MicroRNAs (miRNAs) are short, single-stranded RNA that regulate post-transcriptional control of mRNA translation. Knowledge on the role of these critical regulators in toxicological responses in increasing, but is still limited. Atrazine is a herbicide used throughout the Midwestern US that is reported to frequently contaminate potable water supplies above the maximum contaminant level of 3 parts per billion. Atrazine is a suspected endocrine disrupting chemical and studies have begun to investigate the genetic mechanisms of toxicity; however, studies investigating epigenetic mechanisms are limited. In this study both zebrafish and human miRNAs were significantly altered in response to an embryonic atrazine exposure of 0.3, 3, or 30 ppb in zebrafish. Altered miRNAs are known to play a role in angiogenesis, cancer, or neuronal development, differentiation, and maturation. Targeted analysis of altered human miRNAs with genes previously identified to be altered by atrazine exposure revealed several targets linked to cell cycle and cell signaling. Further analysis of hsa-miRNA-126-3p, which had altered expression in all three atrazine treatments at 72 hpf, revealed alterations also occurred at 60 hpf in the 30 ppb treatment group. Results from this study indicate miRNA deregulation in zebrafish and human miRNAs following an embryonic atrazine exposure in zebrafish.

Pancreatic cancer, mostly pancreatic ductal adenocarcinoma (PDAC), is a leading cause of cancer-related death in the US, with a dismal median survival of 6 months. Thus, there is an urgent unmet need to identify ways to diagnose and to treat this deadly cancer. Although a number of genetic changes have been identified in pancreatic cancer, their mechanisms of action in tumor development, progression and metastasis are not completely understood. Hedgehog signaling, which plays a major role in embryonic development and stem cell regulation, is known to be activated in pancreatic cancer; however, specific inhibitors targeting the smoothened molecule failed to improve the condition of pancreatic cancer patients in clinical trials. Furthermore, results regarding the role of Hh signaling in pancreatic cancer are controversial with some reporting tumor promoting activities whereas others tumor suppressive actions. In this review, we will summarize what we know about hedgehog signaling in pancreatic cancer, and try to explain the contradicting roles of hedgehog signaling as well as the reason(s) behind the failed clinical trials. In addition to the canonical hedgehog signaling, we will also discuss several non-canonical hedgehog signaling mechanisms.

Atrazine is a commonly used herbicide in the United States that is reported to contaminate drinking water sources. Studies indicate atrazine adversely impacts the neuroendocrine and reproductive systems, and that it may be a potential carcinogen. The current maximum contaminant level in drinking water is 3 parts per billion (ppb); however, levels higher than 3 ppb are often reported. Ongoing studies in our laboratory are investigating the immediate and latent adverse health outcomes associated with a developmental atrazine exposure and identifying the genetic and epigenetic mechanisms of toxicity using the zebrafish model system. MicroRNAs (miRNAs) are epigenetic regulators that posttranscriptionally control the translation of mRNA. A preliminary study indicated expression of miR-126, a miRNA associated with angiogenesis and tumorigenesis, to be altered following an embryonic atrazine exposure. To further investigate the developmental expression of miR-126 in zebrafish, quantitative PCR (qPCR) was used to profile expression throughout embryogenesis. Expression of miR-126 was developmental time point specific with significant peaks in expression at 36, 60, and 72 hours postfertilization (hpf). The deregulation of miR-126 by atrazine was also tested using qPCR. Zebrafish embryos exposed to 0.3, 3, or 30 ppb of atrazine were compared to a control treatment at all six developmental time points. While a dose-response trend in upregulation at 36 hpf and in down-regulation at 48 hpf was observed, a significant increase in expression was only observed at 60 hpf in embryos exposed to 30 ppb atrazine. This study is providing a greater understanding of an epigenetic mechanism of atrazine toxicity. Schlotman, K. E. (2013