Xenobiotic metabolites modify immune responses of the cervicovaginal epithelium: potential mechanisms underlying barrier disruption.

OBJECTIVE: Xenobiotic metabolites are exogenous biochemicals that can adversely impact reproductive health. We previously identified xenobiotics in cervicovaginal fluid during pregnancy in association with short cervix. In other organ systems, xenobiotics can modify epithelial barrier function. We hypothesise that xenobiotics dysregulate epithelial cell and macrophage immune responses as a mechanism to disrupt the cervicovaginal barrier. DESIGN: In vitro cell culture system. SETTING: Laboratory within academic institution. SAMPLE: Vaginal, ectocervical and endocervical epithelial cell lines and primary macrophages. METHODS: Cells were treated with diethanolamine (2.5 mM), ethyl glucoside (5 mM) or tartrate (2.5 mM) for 24 h. MAIN OUTCOME MEASURES: Cytokines and matrix metalloproteinases were measured in cell supernatants (n = 3 per condition). One-way analysis of variance (ANOVA) with Dunnett's test for multiple comparisons was performed. RESULTS: Diethanolamine induces inflammatory cytokines, whereas ethyl glucoside and tartrate generally exert anti-inflammatory effects across all cells. Diethanolamine increases interleukin 6 (IL-6), IL-8, interferon γ-induced protein 10 kDa (IP-10), growth-regulated oncogene (GRO), fractalkine, matrix metalloproteinase 1 (MMP-1), MMP-9 and MMP-10 (p < 0.05 for all), factors involved in acute inflammation and recruitment of monocytes, neutrophils and lymphocytes. Ethyl glucoside and tartrate decrease multiple cytokines, including RANTES and MCP-1 (p < 0.05 for all), which serve as chemotactic factors. Vaginal cells exhibit heightened inflammatory tone compared with cervical cells and macrophages, with a greater number of differentially expressed analytes after xenobiotic exposure. CONCLUSIONS: Xenobiotic metabolites present in the cervicovaginal space during pregnancy modify immune responses, unveiling potential pathways through which environmental exposures may contribute to the pathogenesis of cervical remodelling preceding preterm birth. Future work identifying xenobiotic sources and routes of exposure offers the potential to modify environmental risks to improve pregnancy outcomes.

The Oncopig as an Emerging Model to Investigate Copper Regulation in Cancer.

Emerging evidence points to several fundamental contributions that copper (Cu) has to promote the development of human pathologies such as cancer. These recent and increasing identification of the roles of Cu in cancer biology highlights a promising field in the development of novel strategies against cancer. Cu and its network of regulatory proteins are involved in many different contextual aspects of cancer from driving cell signaling, modulating cell cycle progression, establishing the epithelial-mesenchymal transition, and promoting tumor growth and metastasis. Human cancer research in general requires refined models to bridge the gap between basic science research and meaningful clinical trials. Classic studies in cultured cancer cell lines and animal models such as mice and rats often present caveats when extended to humans due to inherent genetic and physiological differences. However, larger animal models such as pigs are emerging as more appropriate tools for translational research as they present more similarities with humans in terms of genetics, anatomical structures, organ sizes, and pathological manifestations of diseases like cancer. These similarities make porcine models well-suited for addressing long standing questions in cancer biology as well as in the arena of novel drug and therapeutic development against human cancers. With the emergent roles of Cu in human health and pathology, the pig presents an emerging and valuable model to further investigate the contributions of this metal to human cancers. The Oncopig Cancer Model is a transgenic swine model that recapitulates human cancer through development of site and cell specific tumors. In this review, we briefly outline the relationship between Cu and cancer, and how the novel Oncopig Cancer Model may be used to provide a better understanding of the mechanisms and causal relationships between Cu and molecular targets involved in cancer.