Our goal is to enhance strengths previously identified and eliminate weaknesses. The focus remains development of a transplacental chemoprevention model integrated with projects 1 &3 to address mechanisms. We examine blocking mechanisms and risk VS benefit to mother and fetus with a focus on epigenetics demanding tight integration among projects. The scope is only possible with the participation of the other projects and cores. The central hypothesis is sulforaphane (SFN) and indole-3-carbinol (I3C) are chemopreventive agents, as are the whole foods, in a PAH-transplacental lymphoma, lung, liver and ovary cancer model. Mechanisms are blocking and/or epigenetic, the degree depending on the phytochemical. Focus on the same phytochemicals enhance integration and synergism. We test the hypotheses by pursuit of 3 integrated aims progressing from discovery and mechanistic studies in pregnant mice to a small human trial. The translational nature is also enhanced by use of a """"""""humanized"""""""" mouse. The trial with human volunteers takes advantage of the remarkable sensitivity of accelerator mass spectromety (AMS).
Specific Aim 1 : Test the response of humanized mice;examine 130 dose-response and compare purified phytochemicals (at human dietary levels) to whole foods;test windows of maternal dietary I3C and SFN exposure;test post-initiation suppression;utilize lung- and liver-specific models;determine role of nrf2 signaling in a gene dosage study;and test transplacental cancer chemoprevention in an F2 generation.
Specific aim 2 : Focus entirely on epigenetics with a known target (CYP1B1), followed by p21, gstp1 and cyclind2, promising targets in common with projects 1 &3.
Specific aim 3 : Utilize AMS to determine pharmacokinetics of a non-carcinogenic PAH in humans and impact of I3C pretreat. Assess bioavailability of I3C derivatives and compare I3C with the whole food (Brussels sprouts). This is a highly translational aim that serves as a prelude to further studies of PAH exposure and transplacental chemoprevention. This project is highly integrated with the other 2 as we will provide tissues to both and, in return, will be able to determine the similarities and differences of chemoprevention mechanisms between mouse and human.
The fetus and infant have a much greater risk of toxicity from exposures to chemicals in the womb or through breast milk. These chemicals include transplacental carcinogens. We developed a novel model to study phytochemicals added to maternal diet in chemoprevention of these cancers. Preliminary evidence points to epigenetic programming of gene expression in offspring being key in this transplacental chemoprevention. We now, integrating with projects 1 &2, address the mechanisms and potential significance to humans.
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|Harper Jr, Tod A; MorrÃ©, Jeff; Lauer, Fredine T et al. (2015) Analysis of dibenzo[def,p]chrysene-deoxyadenosine adducts in wild-type and cytochrome P450 1b1 knockout mice using stable-isotope dilution UHPLC-MS/MS. Mutat Res Genet Toxicol Environ Mutagen 782:51-6|
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