br Conclusion br Declaration of interest br Introduction Gly
Declaration of interest
Introduction Glyphosate [N-(phosphonomethyl)glycine] is the main active ingredient in one of the most widely used herbicides in the world. The commercially used concentrations of glyphosate range from 1% for domestic use to 41% for conventional agricultural uses (Bradberry et al., 2004). Glyphosate has a specific mode of action: the inhibition of enzyme, 5-enopyruvylshikimic acid-3-phosphate synthase (EPSP) (Steinrucken and Amrhein, 1980), an enzyme that is present only in plants and some microorganisms. In Thailand, glyphosate is the highest imported herbicide commonly used in agriculture (Apiwat et al., 2014). Recently, glyphosate and its major metabolite, aminomethylphosphonic SC-10 for (AMPA), have been detected as contaminants in the environment, food chain and agricultural products (Bai and Ogbourne, 2016; Rubio et al., 2014). Interestingly, the presence of glyphosate and AMPA in human serum and breast milk has recently been reported (Ehling and Reddy, 2015; Kongtip et al., 2017; Steinborn et al., 2016), raising concerns about human exposure to these chemicals. Some studies suggest that glyphosate has no or low toxicity in animals and humans; however, other studies have indicated that they can induce toxic effects. For examples, studies have revealed that glyphosate can inhibit the function of cytochrome P450 (CYP450), an important superfamily of metabolizing enzymes (Hietanen et al., 1983; Samsel and Seneff, 2013). Other studies have demonstrated the toxicity of glyphosate to several systems in the rat, including the renal and nervous systems (Hernandez-Plata et al., 2015; Karimi et al., 2013). An epidemiological study on cancer incidence in pesticide applicators showed a statistically significant relationship between the increased risk for certain cancers, such as multiple myeloma, and levels of glyphosate usage (De Roos et al., 2005). Several case-control studies from the USA, Canada and Sweden have indicated an increased risk for non-Hodgkin\'s lymphoma from occupational exposure to glyphosate after adjustment for other pesticide exposures (Guyton et al., 2015). Interestingly, a long-term study shows that rats exposed to glyphosate-based herbicide and/or glyphosate-tolerant maize over 2 years exhibited a wide range of endocrine disruptive effects, including modification of sex hormones and the development of large mammary tumors in female rats (Seralini et al., 2014). Cholangiocarcinoma (CCA) is a malignant tumor arising from the epithelial cells of the biliary system. The increasing incidence and mortality of CCA have been reported worldwide. North-East region of Thailand has the world\'s highest chronic infection incidences related to the liver fluke, Opisthorchis viverrini, which is different from what found in Western countries where the primary sclerosing cholangitis (PSC) is a major related factor. However, there are some possible risk factors that could be considered as other important contributors to CCA (Banales et al., 2016). A previous study suggested that environmental toxicants, such as nitrosamines, may be a major factor that can contribute to the occurrence of CCA (Patel, 2011). It has been shown that glyphosate can be excreted into the bile, suggesting a potential exposure to cells in the biliary system (JMPR, 2004). One of the possible cancer promotion pathways of glyphosate is the disruption of the estrogen function (E2), and estrogen receptor (ER) signaling pathway. It has been suggested that glyphosate can act as an endocrine disruptor (Mnif et al., 2011). In 2005, Richard and coworkers reported that the glyphosate-based herbicide disrupts the aromatase activity and mRNA levels of the enzyme aromatase which is involved in steroid hormone synthesis (Richard et al., 2005). In vitro experiments have shown the exposure to glyphosate resulted in the proliferation of human breast cancer cells via the estrogen receptor (Thongprakaisang et al., 2013). The induction of breast cancer cell growth by glyphosate was also supported by the recent study of Mesnage and coworkers (Mesnage et al., 2017). However, the effects reported by this group were observed at relatively high concentrations of glyphosate.