Supplementary Data

Use of blood Mn concentration during pregnancy for model evaluation

During pregnancy, it was observed that the concentration of Mn in blood gradually increases

compared to the pre-conception period, reaching approximately a two-fold greater level at around the end 

of gestation in humans (Spencer, 1999; Takser et al., 2004). There are several possible explanations for 

the elevated blood Mn. Fractional uptake of Mn during pregnancy is expected to increase due to shared 

absorption mechanisms in the gut with other trace elements, most notably iron, the absorption of which is 

greatly enhanced during pregnancy in humans (Svanberg et al., 1975; Whittaker et al., 1991). The 

molecular basis of this competition between iron and Mn at the level of gut absorption is likely due to the 

broad substrate specificity of DMT-1 (Tallkvist et al., 2000; Aschner and Aschner, 2005). Changes in 

hormonal status could also be one of the reasons for the altered blood Mn concentration compared to prepregnancy. The alterations in calcium and bone metabolism during pregnancy imply that a potential 

change in Mn mobilization from the bone could also occur (Prentice, 2000). Rothenberg et al. (1994)

reported blood lead concentration showed an upward trend during the last half of pregnancy. They 

proposed that mobilization of lead from the bone, increased gut absorption, and increased retention could 

be responsible for the observed changes in blood lead levels. Although more information is still needed, a

similar extent of fluctuation in blood Mn during normal menstrual cycle was reported by some 

researchers (Davis and Greger, 1992; Das and Chowdhury, 1997).

Interestingly, the Mn balance measured in the late pregnancy was slightly positive similar to the 

findings in adult females, with no sign of a substantial increase or decrease in fecal excretion of this 

element (Campbell, 1988) despite the large increase in blood Mn. Assuming that blood Mn is still 

reflective of body Mn status during pregnancy, this could indicate that the biliary induction during 

pregnancy may not be as responsive to the elevated blood Mn as in non-pregnant status. At this point, it is 

not clear whether the observed increase in blood Mn would reflect concomitant changes in the brain of
pregnant women, since the nature of this blood Mn increase is now known. It would be worthwhile to 

explore how much fluctuation in brain Mn could be tolerated without causing neurological effects in 

women not only during pregnancy but also during normal menstrual cycles. Research of this sort could 

determine to what extent variation in brain Mn should be considered normal for the risk assessment 

strategy of this element as suggested in Andersen et al. (Andersen et al., 1999). Considering the limited 

information on underlying mechanisms for increased blood Mn during pregnancy, we were reluctant to 

make changes in Mn absorption and excretion during pregnancy, and thus we did not attempt to fit the 

pregnancy model to the blood Mn data. The same descriptions as the adult females were used for 

fractional uptake and biliary excretion during pregnancy. As a result, blood Mn in the pregnant mother 

was under-predicted by the current model (Table 4). It should be noted that the current description has

some limitations in predicting maternal Mn in blood and possibly in other tissues including the brain 

during pregnancy. 

Although not applied in the final form of the current model, we tested the impact of applying 

several plausible mechanisms that might cause the elevation of blood Mn during pregnancy on the model 

predictions. Tested hypotheses were changes in gut absorption and tissue mobilization of Mn during 

pregnancy. By incorporating a gradual increase in fractional uptake over the period of gestation, we were 

able to simulate the observed increase in blood Mn to a reasonable approximation. At the end of 

pregnancy, the fraction of Mn absorbed into the body was 1.7 fold higher than the basal fractional uptake 

in adult females to reproduce the reported elevation of blood Mn seen throughout pregnancy, especially in 

the late period, in humans along with the placental Mn at the time of delivery (Spencer, 1999; Takser, et 

al., 2004). The concurrent increase in brain Mn was about 150 to 200 % of the normal adult level in late 

gestation, for which, at this point, no information is available to confirm this extent of elevation. If these 

predictions are accurate, they beg the question of how pregnant women tolerate so much fluctuation of 

Mn in brain, while neurological effects were implied to be occurring within a narrow margin of increase 

in blood Mn from the median value in general population (Mergler et al., 1999). Albeit not as serious as 

neurological effects, there is some conjecture of plausible influences of this ‘naturally occurring’ 
elevation of blood Mn on body functions (Penland and Johnson, 1993). These authors proposed potential 

contribution of Ca and Mn intake levels to menstrual distress including mood changes and increased pain 

during the premenstrual phase. 

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