Inhaled manganese alters neurological response to toxic challenges: Implication to developmental exposures

This dissertation investigates the interactive effects on the brain of two dopaminergic toxins, manganese and methamphetamine. Uptake of manganese from ambient sources can be highly bioavailable. Since manganese is an essential element and a neurotoxin when present in excess of biological needs, exposure to manganese from ambient sources could represent an important risk. Methamphetamine, also a neurotoxin, is an increasingly popular drug of abuse and representative of a wide array of amphetamine-type pharmaceuticals. The importance of manganese as an issue of environmental concern has recently increased because of its use as a major industrial product and to replace tetraethyl lead and MTBE as a gasoline additive. This could increase human exposures to airborne manganese. Since inhaled manganese and amphetamines target the same area of the brain, this research was designed to determine whether exposure to manganese by inhalation alters dopaminergic system responses to a subsequent exposure to methamphetamine such that dopaminergic toxicity will occur below the toxic threshold for either of the individual substances. Understanding the potential for a neurotoxic interaction between manganese aerosol and methamphetamine is highly relevant in re-evaluating both the extent to which air pollution may alter human health and the potential risks to populations using amphetamine-type drugs, with respect to neurological disease, drug addiction and neurodegeneration.; Transient inhalation manganese exposure of pregnant rats decreased striatal dopamine levels in progeny by 9%. These changes occurred following an estimated maternal absorbed dose of 2.3 mugMn and were measured in tissue collected 62 days after exposure. This same pattern of altered dopamine levels occurred in rats exposed postnatally to either manganese aerosol or methamphetamine. Prenatal exposure to manganese caused a shift in postnatal methamphetamine-induced analyte response to enhance overall dopaminergic injury by 28% from methamphetamine-alone values and 36% from control values. Summarily, prenatal manganese exposure alters normal dopaminergic response to postnatal challenges of manganese and methamphetamine. Significant effects on morphological structure and striatal axon distribution in response to prenatal manganese and postnatal methamphetamine administration are discussed.; The essentiality of manganese at all stages of development make this research critical in better understanding the neurodevelopmentally toxic action of increasing levels of ambient manganese.