In this study, we determined the association of essential and toxic elements with chromosomal abnormalities in human amniotic fluid in fetuses of the white/Caucasian population in the second trimester of pregnancy. Based on the results, low concentrations of manganese and high concentrations of iron were associated with ahigher occurrence of chromosomal abnormalities (predominantly of trisomy 21, Down’s Syndrome). To the best of our knowledge, this is the first study of Polish pregnant women to demonstrate such a relationship.
This study showed that the presence of chromosomal aberration in fetuses increased with a low level of Mn in AF. Mn plays a crucial role in maternal health and early pregnancy development. Manganese acts by activating certain enzymes and through Mn-dependent metalloenzymes, such as manganese superoxide dismutase, that are needed for proper reproduction and protection against free radicals. In animal and human studies, it was found that a low level of maternal manganese is associated with reduced reproductive function, impaired fetal growth and poor perinatal outcomes. On the other hand, it is known that excess manganese is a potent neurotoxin and may induce adverse neurological, reproductive and respiratory effects. Little is known about the relation between Mn status and chromosomal abnormalities12. the mitochondrial oxidative phosphorylation pathway is a major source of free radicals, and MnSOD plays a crucial role in protection against these radicals and maintains the oxidant/antioxidant balance. A decrease in Mn content caused a low activity of MnSOD and disrupted this balance13. It was found that oxidative stress increases in amniotic fluid in Down’s Syndrome13,14.
It is also known that excess iron is a major cause of oxidative stress because Fe ions can generate free radicals in the Fenton reaction. Hattori et al.15 found that the content of catalytic Fe(II) in amniotic fluid inabnormal pregnancies (also involving trisomy 21 and trisomy 18) was significantly higher than in normal pregnancies. These authors concluded that catalytic iron in AF may be one of the markers of abnormal pregnancy. Our study confirms such a relationship and indicates that high iron levels in AF increased the probability of fetal abnormalities, mainly Down’s Syndrome and trisomy 18. We speculate that increased iron in AF may be swallowed by the trisomic fetus and higher Fe concentrations in its body with chromosomal abnormalities accelerate oxidative stress and progressive oxidative damage of its internal organs. We also noticed that elevated concentration of iron in AF was present not only in DS cases. Extremely high levels of iron (over 1600 ug/L) were found in AF with triploidy.
Other trisomies are also associated with increased oxidative stress, inflammation and nervous system disorders. However, most literature reports about the relationship between minerals and chromosomal abnormalities focus on Down’s Syndrome. Significantly higher ferritin levels and markedly lower transferrin concentrations and TIBC levels were found in adults (18–35 years) with DS compared to healthy individuals16.
It seems that increased oxidative stress observed in people with DS may begin in utero and might play a crucial role in phenotypic traits. Moreover, Down Syndrome and many other chromosomal abnormalities are associated with metabolic diseases such as obesity, insulin resistance, lipid disorders with a great role of oxidative stress in etiopathogenesis7,17. Therefore, based on the obtained results we can assume that increased oxidative stress linked to high Fe and low Mn concentrations in AF in early development may contribute to increased oxidative stress, brain disorders and other metabolic disorders in the later life of people with aneuploidies. It seems that a treatment strategy involving lowering oxidative stress by regulation of element status in AF may potentially protect against the disorders that are observed in people with chromosomal abnormalities.
The relationship of chromosomal aberration with lower Mn concentration and higher iron level in AF may also be associated with the interaction between Fe and Mn on the transport level. Divalent metal transporter 1 (DMT1) is the primary non-heme iron transporter in the intestine to transport iron but also other elements, including manganese. DMT 1 is found not only in the intestine but also in other tissues, also in the placenta, and the transport of excess iron via this transporter decreases the transport of manganese in tissues12.
The concentration of elements in AF may be affected by endogenous and exogenous factors. The correlation between essential elements observed between iron and copper levels as well as between calcium and magnesium levels indicate the transport and metabolic relationships between these elements. It is known that systemic copper deficiency generates cellular iron deficiency. These two essential elements participate in single-electron transfer reactions and owing to this capacity, they also may generate free radicals and increase oxidative status in the body18. As mentioned above, an association between iron excess and neurodegenerative diseases including Down’s Syndrome was found15. In this study, we observed higher iron levels in AF in pregnancy with chromosomal disorders. In a mouse model of Down’s Syndrome it was observed that copper accumulation in the brain increased oxidative stress19. A change in the homeostasis of copper in the brain is also suggested in Alzheimer’s disease8. In the human body, magnesium and calcium metabolism are closely related. There are relations between the intestinal absorption and renal excretion of these two elements20. Positive correlation between toxic elements, e.g. Al and Ni, observed in our study may be the consequence of exposure to environmental concomitants21. Correlation index values are higher for AF with chromosomal abnormalities which may be related to the exposure of pregnant women in this group to different toxic elements during pregnancy. It was found that toxic elements such as Cd, Ni and Al are adversely related to chronic morbidity21,22. Results of the study by McLachlan et al.23 suggest that aluminium accumulation in the brains of patients with Alzheimer’s disease and Down’s Syndrome may contribute to the neuropathology of those neurological diseases.
It is known that advanced age in women increases the risks of infertility and aneuploidy in the offspring, most predominantly Down’s syndrome (trisomy 21), Edwards’ syndrome (trisomy 18), and Turner’s syndrome (monosomy X),. The postulated mechanism is connected with increased oxidative stress which may alter gene expression. Follicular aging can lead to mitochondrial dysfunction and hence disturb MnSOD activation. Chromosome segregation errors occur in aged oocytes during meiosis, which can result in aneuploidy and poor oocyte quality24.
This study has some limitations. First of all, our study group with chromosomal abnormalities was relatively small and rather heterogeneous with different chromosomal abnormalities (nearly 60% were cases with DS). Furthermore, in the present study, we did not determine nutritional and environmental factors that may affect the concentration of elements in AF. We also did not include other maternal parameters such as smoking, body mass, education and socioeconomic status that may influence the content of elements in AF.