Placenta transfer of elements and other materials from maternal into the foetal circulation of the baby in-utero has been well documented especially based on studies from the developed parts of the world [19][20]; however, whether such movement may precipitate or exacerbate abnormal neurodevelopment in the developing baby in-utero remains contentious. Understanding this becomes imperative especially in the aetiology of neurodevelopmental diseases which are generally initiated in early life of the baby in-utero [21]. The development is more worrisome in pregnant mothers occupationally exposed to some of the known essential or toxic elements which as a result of their placenta transfer to the baby may create an elemental imbalance in the baby with possible disruption of sensitive metabolic functions and the attendant systemic dysfunctions. The focus of this work was thus the attendant implications of such transfer on the delicate balance of these elements and its possible influence on the aetiopathogenesis of autism spectrum disorders in children of mothers occupationally exposed to such metals.
In recruiting participants for this project, various environmental peculiarities including anthropometric and anthropogenic factors were considered to ensure that such did not confound the credibility and appropriateness of findings. These anthropometric and anthropogenic factors are known sources of exposure to various contaminants and toxicants [22]. Occupational exposure to them have been established as veritable sources of organophosphates, organo-pesticides and arsenate (insecticides), cadmium (smoking and seafoods) and lead (leaded paints and environmental dust) [23][24][25][26][27]. Hence, the similarities in participants’ exposure in this study in the use of insecticides, passive/active smoking and exposure to various environmental contaminants derivable through dust by virtue of the type of residence and proximity to tarred road may be said to validate appropriateness of the recruited participants. Also, consumption of nutritional supplements and sea food especially during pregnancy was similar in all the participants as derived from the administered structured questionnaire. This was to moderate the possible exposure to toxic metals including cadmium which may be derivable from sea foods and other essential elements that are often constituents of the common nutritional supplements voluntarily administered by pregnant mothers especially in this clime. Inappropriate consumption of nutritional supplements during pregnancy may precipitate alteration in levels of some essential elements resulting in an imbalance in levels of pro- and anti-oxidant elements in the system. The observed similarity in the consumption of these items and the comparative educational levels of mothers and their spouses in this study may also be indicative of similarities in the social and educational standards of participants thus validating their comparison. In summary, similarities in anthropometric and anthropogenic factors by participants in this study (cases and controls) may have ensured appropriateness of the choice of participants and hence validity of deductions from various biochemical data obtained.
In considering the focus of this work which was to examine the possible implications of placenta transfer of various elements from mother to the foetus and their possible involvement in the development of autism, results obtained in this study showed that essential (zinc, selenium, copper, calcium, magnesium) and toxic (cadmium, lead) metals were transferred from maternal to foetal circulation. Levels of these elements and metals in maternal and fetal circulation as observed in this study may be seen as an indication of placental transfer of the elements in-utero. Findings in this study were similar to previous ones [5][10][28]; hence, variations in levels of these elements in cord blood of cases and controls may be seen as evidence of trans-placenta transfer of the elements from the mother to the developing baby in-utero. A closer look at the degree of transfer which affected all elements under consideration showed that Zn was particularly heavily transferred from maternal blood circulation into that of the foetus. The observed level of blood Zn also showed that it accumulated more in the baby than in the mother from which it was transferred. This observation was similar to previous works which documented that cord blood Zn level was elevated in babies than in mothers. (Irwinda et al., 2019).
It could also be seen that Cu level was higher in cord blood of exposed babies than in non-exposed babies as against the picture obtained in maternal circulation where Cu was higher in non-exposed mothers than in exposed mother’s circulation. Although this has also been the findings by previous works (Hu et al., 2015; Irwinda et al., 2019), the import and concern about this is that cord blood Cu would be expected to follow the same pattern since the baby derived her nutrients from that of the mother while still in-utero. Zn and Cu have also been reported to have an inverse relationship especially when one out-number the other (Halsted, et al., 1968). There is therefore the need for a plausible explanation for this phenomenon especially as it may possibly explain some of the issues associated with neurogenesis and its disorders.
Associating differences in the clinical and cognitive functions of children from the two groups of mothers (cases and controls) with alterations in these elements as an aetiological basis of the pathogenesis of autism in early life of the children requires examining the established physiological and biochemical roles of the various elements/metals in neurodevelopmental processes.
Zinc as an essential element is known to be involved in several metabolic activities while its anti-oxidant activities and that of Se especially in the nervous system has been well documented [29][30][31].Zn, Se and Mg are known to be very crucial in the metabolic processes of neurogenesis; their roles in axon development and antioxidation in neurogenesis have been established (Adamo & Oteiza, 2010). Cu, on the other hand, is said to contribute in a number of neurodevelopmental processes and is needed for numerous proper enzymes functioning in the brain. Copper deficiency and toxicity can interfere with brain developments and functions. Zn is known to couple Cu in the Cu/Zn enzyme dismutase which along with glutathione scavenges toxicants in form of ROS that may disturb the oxidant/antioxidant balance in the brain. The observed increased cord Cu level may then be examined in context of its relationship with both Zn and Se that complimentarily maintain the oxidant/antioxidant balance in the brain (de Lucia et al., 2020). Secondly, Zn is known to influence the absorption of Cu in the intestine, a definite relationship (1:1) is known to exist between Zn and Cu in ensuring appropriate biologic functions of the two essential elements [17][19] under normal circumstances. A disturbance of this delicate balance as reflected by an increase in Cu in the foetal circulation emanating from the cord blood (altering the Zn:Cu ratio) has the tendency of converting the Cu into an electron acceptor (from Cu to Cu2+) thus becoming an oxidant. Normally, Zn and Cu are directly associated with the metallothionein formation necessary for scavenging toxic metals; however, a protraction of this disturbance as may be seen in pregnant women exposed to these toxicants (excessive toxic metals and Cu) may exacerbate the condition thereby increasing the toxic burden on the system and its attendant effect on the limited antioxidant pool.
However, the observed high Zn level in cord blood in this study may be likened to the typical scenario in diabetes mellitus where in spite of a high glucose level in the blood, the cells are deprived of the glucose necessary to provide energy that will drive the expected metabolic processes. A plausible inference from this may therefore be that although there was a large amount of Zn transferred from the maternal to the foetal circulation as seen in the cord blood of the babies (exposed and unexposed), it may be inferred that the Zn ions needed in neurogenesis were not available at the cellular level to perform the needed co-enzymatic activity. This may be due to non-development of the various Zn-related enzymatic pathways as a consequence of age which may have precipitated non-availability of Zn at the cellular level to compliment Se both of which constitute the major antioxidant pool in the neurons. Alternatively, it may be that Zn-related enzymes are not involved in the necessary metabolic activities of a developing baby in-utero possibly because of their relative immaturity at that stage or that Zn is non-consequential in that process at that stage. Perhaps, the antioxidant mechanism in the brain of babies at this stage revolves round blood Se and Mg more than on Zn, Se and Mg concentrations. That this is plausible may be seen from the fact that even a higher cord blood Zn level in non-exposed babies than in exposed babies did not result in any neurodevelopmental abnormality in the former. This raised a basic question of whether Zn is actually essential for oxidative balance in the brain of babies in-utero. It is a known fact that for adequate metallothionein activity, blood Zn and Cu levels must be equivalent to ensure the scavenging activity of metallothionein against excess ROS by metal toxicants. Although this antioxidative activity at the neuronal level has been documented to be largely dependent on Zn and Se, its non-effectiveness has been proposed to be marked by an increase blood Cu or a decrease in blood Zn level (Pokusa & Trančíková, 2017). Hence, increase in Zn level as recorded in cord blood of exposed babies in this study should expectedly bring about a corresponding lowering of blood Cu level in those babies (just like relationship between Ca and inorganic phosphorus) if the metallothionein system was functional. The deleterious effect of reduction in metallothionein formation may be exacerbated by the reduced Se level in the cord blood since the latter is also a strong antioxidant against toxic metals. Hence, the reduced Se level observed in cases in this study may be accentuating a reduction in antioxidative capability of the system. Several works have corroborated this theory that reduction in blood Zn and in particular with a concurrent reduction in blood Se may enhance Cd and Pb toxicity [32].
Thus, it may therefore be inferred that absence of this complimentary effect of Zn with Se may overwhelm the capability of Se alone as may be seen in the reduced level of exposed cord blood Se which is grossly low in comparison to the exposed, non-exposed maternal and cord blood Se levels.
The roles of calcium and magnesium especially in modulating movement across cells are interwoven. The biological function of Mg is closely related to that of Ca. Magnesium has also been reported to protect the brain from toxic effects of chemicals while its deficiency has been postulated to facilitate heavy metal toxicity and may be associated with the aetiology of learning disorders in children (Drybanska-Kalita,1995). Optimal Mg level is needed for the formation of glutathione, an important antioxidant system of the body. The observed significant reduction in Mg level in cases in this study may be exacerbating a depletion of the antioxidant pool of the body especially the glutathione level. Hence, a continuous depletion of the glutathione level which a sustained deficiency of Mg may precipitate in occupationally exposed pregnant women may have reversed the functional GSH/GSSG ratio in the developing foetus precipitating an abnormal neurodevelopmental process in the latter. Mg deficiency has been demonstrated in cases of ASD in previous works [33][34]. This shortfall in anti-oxidative capability induced by low Se and low/nonconsequential Zn levels may have overwhelmed the capability of Mg in exposed babies with the increasing antioxidant activity resulting in a decrease of cord blood Mg in exposed babies in comparison to others in the study.
Thus, the interplay of Se and Mg as the main metal antioxidant at the uterine level in exposed babies may also be inferred since even in the maternal circulation (exposed and unexposed), the concentrations of Mg were quite similar.
The apparent downregulation of Se, Zn and Mg in cord blood of cases may have created an imbalance and a shift in the relationship between Cu and Zn thus facilitating the pro-oxidative tendency of Cu thereby increasing the concentration of pro-oxidant and the consequent overwhelming of the antioxidative capabilities of the already reduced concentration of Se and Zn. The damaging effect of this phenomenon may be responsible for the significant reduction in the Mg level thus accentuating the dysfunction in neural activities as clinically manifested in autism at adolescence.
Mg has also been reported to protect the brain from toxic effects of chemicals while deficiency has been postulated to facilitate heavy metal toxicity. Optimal Mg level is also needed for the formation of glutathione, an important antioxidant system of the body (Drybanska-Kalita,1995), it has also been associated with the aetiology of learning disorders in children.
This shortfall in anti-oxidative capability induced by low Se and low/nonconsequential Zn levels may have overwhelmed the capability of Mg in exposed babies with the increasing antioxidant activity resulting in a decrease of cord blood Mg in exposed babies in comparison to others in the study.
Thus, the interplay of Se and Mg as the main metal antioxidant at the uterine level in exposed babies may also be inferred since even in the maternal circulation (exposed and unexposed), the concentrations of Mg were quite similar.
The observed significant reduction in Mg level in exposed babies in this study may be exacerbating a depletion of the antioxidant pool of the body especially the glutathione level.
Hence, it may be deducted that babies continuously exposed to these conditions may ultimately develop reduced metallothionein activity resulting in an imbalance oxidant/antioxidant pool leading to a derangement in many metabolic activities in the body. Such a derangement will be exacerbated and becomes fatal in a developing baby resulting in possible abnormal neurogenesis.
It may therefore be stated that at the uterine level (especially in pregnant mothers occupationally/environmentally exposed to these metals), results from this work showed that Se is the main antioxidant metal in the neuron, the deficiency of which may precipitate abnormal neurodevelopment which may ultimately result in neurodevelopmental disorders like ASD and CP in infancy.
The roles of calcium and magnesium especially in modulating movement across cells are interwoven. The biological function of Mg is closely related to that of Ca. Magnesium has also been reported to protect the brain from toxic effects of chemicals while its deficiency has been postulated to facilitate heavy metal toxicity and may be associated with the aetiology of learning disorders in children. Optimal Mg level is needed for the formation of glutathione, an important antioxidant system of the body. The observed significant reduction in Mg level in cases in this study may be exacerbating a depletion of the antioxidant pool of the body especially the glutathione level. Hence, a continuous depletion of the glutathione level which a sustained deficiency of Mg may precipitate in occupationally exposed pregnant women may have reversed the functional GSH/GSSG ratio in the developing foetus precipitating an abnormal neurodevelopmental process in the latter. Mg deficiency has been demonstrated in cases of ASD in previous works [33][34]. The apparent downregulation of Se, Zn and Mg in cord blood of cases may have created an imbalance and a shift in the relationship between Cu and Zn thus facilitating the pro-oxidative tendency of Cu thereby increasing the concentration of pro-oxidant and the consequent overwhelming of the antioxidative capabilities of the already reduced concentration of Se and Zn. The damaging effect of this phenomenon may be responsible for the significant reduction in the Mg level thus accentuating the dysfunction in neural activities as clinically manifested in autism at adolescence.
This abnormality which could be seen to have started from placental transfer of elements from mother to the foetus may also be exacerbated by the observed higher concentration of the toxic metals (Pb and Cd) which may further increase the ROS burden in the system and overwhelm the antioxidative capabilities of both Zn and Se. Findings in this study are similar to those of --- who established in autistic children studied.
In clinical terms, abnormal head circumference of the newborn baby has been associated with neurodevelopmental disorders by previous workers [35][36] the observed abnormality in the head circumference of babies from cases in comparison to those of controls may be an indication of an ongoing neurodevelopmental disorder in these babies (cases) from birth giving a prognostic indication of an abnormality in neural development which in this case may result in autism syndrome disorders. Hence, in totality, the observed reduction in essential elements in this work in conjunction with elevated levels of toxic metals (Pb, and Cd) may be the basis of the anatomical abnormality as the abnormal head circumference which in adolescence may lead to the clinical symptoms of autism.
Conclusion: Familial imbalance in essential metal levels as indicated by abnormality in cord blood concentration of these metals derived from placenta transfer to the baby in-utero may be a strong indicator of abnormal neurodevelopment which may latter manifest as ASD in adolescence. The pathophysiology may be a gross deficiency in metallothionein formation with the attendant reduction in the scavenging capabilities of the system and a concurrent reduction in glutathione-based antioxidant pool which may also be further aggravated by a concurrent elevated level of toxic metals in the system. The need to monitor the principal metals (Zn, Se, Mg, Cu) associated with this mechanism in children with ASD becomes imperative.