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  • Financial nonfinancial disclosures The authors have reported


    Financial/nonfinancial disclosures: The authors have reported to CHEST the following: M. J. A. has received investigator-initiated grants from Pfizer and Boehringer Ingelheim for unrelated research. None declared (X. D., S. C. D., G. B., N. T. W., J. L. P., J. H., B. E., A. J. L., J. A. B., C. S., C. J. L.). Role of sponsors: The authors alone are responsible for the content and writing of the article. Other contributions: We thank the children and ddhGTP molecular that participated in this research study and the investigators of the study up to the 12-year follow-up: David Hill, FRACP, Cliff Hosking, MD, John Thorburn, FRACP, and Christine Axelrad, BScN. We also thank the following investigators for help with the 18-year follow-up: Catherine Bennett, PhD, Lyle Gurrin, PhD, Rida Khalafzai, MD, Sharon Goldfeld, PhD, Chris Barton, PhD, Vijaya Sundararajan, FRACP, and Mathias Wjst, MD. Additional information: The e-Tables can be found in the Supplemental Materials section of the online article.
    Introduction Prostate cancer (PCa) constitutes a major public health burden globally. According to the statistics estimates from GLOBOCAN, prostate cancer leaded to more than 1.1 million cases and 300,000 deaths worldwide in 2012 (Bray et al., 2012; Ferlay et al., 2015), making it the most common malignancy and the sixth leading cause of cancer-related deaths in men. The Institute for Health Metrics and Evaluation (IHME) study reported that PCa resulted in 61% and 83% increase in disability adjusted life years (DALYs) and mortality between 1990 and 2013, respectively (Global Burden of Disease Study, 2015; Mortality and Causes of Death, 2015). In China, although previous study reported that the prevalence of prostate cancer was 3%–20%, a recent study has suggested the true prevalence may be higher, reaching 28% (Pan et al., 2014; Yang et al., 2015). The prostate morphogenesis and differentiation initiates from the second trimester and is complete at the time of birth in humans, while the critical development time ranges from late fetal period to the first 15 days of life in rodents. According to the Developmental Origins of Adult Disease (DOHaD) hypothesis, the intrauterine period is an important time window for future prostate cancer risk (Barker, 1990). Exposure in utero to environmental chemicals reprograms the tissue thereby eliciting lifelong changes in prostate biology (Barker, 1990; Ekbom, 1998). For instance, IUL exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been found not only to cause delayed or incomplete prostate development in monkey, but also sensitize mice to exogenous-hormone-induced prostate epithelial cell proliferation and alter histopathology of prostate with aging (Arima et al., 2010; Ricke et al., 2016). In addition, epigenetic modification plays an important role in regulating prostate carcinogenesis. Prins et al. found that the developmental exposure of bisphenol A (BPA), an endocrine disrupting chemical, even increase the susceptibility to prostate carcinogenesis which might be related to the hypermethylated PDE4D4 gene (Prins et al., 2008). Di(2-ethylhexyl) phthalate (DEHP) is one kind of most widely used phthalates that are added to polyvinyl chloride as plasticizers to impart softness and flexibility. This typical environmental contaminant existed diffusely in a broad range of consumer products such as clothing, food containers, cosmetics, medical devices, and children's toys. With the estrogen-like effect and anti-androgen-like effect, pre- and postnatal exposure to DEHP has been reported to induce reproductive tract abnormalities and developmental toxicity such as hypospadias, cryptorchidism, retention of nipples, and reduce sperm production and fertilizing ability in male offspring (Lyche et al., 2009; Pocar et al., 2012). Moreover, recent studies suggested that DEHP might also contribute to cancer progression which was observed in prostate cancer cellular models (Hruba et al., 2014; Wang et al., 2017b). Results from our previous study supported it with observations that IUL exposure to DEHP decreased the prostate weight, prostate/body weight ratio and increased prostate specific antigen (PSA) concentrations, prostatic intraepithelial neoplasia (PIN) scores/frequency and Gleason scores/frequency in male pups, which indicated that DEHP could increase the susceptibility of prostate carcinogenesis in male offspring (Wang et al., 2017a). However, the underline mechanism remains unclear.