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The orphan nuclear receptor NR2E3 (Nuclear receptor subfamily 2 group E, Member 3) is an epigenetic player that modulates chromatin accessibility to activate p53 during liver injury. Nonetheless, a precise tumor suppressive and epigenetic role of NR2E3 in hepatocellular carcinoma (HCC) development remains unclear. HCC patients expressing low NR2E3 exhibit unfavorable clinical outcomes, aligning with heightened activation of the Wnt/β‐catenin signaling pathway. The murine HCC models utilizing NR2E3 knockout mice consistently exhibits accelerated liver tumor formation accompanied by enhanced activation of Wnt/β‐catenin signaling pathway and inactivation of p53 signaling. At cellular level, the loss of NR2E3 increases the acquisition of aggressive cancer cell phenotype and tumorigenicity and upregulates key genes in the WNT/β‐catenin pathway with increased chromatin accessibility. This event is mediated through increased formation of active transcription complex involving Sp1, β‐catenin, and p300, a histone acetyltransferase, on the promoters of target genes. These findings demonstrate that the loss of NR2E3 activates Wnt/β‐catenin signaling at cellular and organism levels and this dysregulation is associated with aggressive HCC development and poor clinical outcomes. In summary, NR2E3 is a novel tumor suppressor with a significant prognostic value, maintaining epigenetic homeostasis to suppress the Wnt/β‐catenin signaling pathway that promotes HCC development. [ABSTRACT FROM AUTHOR]

The article discusses the impact of endocrine-disrupting chemicals (EDCs) on human health. EDCs are exogenous compounds that disrupt the synthesis, secretion, and elimination of natural hormones, leading to various health issues such as asthma, cardiovascular diseases, obesity, infertility, and cancers. The article highlights the diverse mechanisms of action of EDCs, including disruption of ligand-receptor interaction, interference of signal transduction, and alteration of epigenetic landscapes. It also presents several studies that explore the effects of specific EDCs on male fertility, testicular function, reproductive health, liver injuries, brain development, behavioral disorders, and cancer development. The research emphasizes the need for updated toxicological approaches to assess the low-dose effects of EDCs and calls for further investigation into the potential risks posed by these chemicals. [Extracted from the article]

Simple Summary: A stem cell origin and nature of a cancer suggests that genetic biomarkers may be pivotal, but cellular context is paramount. When we consider cellular context and when it concerns separation of cancer stem cells (CSCs) from non-CSCs, whether the biomarker is derived from the DNA, RNA, or protein and whether it is detected within the tumor or in the blood (such as CTCs and ctDNA) has biological ramifications and clinical implications for cancer care. Importantly, if CSCs are a relevant biological and clinical entity, then measuring, monitoring, and modulating via genome versus epigenome become imperative for diagnosis, prognosis, and therapeutics in cancer care. Biomarkers play a crucial role in the diagnosis, prognosis, and therapeutics of cancer. We use biomarkers to identify, image, monitor, and target cancer. In many respects, the discovery of pertinent biomarkers that distinguish fulminant from indolent neoplasms and sensitive from refractory malignancies would be a holy grail of cancer research and therapy. We propose that a stem cell versus genetic theory of cancer may not only enable us to track and trace the biological evolution of cancer but also empower us to attenuate its clinical course and optimize the clinical outcome of patients with cancer. Hence, a biomarker that identifies cancer stem cells (CSCs) and distinguishes them from non-CSCs may serve to elucidate inter-tumoral and intra-tumoral heterogeneity, elevate the values and utility of current prognostic and predictive tests, and enhance drug versus therapy development in cancer care. From this perspective, we focus on CSC biomarkers and discuss stemness or stem-like biomarkers in the context of a unified theory and a consideration of stem cell versus genetic origin. We review their role in primary and mixed tumors, in the elaboration of tumor subtypes, and in the imaging and monitoring of minimal residual diseases. We investigate how scientific theories influence the direction of scientific research and interpretation of experimental results, and how genomics and epigenomics affect the dynamics and trajectories of biomarkers in the conduct of cancer research and in the practice of cancer care. [ABSTRACT FROM AUTHOR]

Background: Bisphenol A (BPA) is known to be biologically active in experimental models even at low levels of exposure. However, its impact on endometrial cancer remains unclear. Objectives: This study aimed to investigate whether lifelong exposure to different doses of BPA induced uterine abnormalities and molecular changes in a rat model. Methods: Sprague-Dawley rats were exposed to 5 doses of BPA [0, 25, 250, 2,500, or 25,000 [micro]g/kg body weight (BW)/d] or 2 doses of 17[alpha]--ethynylestradiol (EE2) (0.05 and 0.5 [micro]g/kg BW/d) starting from gestational day 6 up to 1 y old according to the CLARITY-BPA consortium protocol. The BW, uterus weight, and histopathology end points of the uteri were analyzed at postnatal (PND) day 21, 90, and 365. Estrous cycling status was evaluated in PND90 and PND365 rats. Transcriptomic analyses of estrus stage uteri were conducted on PND365 rats. Results: Based on the analysis of the combined effects of all testing outcomes (including immunohistological, morphological, and estrous cycle data) in a semiblinded fashion, using statistical models, 25 [micro]g/kg BW/d BPA [BPA(25)], or 250 [micro]g/kg BW/d BPA [BPA(250)] exerted effects similar to that of EE2 at 0.5 [micro]g/kg BW/d in 1-y-old rats. Transcriptome analyses of estrus stage uteri revealed a set of 710 genes shared only between the BPA(25) and BPA(250) groups, with 115 of them predicted to be regulated by estradiol and 57 associated with female cancers. An interesting finding is that the expression of 476 human orthologous genes in this rat BPA signature robustly predicted the overall survival (p =1.68x[10.sup.-5], hazard ratio = 2.62) of endometrial cancer patients. Discussion: Lifelong exposure of rats to low-dose BPA at 25 and 250 [micro]g/kg BW/d altered the estrous cycle and uterine pathology with similarity to EE2. The exposure also disrupted a unique low-dose BPA-gene signature with predictive value for survival outcomes in patients with endometrial cancer. https://doi.org/10.1289/EHP6875, Introduction Bisphenol A (BPA) is used extensively in the manufacturing of plastic consumer products. It is a key building block of polycarbonate-based plastics and vinyl ester resin (Lorber et al. [...]

Electronic waste (e-waste) generation is increasing worldwide, and its management becomes a significant challenge because of the many toxicants present in electronic devices. The U.S. is a major producer of e-waste, although its management practice and policy regulation are not sufficient to meet the challenge. We reviewed e-waste generation, current management practices and trends, policy challenges, potential health impact, and toxicant exposure prevention in the U.S. A large amount of toxic metals, flame retardants, and other persistent organic pollutants exist in e-waste or can be released from the disposal of e-waste (e.g., landfill, incineration, recycling). Landfill is still a major method used to dispose of obsolete electronic devices, and only about half of the states have initiated a landfill ban for e-waste. Recycling of e-waste is an increasing trend in the past few years. There is potential, however, for workers to be exposed to a mixture of toxicants in e-waste and these exposures should be curtailed. Perspectives and recommendations are provided regarding managing e-waste in the U.S. to protect public health, including enacting federal legislation, discontinuing landfill disposal, protecting workers in recycling facilities from toxicant exposure, reducing toxicant release into the environment, and raising awareness of this growing environmental health issue among the public., Introduction Electronic waste, or e-waste, refers to obsolete electronic devices for disposal, including TVs, desktop and laptop computers, mobile computers (notebooks, netbooks, tablets, e-book readers), cellular phones, printers, copiers, video [...]

Background: Previous studies have uncovered heightened prostatic susceptibility to hormone-induced neoplasia from early-life exposure to low-dose bisphenol A (BPA). However, significant data gaps remain that are essential to address for biological relevance and necessary risk assessment. Objectives: A complete BPA dose-response analysis of prostate lesions across multiple prostatic lobes was conducted that included internal BPA dosimetry, progression to adenocarcinoma with aging and mechanistic connections to epigenetically reprogramed genes. Methods: Male neonatal Sprague-Dawley rats were briefly exposed to 0.1 to 5,000 [micro]g BPA/kg BW on postnatal days (PND) 1, 3, and 5. Individual prostate lobes plus periurethral prostatic ducts were evaluated at 7 mo or 1 y of age without or with adult testosterone plus estradiol (T + E) to promote carcinogenesis. DNA methylation of five genes was quantified by bisulfite genomic sequencing in d-200 dorsal prostates across BPA doses. Serum free-BPA and BPA-glucuronide were quantitated in sera of individual PND 3 pups collected 1 hr postexposure utilizing ultra-high-pressure tandem mass spectrometry (UHPLC-MS-MS). Results: The lowest BPA dose initiated maximal hormonal carcinogenesis in lateral prostates despite undetectable free BPA 1 hr postexposure. Further, prostatic intraepithelial neoplasia (PIN) progressed to carcinoma in rats given neonatal low-dose BPA with adult T + E but not in rats given adult T + E alone. The dorsal and ventral lobes and periurethral prostatic ducts exhibited a nonmonotonic dose response with peak PIN, proliferation and apoptotic values at 10-100 [micro]g/kg BW. This was paralleled by nonmonotonic and dose-specific DNA hypomethylation of genes that confer carcinogenic risk, with greatest hypomethylation at the lowest BPA doses. Conclusions: Developmental BPA exposures heighten prostate cancer susceptibility in a complex dose- and lobe-specific manner. Importantly, elevated carcinogenic risk is found at doses that yield undetectable serum free BPA. Dose-specific epigenetic modifications of selected genes provide a mechanistic framework that may connect early-life BPA to later-life predisposition to prostate carcinogenesis. https://doi.org/10.1289/EHP1050, Introduction Bisphenol A (BPA), a high-volume chemical and widely used synthetic plasticizer, has known estrogenic activity and is a recognized endocrine-disrupting chemical (EDC). Extensive studies over the past two decades [...]

BACKGROUND: Prostatic adenocarcinomas are dependent on androgen receptor (AR) activity for growth and progression, and therapy for disseminated disease depends on ablation of AR activity. Recurrent tumors ultimately arise wherein AR has been re-activated. One mechanism of AR restoration is via somatic mutation, wherein cells containing mutant receptors become susceptible to activation by alternative ligands, including bisphenol A (BPA). In tumors with specific AR mutations, BPA promotes therapeutic bypass, suggesting significant negative impact to the clinical management of prostate cancer. OBJECTIVE: Our goal was to determine the mechanism of BPA action in cancer cells carrying BPAresponsive AR mutants. METHODS: The molecular signature of BPA activity in prostate cancer cells harboring mutant AR was delineated via genetic microarray analysis. Specificity of BPA action was assessed by comparison with the molecular signature elicited by dihydrotestosterone (DHT). RESULTS: BPA and DHT elicited distinct transcriptional signatures in prostate cancer cells expressing the BPA-responsive mutant AR-T877A. BPA dramatically attenuated estrogen receptor beta (ER[beta]) expression; this finding was specific to prostate tumor cells in which BPA induces cellular proliferation. CONCLUSIONS: BPA induces a distinct gene expression signature in prostate cancer cells expressing somatic AR mutation, and a major molecular consequence of BPA action is down-regulation of ER[beta]. Since ER[beta] functions to antagonize AR function and AR-dependent proliferation, these findings reveal a novel mechanism by which BPA likely regulates cellular proliferation. Future investigation directed at dissecting the importance of ER[beta] in the proliferative response to BPA will establish the contribution of this event to adverse effects associated with human exposure. KEY WORDS: androgen receptor, endocrine disruptor, microarray, prostatic adenocarcinoma, xenoestrogen. Environ Health Perspect 115:1646-1653 (2007). doi:10.1289/ehp.10283 available via http://dx.doi.org/ [Online 23 August 2007], Accruing evidence indicates that exposure to environmental compounds that affect the function of the endocrine system may adversely impact human health. These substances deemed "endocrine disrupting compounds," or EDCs, are [...]

Estrogen receptor beta (ER-[beta]) regulates diverse physiological functions in the human body. Current studies are confined to ER-[beta]1, and the functional roles of isoforms 2, 4, and 5 remain unclear. Full-length ER-[beta]4 and -[beta]5 isoforms were obtained from a prostate cell line, and they exhibit differential expression in a wide variety of human tissues/cell lines. Through molecular modeling, we established that only ER-[beta]1 has a full-length helix 11 and a helix 12 that assumes an agonist-directed position. In ER-[beta]2, the shortened C terminus results in a disoriented helix 12 and marked shrinkage in the coactivator binding cleft. ER-[beta]4 and -[beta]5 completely lack helix 12. We further demonstrated that ER-[beta]1 is the only fully functional isoform, whereas ER-[beta]2, -[beta]4, and -[beta]5 do not form homodimers and have no innate activities of their own. However, the isoforms can heterodimerize with ER-[beta]1 and enhance its transactivation in a ligand-dependent manner. ER-[beta]1 tends to form heterodimers with other isoforms under the stimulation of estrogens but not phytoestrogens. Collectively, these data support the premise that (i) ER-[beta]1 is the obligatory partner of an ER-[beta] dimer, whereas the other isoforms function as variable dimer partners with enhancer activity, and (ii) a single functional helix 12 in a dimer is sufficient for gene transactivation. Thus, ER-[beta] behaves like a noncanonical type-I receptor, and its action may depend on differential amounts of ER-[beta]1 homo- and heterodimers formed upon stimulation by a specific ligand. Our findings have provided previously unrecognized directions for studying ER-[beta] signaling and design of ER-[beta]-based therapies. estrogen responsive element | heterodimerization | molecular modeling | steroid receptor coactivator | type | nuclear receptor