Differential sensitivity and response to metal-induced neural tube defects using a comparative mouse model

During the embryonic period of development known as neurulation, Neural Tube Defects (NTDs) manifest due to unknown etiology, comprising of genetic and environmental factors. In rodent models, heavy metals are well-documented as potent teratogens, able to induce NTDs, however, in humans the link between metals and NTDs remains unresolved. Common inbred mouse strains, such as the C57 (sensitive) and SWV, display differential sensitivity to metals (i.e. cadmium) when exposed during neurulation. Using a toxicogenomic approach, the research in this dissertation investigates metal-induced mechanistic responses associated with NTD formation and potential genetic response factors that may confer or associate with sensitivity in the C57 and SWV. This dissertation describes (1) the developmental effects associated with in utero exposure to cadmium or methylmercury during neurulation in C57 and SWV, (2) corresponding gene and protein expression response assessed by microarray and western blot in metal-exposed C57 and SWV embryos, (3) maternal and embryonic cadmium uptake in the C57 and SWV, (4) developmental differences in expression of genes involved in metal ion regulation between C57 and SWV, (5) dose and time-dependent effects of cadmium on gene expression in the C57 strain and (6) expression of identified NTD candidate genes across time, between strain, and with metal exposure. Our results demonstrate the C57 to be more sensitive to cadmium and methylmercury compared to the SWV, corresponding with differential effects on gene and protein expression in cell cycle, apoptosis and nervous system development pathways. Connected with these observations, we identified contributing factors that may underlie differential response, including increased cadmium uptake in the C57 (sensitive) and differential expression of genes involved in metal ion regulation (Mt1, Mt2, DMT1) between strains in unexposed and cadmium exposed conditions. In addition, we identify differential expression of NTD candidate genes between C57 and SWV across the neurulation period. This body of work demonstrates that by using a toxicogenomic approach, we are able to characterize and identify common a and unique mechanistic response(s) to metals during neurulation, genetic response factors that may confer or associate with sensitivity in the rodent model and potential human gene-environment interactions following metal exposure.