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.
|Madeen, Erin P; Williams, David E (2017) Environmental PAH exposure and male idiopathic infertility: a review on early life exposures and adult diagnosis. Rev Environ Health 32:73-81|
|Beaver, Laura M; Kuintzle, Rachael; Buchanan, Alex et al. (2017) Long noncoding RNAs and sulforaphane: a target for chemoprevention and suppression of prostate cancer. J Nutr Biochem 42:72-83|
|Palomera-Sanchez, Zoraya; Watson, Gregory W; Wong, Carmen P et al. (2017) The phytochemical 3,3'-diindolylmethane decreases expression of AR-controlled DNA damage repair genes through repressive chromatin modifications and is associated with DNA damage in prostate cancer cells. J Nutr Biochem 47:113-119|
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|Wang, Rong; Chen, Ying-Shiuan; Dashwood, Wan-Mohaiza et al. (2017) Divergent roles of p120-catenin isoforms linked to altered cell viability, proliferation, and invasiveness in carcinogen-induced rat skin tumors. Mol Carcinog 56:1733-1742|
|Madeen, Erin P; Löhr, Christiane V; You, Hannah et al. (2017) Dibenzo[def,p]chrysene transplacental carcinogenesis in wild-type, Cyp1b1 knockout, and CYP1B1 humanized mice. Mol Carcinog 56:163-171|
|Johnson, Gavin S; Li, Jia; Beaver, Laura M et al. (2017) A functional pseudogene, NMRAL2P, is regulated by Nrf2 and serves as a coactivator of NQO1 in sulforaphane-treated colon cancer cells. Mol Nutr Food Res 61:|
|Ertem, Furkan U; Zhang, Wenqian; Chang, Kyle et al. (2017) Oncogenic targets Mmp7, S100a9, Nppb and Aldh1a3 from transcriptome profiling of FAP and Pirc adenomas are downregulated in response to tumor suppression by Clotam. Int J Cancer 140:460-468|
|Kim, Hyemee; Banerjee, Nivedita; Barnes, Ryan C et al. (2017) Mango polyphenolics reduce inflammation in intestinal colitis-involvement of the miR-126/PI3K/AKT/mTOR axis in vitro and in vivo. Mol Carcinog 56:197-207|
|Wang, Rong; Kang, Yuki; Löhr, Christiane V et al. (2016) Reciprocal regulation of BMF and BIRC5 (Survivin) linked to Eomes overexpression in colorectal cancer. Cancer Lett 381:341-8|
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