate, and total number of piglets born. Stimulated gilts also showed an increase in estradiol (E2) levels. The supraphysiological E2 level was correlated with the decrease in the number of piglets born. Furthermore, we found that high levels of E2 impair uterine receptivity, as shown by the overproliferation of endometrial epithelial cells. In vitro mechanistic studies demonstrated that high levels of E2 hyperactivate FGF-FGFR-ERK signaling cascade in the uterine endometrium, and in turn induces overproliferation of endometrial epithelial cells. Of note, N-acetyl-L-cysteine (NAC) supplementation effectively inhibits ERK hyperphosphorylation and ameliorates endometrial epithelial overproliferation. Importantly, in vivo experiments indicated that dietary NAC supplementation, compared with ovarian stimulation group, improves the uterine receptivity in gilts, and significantly increases the pregnancy rate and total number of piglets born. Ovarian stimulation-induced supraphysiological levels of E2 impairs uterine receptivity by hyperactivating FGF-FGFR-ERK signaling cascade, thereby reducing pregnancy rate and litter size. Supplementing NAC to a conventional diet for gilts ameliorates hyperactivated ERK signaling and improves uterine receptivity, thus rescuing adverse pregnancy outcomes following ovarian stimulation.

中文翻译：

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膳食补充 N-乙酰-L-半胱氨酸可改善子宫内膜中过度激活的 ERK 信号传导，这与猪卵巢刺激后不良妊娠结局有关


外源性促性腺激素控制的卵巢刺激是动物生殖管理的关键步骤，例如猪、羊、牛和其他物种。它有助于同步排卵或刺激多次排卵。然而，许多证据表明，卵巢刺激后妊娠结局意外下降。本研究旨在探讨妊娠缺陷的潜在机制并制定实用的挽救策略。与对照组相比，接受卵巢刺激的后备母猪妊娠率、分娩率和仔猪总数均有所下降。受刺激的后备母猪也显示雌二醇 （E2） 水平增加。超生理 E2 水平与出生仔猪数量的减少相关。此外，我们发现高水平的 E2 会损害子宫容受性，如子宫内膜上皮细胞的过度增殖所示。体外机制研究表明，高水平的 E2 过度激活子宫内膜中的 FGF-FGFR-ERK 信号传导，进而诱导子宫内膜上皮细胞的过度增殖。值得注意的是，补充 N-乙酰-L-半胱氨酸 （NAC） 可有效抑制 ERK 过度磷酸化并改善子宫内膜上皮过度增生。重要的是，体内实验表明，与卵巢刺激组相比，日粮补充 NAC 提高了后备母猪的子宫容受性，并显着提高了妊娠率和出生的仔猪总数。卵巢刺激诱导的超生理水平 E2 通过过度激活 FGF-FGFR-ERK 信号级联来损害子宫容受性，从而降低妊娠率和窝产仔数。 在后备母猪常规饮食中补充 NAC 可改善过度激活的 ERK 信号传导并提高子宫容受性，从而挽救卵巢刺激后的不良妊娠结局。