Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China.
College of Biology Engineering, Henan University of Technology, Zhengzhou 450000, China.
Int J Mol Sci. 2022 Jun 10;23(12):6496. doi: 10.3390/ijms23126496.
Abnormally elevated circulating bile acids (BA) during pregnancy endanger fetal survival and offspring health; however, the pathology and underlying mechanisms are poorly understood. A total of nineteen pregnant sows were randomly assigned to day 60 of gestation, day 90 of gestation (G60, G90), and the farrowing day (L0), to investigate the intercorrelation of reproductive hormone, including estradiol, progesterone and sulfated progesterone metabolites (PMSs), and BA in the peripheral blood of mother and fetuses during pregnancy. All data were analyzed by Student's -test or one-way ANOVA of GraphPad Prism and further compared by using the Student-Newman-Keuls test. Correlation analysis was also carried out using the CORR procedure of SAS to study the relationship between PMSs and BA levels in both maternal and fetal serum at G60, G90, and L0. Allopregnanolone sulphate (PM4S) and epiallopregnanolone sulphate (PM5S) were firstly identified in the maternal and fetal peripheral blood of pregnant sows by using newly developed ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods. Correlation analysis showed that pregnancy-associated maternal BA homeostasis was correlated with maternal serum PM4S levels, whereas fetal BA homeostasis was correlated with fetal serum PM5S levels. The antagonist activity role of PM5S on farnesoid X receptor (FXR)-mediated BA homeostasis and fibroblast growth factor 19 (FGF19) were confirmed in the PM5S and FXR activator co-treated pig primary hepatocytes model, and the antagonist role of PM4S on FXR-mediated BA homeostasis and FGF19 were also identified in the PM4S-treated pig primary hepatocytes model. Together with the high relative expression of in pig hepatocytes, the pregnant sow is a promising animal model to investigate the pathogenesis of cholestasis during pregnancy.
怀孕期间循环胆汁酸（BA）水平异常升高会危及胎儿生存和后代健康，但病理和潜在机制尚不清楚。总共 19 头妊娠母猪被随机分配到妊娠第 60 天（G60）、妊娠第 90 天（G90）和分娩日（L0），以研究妊娠期间母代和胎儿外周血中生殖激素（包括雌二醇、孕酮和硫酸化孕酮代谢物（PMSs））与 BA 的相互关系。所有数据均采用 Student's -test 或 GraphPad Prism 的单因素方差分析进行分析，并进一步通过 Student-Newman-Keuls 检验进行比较。还通过 SAS 的 CORR 过程进行了相关性分析，以研究 G60、G90 和 L0 时母代和胎儿血清中 PMSs 和 BA 水平之间的关系。通过新开发的超高效液相色谱-串联质谱（UPLC-MS/MS）方法，首次在妊娠母猪的母代和胎儿外周血中鉴定出别孕烯醇酮硫酸盐（PM4S）和表孕烯醇酮硫酸盐（PM5S）。相关性分析表明，与妊娠相关的母代 BA 内稳态与母代血清 PM4S 水平相关，而胎儿 BA 内稳态与胎儿血清 PM5S 水平相关。在 PM5S 和 FXR 激活剂共同处理的猪原代肝细胞模型中，证实了 PM5S 对法尼醇 X 受体（FXR）介导的 BA 内稳态和成纤维细胞生长因子 19（FGF19）的拮抗作用，并且在 PM4S 处理的猪原代肝细胞模型中也鉴定了 PM4S 对 FXR 介导的 BA 内稳态和 FGF19 的拮抗作用。结合猪肝细胞中相对高表达的，妊娠母猪是研究妊娠期间胆汁淤积症发病机制的有前途的动物模型。
