This research program investigates the effect of aluminum (Al) ingestion on the function of the nervous and immune systems in mice with a particular focus on exposures during pregnancy and lactation. Al ingestion has been implicated in the etiology of several human neuropathology syndromes, but causal relationships have been difficult to establish and animal models are lacking. Information on effects of Al ingestion on immune function in humans and animals in minimal. This project has demonstrated overt neurotoxicity in lactating mice fed excess Al in a nutritionally marginal diet and neurological signs in offspring of mice fed excess Al in a nutritionally optimal diet. In addition, decreased host resistance to bacterial infection was seen in maternal mice under optimal nutritional conditions. This suggests that nutritional and reproductive/developmental status are important determinants of susceptibility to adverse effects of Al ingestion. The proposed experiments will investigate dietary factors that influence Al-induced neurotoxicity with an emphasis on the dietary content of essential trace metals Mn, Ca, Mg and P. In addition, potential cognitive aspects of the syndrome seen in offspring will be evaluated using a selection of behavioral tasks. Reversibility of the syndrome with discontinued Al exposure will also be studied. To identify sensitive periods for induction of the syndrome, maternal and fetus/pup Al body burdens during various periods of pregnancy/lactation will be determined. Inquiry into mechanisms of neurotoxicity will focus on Al-induced peroxidative damage to membranes. Consideration of impacts on immune function will be extended by studies of mucosal immunity. These studies will be valuable in identifying factors which determine sensitivity to the impact of Al ingestion on important adaptive capabilities mediated by the nervous and immune systems.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Toxicology Subcommittee 2 (TOX)
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University of California Davis
Schools of Medicine
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Golub, Mari S; Zhang, Wei; Keen, Carl L et al. (2002) Cellular actions of Al at low (1.25 microM) concentrations in primary oligodendrocyte culture. Brain Res 941:82-90
Golub, M S; Germann, S L (2001) Long-term consequences of developmental exposure to aluminum in a suboptimal diet for growth and behavior of Swiss Webster mice. Neurotoxicol Teratol 23:365-72
Golub, M S; Germann, S L; Han, B et al. (2000) Lifelong feeding of a high aluminum diet to mice. Toxicology 150:107-17
Kwik-Uribe, C L; Golub, M S; Keen, C L (2000) Chronic marginal iron intakes during early development in mice alter brain iron concentrations and behavior despite postnatal iron supplementation. J Nutr 130:2040-8
Kwik-Uribe, C L; Gietzen, D; German, J B et al. (2000) Chronic marginal iron intakes during early development in mice result in persistent changes in dopamine metabolism and myelin composition. J Nutr 130:2821-30
Golub, M S (2000) Adolescent health and the environment. Environ Health Perspect 108:355-62
Kwik-Uribe, C L; Golubt, M S; Keen, C L (1999) Behavioral consequences of marginal iron deficiency during development in a murine model. Neurotoxicol Teratol 21:661-72
Golub, M S; Keen, C L (1999) Effects of dietary aluminum on pubertal mice. Neurotoxicol Teratol 21:595-602
Golub, M S; Han, B; Keen, C L (1999) Aluminum uptake and effects on transferrin mediated iron uptake in primary cultures of rat neurons, astrocytes and oligodendrocytes. Neurotoxicology 20:961-70
Golub, M S; Tarara, R P (1999) Morphometric studies of myelination in the spinal cord of mice exposed developmentally to aluminum. Neurotoxicology 20:953-9

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