Ingestion of Mn and Pb by rats during and after pregnancy alters iron metabolism and behavior in offspring

Abstract

Manganese (Mn) and lead (Pb) exposures during developmental period can impair development by direct neurotoxicity or through interaction with iron metabolism. Therefore, we examined the effects of maternal ingestion of Mn or Pb in drinking water during gestation and lactation on iron metabolism as well as behavior in their offspring. Pregnant dams were given distilled water, 4.79 mg/ml Mn, or 2.84 mg/ml Pb in drinking water during gestation and lactation. Pups were studied at time of weaning for 59Fe absorption from the gut, duodenal Divalent Metal Transporter 1 (DMT1) expression, hematological parameters, and anxiety-related behavior using an Elevated Plus Maze (EPM) test. Metal-exposed pups had lower body weights and elevated blood and brain concentrations of the respective metal. Pb-exposed pups had lower hematocrits and higher blood Zn protoporphyrin levels. In contrast, Mn exposed pups had normal hematological parameters but significantly reduced Zn protoporphyrin. Pharmacokinetic studies using 59Fe showed that intestinal absorption in metal-exposed pups was not different from controls, nor was it correlated with duodenal DMT1 expression. However, intravenously injected 59Fe was cleared more slowly in Pb-exposed pups resulting in higher plasma levels. The overall tissue uptake of 59Fe was lower in Mn-exposed and lower in the brain in Pb-exposed pups. The EPM test demonstrated that Mn-exposed, but not Pb-exposed, pups had lower anxiety-related behavior compared to controls. We conclude that gestational and lactational exposures to Mn or Pb differentially alter Fe metabolism and anxiety-related behavior. The data suggest that perturbation in Fe metabolism may contribute to the pathophysiologic consequences of Mn and Pb exposure during early development.

Effect of olfactory manganese exposure on anxiety-related behavior in a mouse model of iron overload hemochromatosis

“…Hence, the prolonged time spent in the open arms in Mn-instilled mice indicates that olfactory Mn exposure decreases anxiety and/or increases impulsivity, likely by deficits in disinhibition control. These results are in line with our previous findings that Mn-exposed rat pups reduce anxiety-related behavior (Molina et al, 2011). We note that our results are disparate from those by Kern et al (Kern et al, 2010), who reported no behavioral changes upon Mn exposure by the EPM test, likely due to different exposure protocols and routes of administration (i.e., oral administration during the preweaning stage (Kern et al, 2010) vs. intranasal instillation to mice after weaning in the present study).…”

Maternal hemochromatosis gene H63D single-nucleotide polymorphism and lead levels of placental tissue, maternal and umbilical cord blood

“…Lead has adverse effects to mainly renal, hematopoietic and neurologic systems. The most susceptible populations to the adverse neurodevelopmental effects of lead are children, particularly infants in the neonatal period and fetus since neurodevelopment begins in this period and the blood-brain barrier is still immature (Goyer, 1990;Goyer, 1997;Molina et al, 2011). Moreover, exposure levels that do not harm the mother can be fetotoxic because of the differences between the many biochemical pathways of the adult and the fetus (Baghurst et al, 1991;Al-Saleh et al, 2011).…”

“…In experimental models, it was demonstrated that umbilical cord blood flow rate affected the transfer of lead linearly (Goyer, 1990). Furthermore, iron deficiency or dietary iron consumption of the mother can also alter lead uptake (Molina et al, 2011). Hence, genes related to iron metabolism could modify lead absorption and pregnant women with genetic variants affecting iron metabolism could have children at increased risk of exposure to lead.…”

Arsenic and Manganese Alter Lead Deposition in the Rat

“…In addition, once within the cells, a particular metal may occupy abundant binding sites [27] on metalloproteins or target molecules, in turn, modifying the compartmentalization of other metals, thus leading to aberrant binding and toxicity [26]. A given metal may induce overexpression of transporters and/or binding proteins that alter the uptake of other metals [27, 28]. These events may modify the uptake and/or retention of metals in cells, affecting their toxicokinetics profile and toxicity [1, 29].…”