Role of placental barrier on trace element transfer in maternal fetal system and hypertensive disorders complicating pregnancy and gestational diabetes mellitus

As an effective component of hemoglobin, Fe is rich in maternal blood and umbilical cord blood. The placenta is the key hub for the transfer of Fe from the mother to the fetus. The movement of Fe in the maternal-fetal system is unidirectional - from the mother to the fetus. Therefore, the level of Fe on the fetal side does not change the dynamic characteristics of Fe absorption into the placenta [8]. Studies have shown that GDM-mediated hyperglycemia can affect placental Fe homeostasis [9]. Our study observed a negative correlation between placental Fe and Apgar score in the normal group, but this was reversed in the GDM group, and placental Fe had a higher promoting effect on Apgar score (Table 2). In addition, the content and distribution of Fe in the maternal blood, placenta and umbilical blood in the GDM group (Fig. 2E) also changed compared with those in the normal group(Fig. 2A). Fe can be used as an oxidant to participate in the pathogenesis of GDM, its main function is to induce insulin resistance and interfere with insulin release from pancreatic beta cells [10]. Therefore, the abnormal distribution of Fe content in the maternal-fetal system in the GDM group may be mainly caused by the maternal side. More and more studies suggest that maternal Fe content is a risk factor for GDM [11]. The occurrence of GDM can also affect the barrier and transport function of the placenta about Fe, thus affecting the transfer efficiency of Fe in the maternal-fetal system and increasing the risk of fetal health.

Fe is the producer of free radicals (FRs) (oxidants), and Fe supplementation may put people at risk of excessive intake of Fe [12]. Indeed, the chemical properties of Fe give it potential harm. This is mainly due to the key role of Fe in the Fenton reaction, which leads to the production of highly toxic hydroxyl radicals (·OH) [13]. Since free-form sub-Fe ions (Fe²⁺) can cause the production of FR or reactive oxygen species (ROS), which can lead to peroxidation and FR chain reactions and finally to molecular damage [12]. A high Fe content will increase the risk of HDCP (e.g., PE) [14, 15]. It is worth noting that the content of Fe in maternal blood, placenta and umbilical cord blood in the HDCP group was higher than that in the normal group (Fig. 3B), and the results were consistent with previous literature reports [14, 16]. With the improvement of living standards and the enhancement of people’s awareness of health care, it is generally believed that the demand for Fe during pregnancy is very high, so Fe is traditionally used as a supplement during pregnancy. Although this may be correct in a few cases, most pregnant women do not need to take excessive Fe supplements [12].

Mn is an important trace element in the human body. Its normal level in the body is very important for the health of the mother and fetus [17]. This study observed that the content of Mn in the placenta in different groups was significantly higher than that in maternal blood, which mainly reflected the active transport of Mn from the mother to the placenta in the maternal-fetal system. In addition, studies have shown that Mn is involved in glucose metabolism in the human body and inhibits glucose interference with insulin secretion through the activation of related pathways, thus increasing the risk of GDM [18‐20]. The content and distribution of Mn in maternal blood, placenta, and umbilical blood in the GDM group (Fig. 2F) were changed compared with that in the normal group(Fig. 2B). The occurrence of GDM may affect the placental transport of Mn and lead to the risk of excessive intake of fetal Mn. Studies have shown that high levels of Mn exposure can affect indicators of fetal development [21]. In addition, there was no significant difference in Mn content between the normal group and the GDM group (Fig. 3E), which was consistent with other research results [22‐24].

The placenta plays an important role in the transfer of Ni from the mother to the fetus, although the placenta provides a protective barrier against Ni toxicity [25], However, with increased pregnancy duration, the ability of the placenta to absorb and retain Ni also increases [26]. Studies have shown that in the maternal-fetal system with gestational diseases, the transportation of Ni in the placenta will significantly change the morphology and permeability characteristics of the placenta during development [26]. The barrier and normal function of the placenta are damaged, as shown in Fig. 3D, which shows that the Ni content in the cord blood of the HDCP group and GDM group was significantly higher than that of the normal group (P < 0.05). Therefore, we speculate that Ni in the HDCP group and GDM group can not only accumulate in the placenta but also damage the placental barrier function of Ni so that more Ni can pass through the placenta and enter the fetal side. In addition, Ni hurts glucose metabolism, and the increase of maternal Ni content is associated with the risk of GDM [27], but the relevant evidence is limited, and more studies are needed to verify and explore its pathogenesis.

Carbohydrate residues were found in the placental structure of normal and healthy pregnant women [28]. The abnormal morphology and function of the placenta in pregnant women with HDCP will lead to changes in carbohydrate morphology [29]. It has been documented that Cr is involved in the metabolism of carbohydrates and lipids [30]. HDCP may affect placental function by altering the placental structure, resulting in an imbalance of Cr transport in the maternal-fetal system, resulting in an increased risk of fetal Cr exposure (Fig. 3F). Abnormal Cr content can increase the rate of spontaneous abortion, affect fetal intrauterine growth and increase the risk of adverse outcomes [31]. The correlation analysis between trace elements and the Apgar score showed that Cr content in the placenta was negatively correlated with the Apgar score(Table 2). Apgar scores are associated with an increased risk of neurological and cognitive impairment in early adulthood [32]. In addition, Cr also plays a very important role in the process of glucose metabolism, but no significant correlation was found between Cr content and the risk of GDM in this study, which is consistent with the results of other case-control studies [33, 34].

Zn and Cu are important trace elements in the human body and are very important for maternal health and fetal development. Zn and Cu can be used as micronutrients, which play a positive role in maternal and fetal health, and as antioxidant elements, which participate in oxidative stress processes [35, 36]. Oxidative stress is one of the key pathogenesis of pregnancy diseases (e.g., PE). The results of this study show that the content and distribution of Zn and Cu in the pregnancy disease group (Fig. 1E-F, I-J) were not significantly different from those in the normal group (Fig. 1A-B). It can be seen that Zn and Cu have little or no change in homeostasis in the maternal-fetal system of HDCP and GDM. It has also been reported that there are a large number of enzymes containing Zn and Cu in the placenta itself [37‐39]. The neutralization of physiological and pathological mechanisms may explain this result.

To the best of our knowledge, this is one of the few studies in which collected paired samples of maternal blood, placenta, and umbilical cord blood from both normal and disease groups. We observed that the distribution characteristics of trace elements (Zn, Cu, Fe, Mn, Ni, Cr) in the maternal-fetal system and related to HDCP and GDM. Our work also has its limitations: an insufficient number of participants was in each group. The previous evidence is limited and contradictory, and the etiology of HDCP and GDM and the factors affecting the transfer of trace elements are diverse. Therefore, we only performed a preliminary analysis of the distribution characteristics of trace elements in the maternal and fetal systems of HDCP and GDM and did not further examine how trace elements increase health risks. The interaction of HDCP and GDM with trace elements in the maternal-fetal system needs further investigation.