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Targeted metabolomics analysis of maternal-placental-fetal metabolism in pregnant swine reveals links in fetal bile acid homeostasis and sulfation capacity

Peng Wang, Heju Zhong, Yumo Song, Peiqiang Yuan, Yunxia Li, Sen Lin, Xiaoling Zhang, Jian Li, Lianqiang Che, Bin Feng, Yan Lin, Shengyu Xu, Yong Zhuo, Gang Tian, Daiwen Chen, De Wu, Douglas Burrin, Zhengfeng Fang
American journal of physiology 2019 v.317 no.1 pp. G8
bile acids, cholestasis, fetal death, fetus, gene expression regulation, gestation period, homeostasis, maternal-fetal transfer, metabolism, metabolomics, mothers, neonates, physiological transport, placenta, pregnancy outcome, sows, sulfates, uterus
Cholestasis of pregnancy endangers fetal and neonatal survival, yet systematic knowledge of the cause and effect of disrupted bile acid (BA) homeostasis in pregnancy is limited. Here we show that gestation stage-associated BA dysregulation in swine correlated with fetal death resulting from compromised capacity for BA secretion and increased alternative systemic efflux. The balance of BA input and output in the developing uterus suggested little uptake and metabolism of maternal BA by the placenta-fetus unit, implying a protection role of placenta in preventing maternal BA transported into the fetus. We showed that the maternal origin of BA accounted for the increase in placental total BA, leading to dysregulated expression of genes involved in BA transport and potentially impaired transplacental export of fetus-derived BA. Correspondingly, the secondary BA, mainly derived from the mother, gradually decreased in the fetus. Finally, we identified that sulfation rather than glucuronidation played pivotal roles in maintaining BA homeostasis of the developing fetus. These novel and systemic findings contribute to a whole picture of BA metabolism in pregnancy and provide new insights into mechanisms responsible for maternal and fetal BA homeostasis.