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, 4.79mg/ml Mn, or 2.84mg/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.
Highlights
Neurodevelopment begins in utero and continues throughout the postnatal period
In this study we evaluated the offspring of Mn and Pb exposed dams for 1) disruptions in iron metabolism such as altered iron status, Zn protoporphyrin (ZPP), 59Fe kinetics, and intestinal Divalent Metal Transporter 1 (DMT1) regulation, and 2) neurobehavioral outcomes, using anxiety-related responses in an Elevated Plus Maze (EPM) test.)
These concentrations were selected based on published data (Brockel and Cory-Slechta, 1999a, Dorman et al, 2000, Lasley and Gilbert, 2000, Pappas, Zhang, 1997) and reflected the maximum doses tolerated by the dams
Summary
Neurodevelopment begins in utero and continues throughout the postnatal period. This period of rapid development is highly susceptible to metal toxicity. Exposure of rats to Pb during gestation (Yang et al, 2003), or during both gestation and lactation (Kuhlmann et al, 1997), led to long-term cognitive deficits in adult offspring. They found that animals exposed during both gestation and lactation via the mother showed significant behavioral effects even when tested as adults, when tissue Pb levels had returned to control values. Animals exposed only after weaning failed to demonstrate behavioral alterations despite elevated tissue Pb levels (Kuhlmann, McGlothan, 1997)
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