Project: WHCOHH - Cellular and Molecular Mechanisms Underlying Long-Term Effects of Early Life Exposure to HAB Toxins

The overall objective of the proposed research is to elucidate the cellular and molecular mechanisms by which early-life exposure to domoic acid (DA) and saxitoxin (STX)— HAB toxins with demonstrated human exposures—can cause neurobehavioral abnormalities later in life.  Most HAB toxins are known to be acutely toxic, causing severe neurotoxicity soon after exposure to high doses. However, there is also extensive and possibly growing human exposure to HAB toxins at low levels that do not cause obvious acute signs of toxicity. Accumulating epidemiological and experimental evidence indicates that exposures during early life can have a profound effect on health later in life (the developmental origins of adult health and disease hypothesis).  In rodents early life exposure to low levels of neuro-active chemicals, including some HAB toxins and chemical pollutants, can cause physiological abnormalities and behavioral defects such as altered cognitive function later in life. However, the mechanisms by which developmental exposure elicits effects in developing animals and later in life are not understood. DA and STX act on ionotropic glutamate receptors and voltage-gated sodium channels, respectively. Both of these protein families are expressed widely in the developing nervous system and critical to establishing proper neuronal function in the central nervous system. The central hypothesis of the proposed research is that early life exposure to HAB toxins alters neurotransmitter receptors and ion channels changing prenatal programming of neurodevelopment, leading to altered gene expression and functional changes in neuronal and glial cells in the developing nervous system that ultimately contribute to altered neurobehavioral function in adults.  We will address this hypothesis using zebrafish, a powerful model organism for research on developmental mechanisms including those involved in neurodevelopment and developmental neurotoxicity. Our preliminary research has identified a novel mechanism by which early life exposure to DA disrupts neurodevelopment through effects on myelination. Additional studies demonstrated altered expression of genes involved in axonal extension in embryos exposed to low levels of STX. Linking these studies with past and future HAB occurrence and toxin exposure scenarios (Project 2) will provide an understanding of the long-term health consequences of developmental exposure to HAB toxins, critical for assessing public health risks associated with widespread exposure to these chemicals.