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Grant Abstract: Mechanisms and therapies for the neurobehavioral deficits from early Mn exposure

Grant Number: 5R01ES028369-02
PI Name: Smith
Project Title: Mechanisms and therapies for the neurobehavioral deficits from early Mn exposure

Abstract: Elevated environmental manganese (Mn) exposure is emerging as a significant public health problem in the US and elsewhere, where vulnerable young children may be exposed to elevated levels of Mn from drinking water, soil and dust, and their diet. Human epidemiological studies have reported associations between Mn exposure and deficits in cognition, attention, impulse control, and fine motor function in children and adolescents, and our recent pre-clinical findings have shown that developmental Mn exposure can cause these functional impairments. Currently, there are no proven therapeutic strategies for alleviating or treating the cognitive deficits caused by developmental Mn exposure. Recent evidence suggests that maternal choline supplementation (MCS) produces lifelong improvements in offspring memory, attention, and emotion regulation, and lessens the cognitive and/or affective dysfunction in numerous models of neurodevelopmental and neurodegenerative disorders, as well as protects against the cognitive dysfunction caused by perinatal exposure to stress or alcohol. MCS has also been shown to produce lasting changes in DNA methylation and gene/protein expression, and several studies have shown that dietary methyl supplementation with folic acid, genistein, or L-methionine lessens the epigenetic changes produced by developmental exposure to toxins (Bisphenol A, cocaine). However, no studies have evaluated links between these epigenetic changes, related changes in gene/protein expression, and the cognitive/affective benefits of MCS. This application for an administrative supplement (FOA PA-18-817) to our parent grant (R01ES028369, awarded 9/30/18) will address this knowledge gap by testing the hypothesis that supplementing the maternal diet with additional choline during pregnancy and lactation can protect against/lessen the cognitive and fine motor dysfunction caused by early postnatal Mn exposure, and that this benefit relates to normalized levels of catecholamine system proteins in the prefrontal cortex, possibly through epigenetic mechanisms relating to choline’s role as the major dietary source of methyl groups. This will be addressed via the following Aims: Aim 1 will test the hypothesis that MCS during pregnancy/lactation protects against the attention, impulse control and fine motor deficits caused by early postnatal Mn exposure. Aim 2 will test the hypothesis that MCS during pregnancy/lactation will protect against the lasting changes in levels of the key PFC catecholaminergic system proteins caused by developmental Mn exposure. Mn-induced changes in these proteins has been implicated in the concomitant lasting attentional and fine motor deficits. This study will be the first to identify a potential dietary nutritional therapy (MCS) for the prevention of attentional and co-morbid fine motor deficits due to developmental Mn exposure, and to elucidate the underlying neural mechanisms. If MCS during pregnancy/lactation can protect against the neurobehavioral deficits caused by early life environmental Mn exposure, then the societal benefits in at risk populations will be immense.

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