Maternal iron supplementation during pregnancy affects placental function and iron status in offspring

https://doi.org/10.1016/j.jtemb.2022.126950Get rights and content

Abstract

Background

Iron deficiency and overload during pregnancy damage to maternal and fetal health. Placenta as an organ for the transport of nutrients between mother and fetus protects fetus from the harmful effects of iron deficiency and iron overload through regulation of placental iron homeostasis.

Methods

To determine the effect of dietary iron supplementation during pregnancy on reproduction and the mechanism of placental iron regulation, we designed dietary high iron (HI: 344 mg/kg), medium iron (MI: 40 mg/kg), low iron (LI: 2 mg/kg) groups of pregnant female mice fed ferrous citrate 2 weeks before mating to 18.5 days of gestation.

Results

We find dietary iron supplementation during pregnancy effect maternal liver iron, placental iron, hemoglobin and fetal iron. Dietary iron significantly improves reproductive performance as litter weight and fetal weight. Correlation analysis suggest placental iron increased with liver iron, higher and lower liver iron is not conducive to the accumulation of fetal iron, placental iron deficiency and excess reduce litter weight. Placental transcriptome analysis revealed DEGs with the same trend in HI and LI groups compared with MI group, dietary iron may change biology process of ion transport and gland development in placenta. Granzyme may affect the placental trophoblast structure prior to delivery with iron overload uniquely.

Conclusion

This research highlights the importance of moderate iron supplements in pregnancy due to damage of reproduction by affecting placental function under different dose of maternal iron supplementation.

Introduction

Iron is an essential trace element for animals. Iron deficiency is one of the main causes of anemia. Iron deficiency anemia prevalence between estimated 20%− 80% all over the world and consists of a primarily female population [1]. Especially during pregnancy, anemia can be aggravated by various conditions such as uterine or placental bleedings, gastrointestinal bleedings, and peripartum blood loss. Anemia can cause many adverse pregnancy consequences included intrauterine growth retardation, prematurity and abortion to damage to maternal and fetal health [2], [3]. Oral iron is the most convenient and safe prevention way compared with intravenous iron for iron deficiency anemia during pregnancy [4], [5].

Dietary iron is absorbed mainly in the duodenum in the form of ions, Fe2+ enters intestinal epithelial cells through discovery of divalent metal transporter 1 (DMT1) [6], in addition to ferritin synthesis, Fe2+ is transported to the blood through ferroportin (FPN) in the basal membrane of intestinal epithelial cells to complete the absorption of iron in the diet [7], [8]. Iron homeostasis is mediated by hepcidin in animals, and recent research shows maternal hepcidin restricts transport of iron in the placenta to regulate embryo iron homeostasis and health [9]. In humans and mice, trophoblasts of the placental villi uptakes transferrin (Tf) directly from maternal blood through mediated by transferrin receptor 1 (TFR1) [10], then Fe3+ dissociates from Tf into the cytoplasm via DMT1 or Zrt and Irt-like protein 14 (ZIP14) in placenta and is reduced to Fe2+, Fe2+ in placenta is exported by the iron exporter FPN to bind to fetal Tf. Finally, iron is transported across epithelial cells to the fetus [11].

Study have shown that low daily iron supplementation (30 mg/kg) during pregnancy enhance maternal iron status and protect fetus from iron deficiency anemia, diet iron supplementation also improves birth weight of infant [12]. Dietary iron supplementation (80 mg/kg) of sows promotes iron transport in placenta to improve reproductive performance and enhance iron status of nursing pig [13], [14]. Iron excess can also lead to adverse effects on pregnancy, including oxidative stress, increased blood viscosity and inflammation, statistics show a U-shaped curve for risk associated with iron status or iron supplementation, both low and high iron status of matrix increase the risk of an adverse pregnancy [15]. Oxygen and iron excess cause excessive membrane lipid peroxidation and ferroptosis in trophoblast cells may be the main reason of reproductive disorders, iron supplementation was suggested to be limited less than 60 mg/kg per day during pregnancy [16]. It has been reported that placenta will priority maintain placental iron homeostasis through the expression of TFR1 and FPN facing maternal iron deficiency and overload [17], this mechanism may protect the fetus from placental dysfunction. Both dietary iron deficiency and iron overload supplementation seem to be detrimental to reproduction and fetal development. However, the safe and effective dose of dietary iron supplementation during pregnancy, the consequences and causes of dietary iron supplementation still unclear. Therefore, we explored the effects of dietary iron supplementation on reproductive performance of mice, and revealed the possible reason of dietary iron supplementation affecting reproduction through correlation analysis and placental transcriptome analysis.

Section snippets

Animals, diets and experimental design

All animal experiments were approved by the Animal Care and Use Committee of the Chinese Academy of Sciences (Beijing, China), and all procedures were conducted in accordance with the Chinese Guidelines for Animal Welfare.

The animal experiment was conducted at Institute of Subtropical Agriculture, Chinese Academy of Sciences. C57BL/6 mice aged 7 weeks were provided by the SLAC Laboratory Animal Central (Changsha, Hunan, China). The basal diet was customized at Bilag Biotechnology Co., Ltd

Dietary iron affects maternal and fetal iron status

To determine whether dietary iron supplementation effect maternal and fetal iron status, we examined indicators related to iron metabolism in high iron, medium iron and low iron groups. C57BL/6 female mice were either fed diet contain different iron (2, 40, 344 ppm) from 2 weeks before mating to gestation 18.5 days (gestation in C57BL/6 is about 19 days). All measures were analyzed at 18.5 days of gestation.

In maternal mice, liver iron and HGB changed as excepted depending on the dietary iron

Discussion

The main aim of our research was to investigate effect of dietary iron level on reproductive performance in pregnancy. Therefore, we used mice as animal models to set up iron low group (LI), medium iron group (MI) and high iron group (HI) through different dietary supplementation of ferrous citrate. We measured iron metabolism by routine blood and tissue iron content, we also recorded reproductive performance of female mice. Finally, transcriptome data from placental tissue were analyzed.

It is

CRediT authorship contribution statement

Yulong Yin, Dan Wan: Designed research program. Liu Guo: Analyzed the samples, Write this manuscript. Dongming Zhang, Shuan Liu, Zhenglin Dong, Jian Zhou: Conducted experiment.

Acknowledgements

This work was supported by the National Key R&D Program of China (2016YFD0501201), the Changsha Science and Technology Project (kq1907073), the Young Elite Scientists Sponsorship Program by CAST (2018QNRC001), the Science and Technology Program of Hunan Province (2020NK2013, 2020GK4095), Outstanding Youth Fund of Hunan Natural Science Foundation (2021JJ20045), the Key R&D Program of Guangxi Province (2021AB20063).

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