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    • Activation of the proto oncogene c

    2018-11-09

    Activation of the proto-oncogene c-myc is associated with cellular growth and proliferation programs (Dang, 2013) and is therefore an important feature of cancer initiation and maintenance (Gabay et al., 2014). Furthermore, c-myc induces the expression of telomerase reverse transcriptase (TERT) and telomerase activity, thus delaying telomere attrition (Daniel et al., 2012; Greenberg et al., 1999). Telomeres are repeating hexanucleotide sequences (TTAGGG) that protect UC 112 against chromosomal end–end fusion and non-reciprocal translocations. During normal DNA replication, the enzyme TERT adds the TTAAGG sequence to the chromosomal ends to compensate for the progressive loss of telomeric sequence during every replication to promote chromosomal stability (Aubert and Lansdorp, 2008). The telomeres shorten with each cell division until they reach a markedly short length, inducing replicative senescence, or irreversible cell growth arrest and apoptosis (Finkel et al., 2007). Several studies indicate that, independently of chronological age, shorter telomere length (TL) is associated with cardiovascular disease (Haycock et al., 2014), diabetes (Zee et al., 2010), and mortality (Weischer et al., 2012). Longer TL should allow for longer cellular survival, increasing the chance of accumulation of genetic mutations, such as those that promote cancer (Noy, 2009). In contrast, excessive telomere loss may lead to genomic instability and promote carcinogenesis (Blasco, 2005). Until now, the epidemiological evidence for associations between circulating leukocyte telomere length (LTL) and cancer has been inconsistent and this may be attributed to technical methodology (Cunningham et al., 2013) and the effects that specific cancer types may have on LTL (Gu and Wu, 2013). Shorter telomeres are associated with increased risk for several cancers, including bladder, breast, ovarian, kidney, head and neck, esophagus, stomach, and lung cancer (Wentzensen et al., 2011). However, the meta-analysis stratified by study design reported that the increased cancer risk associated with shorter telomeres was mainly driven by case–control studies (Wentzensen et al., 2011). This finding suggests the possible effects of reverse causation in case–control studies where therapeutic procedures or cancer itself may affect TL. In prospective studies, longer telomeres have been associated with an increased risk of several cancers such as lung cancer (Lan et al., 2013; Seow et al., 2014), melanoma (Han et al., 2009), non-Hodgkin lymphoma (Lan et al., 2009), pancreatic cancer (Lynch et al., 2013), and prostate cancer (Julin et al., 2015). Interestingly, in a 12years follow-up of 792 normative aging study participants, it was observed a decelerating age-adjusted LTL attrition in cancer cases as they approached diagnosis with significant longer LTL within 4years pre-diagnosis (Hou et al., 2015). This observation suggests that LTL elongation appears early during cancer development (Hou et al., 2015). Leukocyte telomere length has been measured in a representative sample of US adults (20years of age and older) who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002. In this study, we examined the potential association of various metabolite compounds of phthalates with LTL. Because of the role of phthalates to induce c-myc and promote cellular growth, we hypothesized that phthalate exposure will be associated with longer LTL.
    Methods
    Results The weighted distributions of study population (n=2472) characteristics of the total sample are shown in Table 1. Briefly, the geometric mean of LTL was 1.02. Women represented approximately 52% of the sample; the geometric mean age of the participants was approximately 43years old. Obesity prevalence was almost 33%. The prevalence of former smokers and people who had never smoked was approximately 25% and 51%, respectively, and almost 31% of the participants had never consumed alcohol. The geometric mean (GM) of urinary MEP, MBP, MBzP and MEHP was 123.77ng/mL, 20.85ng/mL, 8.86ng/mL and 3.59ng/mL, respectively, in the study population.