During the prenatal period, the fetus begins to form one of the most complex structures in nature, the human brain. This process is called neural embryogenesis and it represents one of the most complicated processes in prenatal life. The process relies on the tight regulation of behavior of the cells that will make up the brain. Neuronal stem cells (NSC) play a key role in embryonic brain development.
NSCs need a special environment in order to be able to carry out their function in neural embryogenesis, the creation of new cells to populate the nervous system. However, in some cases, harmful environmental exposure can result in abnormal NSC behavior. Prenatal exposure to lead is one of these harmful influences that may overwhelm the NSCs’ mechanisms of coping with cellular damage. As a result, NSC-regulated processes in neural embryogenesis may become affected, often leading to neurodevelopmental disorders.
Upon fertilization, from a single cell, a mass of cells is formed and later this mass divides into several layers from which all structures of the human body originate. This is also the case for the central nervous system. It derives from one of the layers that forms the neural tube, the precursor to the brain, brainstem, and the spinal cord. Initially, the neural tube is rather small, but due to the creation of new cells from NSCs it gradually enlarges. Later, the cells in the neural tube get specialized to different functions by changing their cellular and biochemical characteristics. Evidently, if something goes wrong at any of these steps, developmental brain abnormalities may occur.
Lead has been a part of human civilization for a long period of time. However, only recently has the mechanisms by which lead causes negative health effects began to emerge. Lead is particularly harmful to NSCs, even when the exposure is minimal. Very minimal prenatal exposure to lead has been linked to lower IQ, aggressiveness, and other problems. Research studies have also shown that prenatal exposure to lead produces more harm than exposure during the postnatal period. These findings have been linked to the mechanisms behind cellular injury of NSCs by lead. The proposed mechanisms affect essential cellular functions that result in an increase in reactive oxygen species (ROS) and alterations in DNA methylation.
Reactive oxygen species are molecules that are naturally occurring as a result of cellular respiration. However, during pathologic conditions their levels can increase substantially. Chronic lead intoxication results in the increase of ROS through several mechanisms. Among them, there is a direct effect of lead ions on the proteins that regulate ROS levels. Additionally, lead can increase the level of ROS indirectly through interaction with aminolevulinic acid, a biochemical precursor for the components of hemoglobin. ROS can damage various structures in the cell and while doing this, create even more ROS. Additionally, ROS are involved in cellular death signalling and other cellular responses.
DNA methylation is one of the mechanisms regulating gene expression, and the regulation of gene expression is one of the bases of cellular differentiation. It has been shown that exposure to lead results in the alteration of DNA methylation, which in turn is associated with the inhibition of NSCs differentiation. Through mechanisms that are not yet known, lead causes changes in the methylation patterns close to genes strongly associated with neuronal differentiation.
Cells do not remain passive during these processes. Like other cells, NSCs have mechanism by which they counteract many of these harmful events. One the most recent investigation has studied the process involving the protein Nrf2.
Nrf2 has been directly linked to NSC’s protective mechanism against oxidative stress caused by exposure to lead. Nrf2 is associated with protein KEAP1 in the cytoplasm. When the levels of ROS increases, Nrf2 separates from the KEAP1, migrates to the nucleus and binds to specific DNA regions called antioxidant response elements (AREs). Upon Nrf2 binding, AREs activate expression of its target genes that code for diverse proteins responsible for cellular ROS detoxification.
Additionally, a new Nrf2 target, SPP1 protein, has been recently identified. SPP1 has particular significance in the lesion of NSC because it has been associated with neuroprotective properties through in vitro studies and through the association of mutations in its coding gene sequence with neurological diseases. These effects are the result of the signalling mechanism involving an anti-apoptotic and pro-proliferative process. The process results in compensatory responses to lead inhibition of NSCs proliferation. As a result, SPP1 has been proposed as a protective mediator of neurotoxicity in lead exposure.
Many diseases result from excessive cellular damage that cells are not able to adapt to. This is the case for NSCs where essential neurodevelopmental processes can be altered by lead toxicity. Although NSCs are equipped with protective mechanisms, they are often not powerful enough to counteract the harmful environmental influences. In such cases, the alterations of neural embryogenesis, proliferation, and differentiation take place. Specific changes leading to particular neurological manifestations still remain to be investigated in detail.
Our improved understanding of the harmful effect of lead on prenatal neurodevelopment calls for increased attention to avoid the exposure of future mothers to this toxic element. It is believed that millions of pregnant women around the world are regularly exposed to high concentrations of lead in food and drinking water. This often affects the health of the younger generation in many countries around the world.
References
Peter J. Wagner, Hae-Ryung Park, Zhaoxi Wang, Rory Kirchner, Yongyue Wei, Li Su, Kirstie Stanfield, Tomas R. Guilarte, Robert O. Wright, David C. Christiani, and Quan Lu (2016) In Vitro Effects of Lead on Gene Expression in Neural Stem Cells and Associations between Upregulated Genes and Cognitive Scores in Children. Environ Health Perspect; DOI:10.1289/EHP265
Temple S. (2001) The development of neural stem cells. Nature 414(6859): 112-7. DOI: 10.1038/35102174
Senut MC, Sen A, Cingolani P, Shaik A, Land SJ, Ruden DM (2014) Lead exposure disrupts global DNA methylation in human embryonic stem cells and alters their neuronal differentiation. Toxicol Sci. 139(1): 142-61. DOI: 10.1093/toxsci/kfu028.
Seiji Ishii and Kazue Hashimoto-Torii (2015) Impact of prenatal environmental stress on cortical development. Front. Cell. Neurosci. 9: 207. DOI: 10.3389/fncel.2015.00207
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