@article{9bc63662a73944b49224a93e96732b32,
title = "Effects of the maternal gut microbiome and gut-placental axis on melatonin efficacy in alleviating cadmium-induced fetal growth restriction",
abstract = "Cadmium (Cd) is a major environmental stressor that induces fetal growth restriction (FGR). Also, changes in gut microbiome diversity-which can be modulated positively by melatonin (Mel) have implications on fetal development and placental functions. Therefore, this study aimed to explore whether the role of Mel in counteracting the Cd-induced FGR by regulating placental barrier injury, endoplasmic reticulum stress (ERS) and mitophagy in pregnant mice is mediated-in part- via the gut microbiota modulations. Pregnant mice were intraperitoneally injected with CdCl2 (5 mg/kg) and Mel (5 mg/kg) once daily, respectively, at the same time from gestational day (GD) 8 to GD18, and then the maternal colon and placental tissues were collected for detection. To investigate the inner relationship between intestinal flora and the protection of Mel on FGR caused by Cd, gut microbiota transplantation (GMT) was carried out from GD0 to GD18 after the removal of intestinal microbiota by antibiotics. Results indicated that Mel relieved barrier injury, ERS and mitophagy in the placenta, and reversed the maternal gut microbiota dysbiosis. The GMT approach suggested a role of intestinal microbiota in placental barrier injury, ERS and mitophagy induced by Cd. Overall, the results highlighted that the intestinal microbiota and gut-placental axis play a central role in the protective effect of Mel against Cd-induced FGR.",
keywords = "Cadmium, Fetal growth restriction, Gut microbiota, Gut-placenta axis, Melatonin",
author = "Hao Zhang and Xiaoyun Liu and Yi Zheng and Xia Zha and Mabrouk Elsabagh and Ying Zhang and Yi Ma and Loor, {Juan J.} and Mengzhi Wang and Hongrong Wang",
note = "The research was supported by the fund for the National Natural Science Foundation of China (Grant number 31902180), the Top Talents Award Plan of Yangzhou University (2020), and the Cyanine Project of Yangzhou University (2020). The authors thank all the members of Hong Rong Wang's laboratory for their contribution to sample determination. Deeper research validated that gestational exposure to environmental Cd resulted in fetal growth restriction (FGR) in animal (Zhu et al. 2019). Furthermore, it was reported that Cd was chiefly accumulated in placenta while it was hard to permeate into the embryo (Ji et al. 2011). Consequently, Cd may cause FGR through placenta. Study has demonstrated that placental mitochondria possessed excellent adaptability during normal gestation in animal experiment, which contributed to promote fetal growth (Sferruzzi-Perri et al. 2019). It was found that placental BNIP3-dependent mitophagy had protection effect on Cd-induced FGR (Zhu et al. 2021). However, the exploration to unfold the influence of placental mitophagy and ERS on fetal growth in response to environmental stress is still scarce currently. Gut microbiome is not only important for the growth of embryo and fetus, but also closely related to the success of pregnancy. Based on that, we supposed that a {\textquoteleft}gut–placenta{\textquoteright} axis was vital for us to explore the aetiology of FGR. Previous studies indicate that Mel has some connections with intestinal microbiota, but the connections among Mel or intestinal microbiota and placental ERS or mitophagy remain unclarified. The general hypothesis was that Mel altered placental ERS and mitophagy in Cd-induced FGR in mice partly via its regulation on gut microbiota and intestinal barrier. Therefore, the aim of this research was to explore the effects of maternal intestinal microorganisms and placenta axis on Mel alleviating Cd-induced FGR and placental ERS and mitophagy. We confirm that the manuscript has not been published elsewhere and is not under consideration by other journals. All authors have approved the manuscript and agree with submission to Ecotoxicology and Environmental Safety. The authors have no conflicts of interest to declare. The research was supported by the fund for the National Natural Science Foundation of China (Grant number 31902180 ), the Top Talents Award Plan of Yangzhou University ( 2020 ), and the Cyanine Project of Yangzhou University ( 2020 ). The authors thank all the members of Hong Rong Wang{\textquoteright}s laboratory for their contribution to sample determination.",
year = "2022",
month = jun,
day = "1",
doi = "10.1016/j.ecoenv.2022.113550",
language = "English (US)",
volume = "237",
journal = "Ecotoxicology and Environmental Safety",
issn = "0147-6513",
publisher = "Academic Press",
}