In response to PAR-04-104: """"""""The Fetal Basis of Adult Disease: role of the environment"""""""" aimed at the application of high-throughput functional-genomic technologies to understand which and how environmental agents contribute to currently unsuspected in-utero exposures that cause permanent functional changes that are not overtly teratogenic yet result in increased susceptibility to disease/dysfunction later in adulthood, and given research data by others showing susceptibility of brain microvasculature to subtoxic Pb-levels, and our preliminary data validating two rat models of fetal basis of adult-onset stroke (cerebral hemorrhage subtype) FeBAD(STROKE), our research proposal aims to test the hypothesis that fetal subtoxic-Pb exposure results in brain microvascular endothelial changes, which in individuals with stroke risk factors, such as hypertension and/or hypercholesterolemia, exacerbate said risk for adult-onset stroke. Accordingly, the following specific aims are prioritized to examine causal effects of fetal Pb-exposure.
Aim 1. Determine whether dose-response effects of fetal exposure to subtoxic Pb-levels (10 mu g/dl, 20 mu g/dl, 40 mu g/dl) exacerbates risk for adult-onset hemorrhagic stroke in two FeBAD(STROKE) rat models: 1) transgenic (hypercholesterolemia + hypertension) and 2) nontransgenic (hypertension alone) rat models, comparing female and male rats by analyzing: a. disease course: degree of hypertension and hyperlipidemia, levels of cellular and circulating markers of endothelial dysfunction and neutrophil activation at pre-stroke stage (2-,3-months of age), and b. disease end-point: onset and severity of hemorrhagic stroke.
Aim 2. In accordance with PAR guidelines for high throughput genomics-based analysis, we will determine the effects of subtoxic Pb-exposure on cortical and cerebellar transcription profiles in both transgenic and non-transgenic FeBAD-stroke rat models at embryonic E18.5 and postnatal p21 days. We prioritized transcription profile analysis of cortex and cerebellum to enhance detection of contrasting gene expression changes, since the cortex is a stroke-sensitive brain region, whereas the cerebellum is a relatively stroke- resistant brain region. Briefly, these studies will determine whether fetal programming induced by subtoxic lead exposure exacerbates FeBAD-adult-onset hemorrhagic stroke (Aim 1) and provide key insight into possible pathogenic gene networks (Aim 2). Determining the impact of environmental toxicants, such as Pb, on fetal basis of adult-onset diseases is imperative from a public health prevention perspective. Determination of interactions between environmental toxicant and fetal basis of complex diseases needs to be done prior to any genetic analysis. Currently, environmental subtoxicant-induced fetal programming is not factored in as confounder in genetic studies of susceptibility to complex multifactorial diseases.
| Decano, Julius L; Viereck, Jason C; McKee, Ann C et al. (2009) Early-life sodium exposure unmasks susceptibility to stroke in hyperlipidemic, hypertensive heterozygous Tg25 rats transgenic for human cholesteryl ester transfer protein. Circulation 119:1501-9 |
