4.1 summary of the study
We found interestingly that concentrations of Pb, Se, Fe, Zn, Mo all dropped during pregnancy, while Cu increased in the opposite. Interestingly, concentrations of Rb decreased first but subsequently increased. In addition, elements as Al, Co, Se, Cu, Ni showed significantly lower levels in cord than in maternal plasma, while elements as Sr, Fe, Rb, Mn, Zn displayed significantly higher levels in cord than in maternal plasma.
What’s more, positively-interacted clusters were found in Ni-Co-Cu-Al-Rb-Zn and Zn-Mn-Al-Pb in maternal blood. Similar positively-interacted clusters were found in Zn-Ni-Co, Zn-Ni-Fe, Mn-Al-Pb, Fe-Pb-Mn, Fe-Ni-Cu and Rb-Cu-Sb-Fe-Mn in cord plasma.
Last but not least, correlations between paired maternal and cord blood samples for As, Sr and Mo were statistically significant, indicating that the fetus burden might reflect the maternal exposure to some extent.
4.2 Concentration of trace elements during pregnancy
We found that Pb, Se, Fe, Ni, Zn and Mo investigated here significantly decreased during pregnancy, which might result from fetus’ mobilization during pregnancy or diluting effect from expansion of maternal plasma volume. (Table. 2, Fig. 1)
Pb exposure is a persistent global health hazard, with no safe exposure threshold[17]. Pb is a naturally occurring non-essential element, and human industrial practices can promote Pb exposures through the contamination of dust, food, and water.[18] The increased demands for calcium during pregnancy lead to increased bone turnover and increased circulating Pb levels[19]. Previous studies reported that the third trimester is the period during pregnancy that contains the greatest mobilization of Pb from maternal bone and fastest fetal growth.[20] However, in our studies, the overall trend pf Pb during pregnancy was a decrease, possibly arising from larger plasma volume. Lead was detected in all cord blood samples, confirming its placental transfer. Cord blood lead has been used in many studies as an index of prenatal lead exposure and is considered as a potential predictor of child development.[21] Though we found no correlation between maternal and cord blood lead levels, it seems the placenta might still partially hinder the passage of lead to the fetus and reduce its toxic effect.[22] Notably, other studies reported significantly higher blood levels of Pb than our study. In addition to differences in exogenous exposure, blood Pb concentrations can vary because of changes in hematocrit and Ca levels, plasma volume, and mobilization of Pb from bones during pregnancy [23, 24]
It has been universally recognized that Se has many functions in the body, primarily as selenocysteine-containing proteins (seleno proteins). Se deficiencies could play an important role in adverse outcomes such as miscarriages, neural tube defects, diaphragmatic hernia, premature birth, low birth weight, pre-eclampsia, glucose intolerance and gestational diabetes. [25] We found that Se content declined during pregnancy. Previous studies also found that Se stores in the body are depleted throughout pregnancy, with most depletion occurring at the end of pregnancy. [26, 27]
Fe is an essential, multifunctional micronutrient. The ability of Fe to easily transition between two oxidation states (Fe2+ and ferric Fe3+) underlies its involvement in a broad range of biological processes including oxygen transport, function of the electron transport chain and DNA synthesis[28]. Fe supply to the fetus is wholly dependent on the transfer across the placenta. The flux of Fe through the placenta is unidirectional, and is greatest in the third trimester, with several milligrams of Fe transferred to the fetus daily.[29] Considering that placental transfer of Fe is dependent on the bioavailability of Fe in the maternal circulation, the decrease of Fe during pregnancy might arise from mobilization of the fetus.
Similar to Fe, Zn decline during pregnancy has been reported by many researchers and found also in our study.[30–35]. The decrease in serum zinc concentration during pregnancy might reflect maternal- fetal Zn transfer in response to fetal growth.[30] Also, the expansion of maternal plasma volume can cause part of the diluting.[32] Furthermore, previous studies have suggested that the declining circulating Zn might be related to hemodilution, decreased levels of Zn-binding protein and hormonal changes.[24] The main characteristics following a Zn deficiency included weight loss, failure to thrive, and enhanced susceptibility to infections; the Zn supplementation may have a positive effect on neonatal immune status and infant asthma from infectious diseases, as well as reduce the risk of preeclampsia in pregnant women and preterm births.[36]
On the contrary, Cu levels significantly increased during pregnancy, probably due to the increased mothers’ metabolic demand of these nutrients[24]. In fact, Cu is mobilized in the mother during pregnancy, resulting in a significant increase in maternal serum Cu concentrations compared to umbilical cord serum. It should be mentioned that Cu deficiency can lead to anemia, neutropenia, bone disease and growth retardation in pediatric patients, as well as the increased risks of preterm births.[24] Furthermore, low Cu in early pregnancy is a risk factor for spontaneous abortion and CNS malformations, so supplementation before conception seems essential, and low Cu in later pregnancy is a risk factor for premature rupture of membrane.[36]
Interestingly, we found that concentrations of Rb decreased first but subsequently bounced back during pregnancy. Previous studies reported that Rb exhibited negative associations with miscarriage. [37] The interesting variation pattern cannot be explained to our knowledge yet. No previous research has reported similar results to our knowledge.
4.3 Concentration of trace elements in paired maternal and cord plasma.
The concentration of elements in the umbilical cord plasma of newborns influences the organism of the developing fetus and the adaptation of the newborn after birth to ectopic life, regulating several vital processes. Some elements are retained by the placental barrier, thus preventing them from entering the developing child’s body; however, the placenta is not an effective barrier for some xenobiotic elements as they are observed in the cord blood of newborns.
In our study, we mainly found lower levels of Al, Co, Se, Cu and Ni in cord than paired maternal plasma, which might arise from partially placental barrier, or fewer needs of the infants. [38] (Table.3, Fig, 3)
The major routes of human exposure to Al include the respiratory tract, gastrointestinal tract and skin.[39] Multiple epidemiological studies have reported an association between Al exposure and adverse pregnancy outcomes, including placental abruption[40], low birth weight[41], and birth defects [42]. Lower Al concentrations in cord blood might suggest that placental partially block its transfer and to our knowledge, no previous study has investigated the association between Al concentrations in maternal serum and placental tissue.
Co, as an essential component of vitamin B12, mainly acquired from dietary sources.[43] Previous study has shown that lower maternal serum Co concentration might associate with the incidence of pregnancy-induced hypertension syndrome[44] and preterm births[45] in Chinese population.
Cu content was comparatively lower in cord than maternal plasma, similar to other studies’ results, [24, 46, 47] indicating a limited transplacental passage of Cu from mother to fetus. This might arise from the low ceruloplasmin in the serum of newborns binding 96% of serum Cu[48]. In fact, Ceruloplasmin cannot penetrate the human placenta as the cord blood Cu did not strongly correlate with the maternal blood or colostrum concentrations, which is consistent with previous studies.[49]
On the contrary, we found that Sr, Fe, Rb, Mn, Zn demonstrated a higher level in cord than in paired maternal plasma, indicating that the placenta is no barrier for these elements and these elements might actively transport via placenta, consistent with previous studies[49]. (Table.3, Fig, 3)
Fe supply to the fetus is wholly dependent on the transfer across the placenta. The flux of iron through the placenta is unidirectional, and is greatest in the third trimester, with several milligrams of iron transferred to the fetus daily.[29] In this view, the mobilization of Fe might thus cause the comparatively higher level of Fe in cord plasma.
Regarding the significant higher Mn levels in cord blood compared to maternal blood, it could reflect the active transport of this element from mother to fetus.
Mn is vital for healthy brain and nervous system function as well as maintaining metabolism and hormone production.[36] Mn levels appear to increase throughout pregnancy due to low iron levels and accelerated erythropoiesis associated with pregnancy.[50] The limited data available on placental Mn transfer suggest that Mn is transported actively since the Mn amount was significantly higher in umbilical cord blood than in maternal serum.[49] Reduced iron status in pregnancy and particularly late pregnancy may lead to increased uptake of dietary Mn due to an up-regulated iron absorption, since the intestinal transport mechanism for iron is unable to differentiate between iron and Mn. [51] Low levels of manganese are associated with lower birth weight [52] and possibly with preterm births.[53] However, since we did not find a correlation between paired maternal/cord blood Mn concentrations, other reasons might explain the higher Mn in cord blood, such as the lower or restricted elimination of Mn by the fetus or the inability of the fetus to utilize this element.[54]
Notably, previous studies reported significantly higher levels of Mn than our study, which might result from different diets, use of supplements and metals (as Fe) deficiency status, which might have something to do with age loss.
4.4 Correlation between paired samples of trace elements
We found a significant correlation of As, Sr and Mo in paired maternal and cord plasma. (Table. 4)
Similar to our findings, significant correlations of As were reported in blood of mother/newborn pairs of South African, Flanders, Argentina and Spain populations, [24, 46, 55], indicating that the developing fetus may be at risk for these elements’ exposure via placental transfer. However, no previous studies have reported similar correlation relationship of Sr and Mo, to our knowledge.
Notably, correlation-calculations for other paired trace elements investigated here show no significant direct or inverse correlations. It can be speculated that the missing correlations reflect that the uptake by nutrition, the body-pools and their mobilization of the mother during pregnancy are sufficiently high for these elements for an adequate supply of fetus.[48] Other explanations are partially placental transfer and fetus’ little demand.
4.5 Correlation Between Two Element Concentrations
Positively-interacted clusters were found in Ni-Co-Cu-Al-Rb-Zn and Zn-Mn-Al-Pb in maternal blood, suggesting that those elements might arise from similar exposure source. In fact, exposure to metal mixtures rarely occurs alone but often in the form of mixtures of common sources.[56, 57] (Fig. 3, 4)
Similar positively-interacted clusters were found in Zn-Ni-Co, Mn-Al-Pb and Rb-Cu-Sb-Fe-Mn in cord plasma, suggesting that these elements might have similar placental transfer mechanisms or synergic interactions. (Fig. 5,6)
4.6 AMA pregnancy
Since most toxic elements are cumulative and the burden rises with years, maternal age was thought to be associated with trace elements’ concentrations.[55] On the other hand, some essential elements will lose with age. In fact, previous studies have already reported age-dependent variation of Cu, Zn, Ca, Mg, Pb, Mn, As, Cd and Hg with age, with essential elements such as Cu, Ca, Mg, and Mn decreased over ages while toxic elements such as Pb, As, Cd, and Hg accumulated over ages. [55]