Silencing HOXC13 exerts anti-prostate cancer effects by inducing DNA damage and activating cGAS/STING/IRF3 pathway.

BACKGROUND: Advanced prostate cancer (PCa) will develop into castration-resistant prostate cancer (CRPC) and lead to poor prognosis. As the primary subtype of CRPC, CRPC-AR accounts for the major induction of PCa heterogeneity. CRPC-AR is mainly driven by 25 transcription factors (TFs), which we speculate may be the key factors driving PCa toward CRPC. Therefore, it is necessary to clarify the key regulator and its molecular mechanism mediating PCa progression. METHODS: Firstly, we downloaded transcriptomic data and clinical information from TCGA-PRAD. The characteristic gene cluster was identified by PPI clustering, GO enrichment, co-expression correlation and clinical feature analyses for 25 TFs. Then, the effects of 25 TFs expression on prognosis of PCa patients was analyzed using univariate Cox regression, and the target gene was identified. The expression properties of the target gene in PCa tissues were verified using tissue microarray. Meanwhile, the related mechanistic pathway of the target gene was mined based on its function. Next, the target gene was silenced by small interfering RNAs (siRNAs) for cellular function and mechanistic pathway validation. Finally, CIBERSORT algorithm was used to analyze the infiltration levels of 22 immune cells in PCa patients with low and high expression of target gene, and validated by assaying the expression of related immunomodulatory factor. RESULTS: We found that HOX family existed independently in 25 TFs, among which HOXC10, HOXC12 and HOXC13 had unique clinical features and the PCa patients with high HOXC13 expression had the worst prognosis. In addition, HOXC13 was highly expressed in tumor tissues and correlated with Gleason score and pathological grade. In vitro experiments demonstrated that silencing HOXC13 inhibited 22RV1 and DU145 cell function by inducing cellular DNA damage and activating cGAS/STING/IRF3 pathway. Immune infiltration analysis revealed that high HOXC13 expression suppressed infiltration of γδ T cells and plasma cells and recruited M2 macrophages. Consistent with these results, silencing HOXC13 up-regulated the transcriptional expression of IFN-ß, CCL2, CCL5 and CXCL10. CONCLUSION: HOXC13 regulates PCa progression by mediating the DNA damage-induced cGAS/STING/IRF3 pathway and remodels TIME through regulation of the transcription of the immune factors IFN-ß, CCL2, CCL5 and CXCL10.

CircPDHX promotes prostate cancer cell progression in vitro and tumor growth in vivo via miR-497-5p/ACSL1 axis.

BACKGROUND: Circular RNAs (circRNAs) have been proved could regulate many cancers, including prostate cancer (PCa). In this paper, we reconnoitered the roles of circRNA pyruvate dehydrogenase complex component X (circPDHX) in PCa. METHODS: The circPDHX, microRNA (miR)-497-5p and acyl-CoA synthetase long chain family member 1 (ACSL1) contents were detected by quantitative real-time PCR and Western blot analysis. Cell proliferation was measured by cell counting kit-8 assay, 5-Ethynyl-2'-deoxyuridine assay, and colony formation assay. Cell migration was examined by wound healing assay. The apoptosis was detected by flow cytometry assay. The ELISA kits were applied to quantify the fatty acid metabolites. Furthermore, the interplay between miR-497-5p and circPDHX or ACSL1 was detected by dual-luciferase reporter assay and RIP assay. The role of circPDHX in PCa was supplementary substantiated in vivo. RESULTS: CircPDHX and ACSL1 contents were upregulated, and the miR-497-5p level was downregulated in PCa. CircPDHX deficiency attenuated PCa cell proliferation, migration, and fatty acid metabolites, while intensified cell apoptosis. CircPDHX bound to miR-497-5p to adjust ACSL1. Moreover, miR-497-5p inhibited the PCa progression by regulating ACSL1. In the meantime, circPDHX deficiency repressed PCa tumor growth in vivo. CONCLUSION: CircPDHX stimulated PCa development via miR-497-5p/ACSL1, which presented a new thought for PCa treatment.

Plastic Additives in Ambient Fine Particulate Matter in the Pearl River Delta, China: High-Throughput Characterization and Health Implications.

Elucidation of the chemical components of airborne fine particulate matter (PM2.5) facilitates the characterization of atmospheric contamination sources and associated human exposure risks. In the present study, we employed a high-throughput analytical approach to investigate the abundance and distribution of 163 plastic additives in ambient PM2.5 collected from 94 different sites across the Pearl River Delta region, China. These chemicals are from six categories, including organophosphate esters (OPEs), phthalate esters (PAEs), PAE replacements, bisphenol analogues, UV stabilizers, and antioxidants. Ninety-three of them exhibited a detection frequency greater than 50% in PM2.5, while the combined concentrations of target plastic additives ranged from 610 to 49,400 µg/g (median: 3500 µg/g) across sites. By category, concentrations of PAEs (median: 2710 µg/g) were one to three orders of magnitude greater than those of other groups, followed by PAE replacements (540 µg/g) and OPEs (76.2 µg/g). Chemical-dependent exposure risks to PM2.5-bound plastic additives were characterized via the estimated daily intake and hazard quotient (HQ) approaches, which resulted in two different risk prioritization systems. Although the HQ approach suggested no or very low health concerns when considering individual chemicals, the complexity of co-concurrent chemicals in PM2.5 raises the concern on potential health risks from exposure to airborne particles and a cocktail of chemical components.

The associations of birth outcome differences in twins with prenatal exposure to bisphenol A and its alternatives.

BACKGROUND: Bisphenol A (BPA) and its alternatives, including BPF and BPS, exhibit endocrine disruption activities. However, the effects of bisphenols on fetal growth in twins remain unclear. OBJECTIVE: To explore the associations of prenatal BPA, BPF, and BPS exposure with birth outcome differences in twins. METHODS: We recruited 289 twin pregnant women who visited the hospital for prenatal examination during the first trimester from 2013 to 2016. Urinary bisphenol levels were determined during the first, second, and third trimesters. The associations of maternal exposure to bisphenols with birth outcome differences in twins were analyzed after stratification by different trimesters. We applied the multiple informant model to estimate trimester-specific associations between urinary bisphenol concentrations and birth outcome differences in twins. RESULTS: We found low reproducibility (ICC<0.40) for maternal urinary BPA and moderate reproducibility (0.40 < ICC<0.75) for BPF and BPS. Urinary BPA concentrations were positively associated with within-pair twin birth weight difference when comparing the third vs. the first tertile in each of the three trimesters (i.e., 133.06 g, 95% CI: 68.19, 197.94; 144.5 g, 95%CI: 81.82-207.18 g; and 135.04 g, 95%CI: 71.37-198.71 g for the 1st, 2nd, and 3rd trimester, respectively). The effect of urinary BPA concentration on increased birth length difference within-pair twins were also observed across different trimesters (All P for trends < 0.05). Urinary BPA levels were positively associated with the within-pair birth weight and birth length differences across pregnancy trimesters (All of Type 3 P for values < 0.05). CONCLUSION: Maternal BPA exposure appeared to influence birth wight and birth length differences in twins. Our results warrant further confirmation.

Novel Organophosphate Esters in Airborne Particulate Matters: Occurrences, Precursors, and Selected Transformation Products.

Organophosphate esters (OPEs) represent an important group of industrial additives with broad applications. However, their occurrences and fate in the atmospheric environment have not been sufficiently investigated. Our study focused on four novel OPEs, including tris(2,4-di-tert-butylphenyl) phosphate (AO168 = O), bis(2,4-di-tert-butylphenyl) pentaerythritol diphosphate, triisodecyl phosphate, and trisnonylphenol phosphate, and characterized their organophosphite antioxidant (OPA) precursors and selected transformation products, in airborne fine particles from South China. House dust from South China was also studied for comparison. Among these four OPEs, exceedingly high concentrations were determined for AO168 = O (i.e., median: 25 500 ng/g in PM2.5, 52 900 ng/g in PM1.0, and 10 700 ng/g in indoor dust), reaching 1 order of magnitude greater than those of traditional OPEs. Their OPA precursors were not detectable in airborne particles but hypothesized as one of the sources for airborne OPEs. In addition, potential transformation products of AO168 = O, including bis(2,4-di-tert-butylphenyl) phosphate (B2,4DtBPP) and 2,4-di-tert-butylphenol (2,4DtBP), also exhibited broad distributions. The levels of 2,4DtBP even surpassed those of AO168 = O in particles. The links between OPAs, OPEs, and other transformation products indicate the complexity of OPE-related chemicals in atmospheric environments. These links should be taken into consideration for a better characterization of OPEs' environmental and health risks.

Value of serum free prostate-specific antigen density in the diagnosis of prostate cancer.

PURPOSE: To investigate the value of serum free prostate-specific antigen density (fPSAD) in the diagnosis of prostate cancer (PCa). METHODS: The data of 558 patients who underwent transrectal ultrasound-guided prostate biopsy were retrospectively analyzed. According to the pathological results, the patients were divided into a PCa group and a benign prostatic hyperplasia (BPH) group. Receiver operating characteristic curves were plotted, based on which the sensitivity, specificity, Youden index, concordance, and kappa values of free prostate-specific antigen (fPSA), the free-to-total f/tPSA, prostate-specific antigen density (PSAD), the free-to-total (f/t)/PSAD ratio, and fPSAD were compared. The patients were divided into three groups by PSA levels (PSA < 4 ng/mL, PSA = 4-10 ng/mL, and PSA > 10 ng/mL), into three groups by age (age < 60 year, age = 60-80y, and age > 80 years), and into two groups by prostate volume (PV) (PV ≤ 80 mL and PV > 80 mL) to compare the sensitivity, specificity, and concordance of indicators. RESULTS: tPSA, PSAD, (f/t)/PSAD, and fPSAD had high accuracy in predicting PCa with AUC values of 0.820, 0.900, 0.846, and 0.867. fPSAD showed lower diagnostic sensitivity but significantly higher specificity and concordance for PCa than tPSA, f/tPSA, (f/t)/PSAD, or PSAD. Thus, fPSAD had the highest accuracy in the diagnosis of PCa. In the groups with different PSA, age, and PV stratification, the concordance of fPSAD was significantly higher (88.61%, 90.74%, and 90.38%) than that of other indicators. CONCLUSION: With the optimal cutoff value of 0.062, fPSAD has a higher diagnostic value for PCa than tPSA, f/tPSA, (f/t)/PSAD, and PSAD, and can well predict the risk of PCa, significantly improve the clinical diagnostic rate of PCa, and reduce unnecessary biopsy.

Exposure profiles and predictors of a cocktail of environmental chemicals in Chinese men of reproductive age.

Personal care products, such as additives, have raised widespread concerns about the potential threat to male reproductive health. The spermatogenesis in humans lasts for approximately 90 days, the average levels of these chemicals remain unclear during spermatogenesis. In our study, we pooled urine samples from each man during the days of 1-15, 16-31, 32-63, and ≥64, and examined exposure to 48 typical additive chemicals. By principal component analysis (PCA), k-means clustering, and Spearman's rank correlations, we then identified 6 PC scores and 4 clusters based on profiles of these chemicals. Some industrial, commercial or structural similar chemicals (e.g., phthalates) were significantly correlated compared to unrelated chemicals (e.g., benzophenone). PCA scores were associated with individual lifestyles (e.g., household income, tea consumption, and drinking tap water). Distinct exposure components and exposure patterns of personal care products may help the reproductive health assessment of men. We suggested more concerns for widespread exposure to these chemicals for men.

Plastic additives and personal care products in south China house dust and exposure in child-mother pairs.

Indoor environment constitutes an important source of industrial additive chemicals to human exposure. We hypothesized that the influence of residential environment on human exposure varies among different types of additive chemicals and differs between children and mothers. This study determined a suite of additive chemicals in house dust from South China dwellings (n = 47) and urine from child-mother pairs. Concentrations of phthalates (PAEs; median 601 µg/g) were 2-3 orders of magnitude greater than those of parabens (0.82 µg/g), bisphenols (3.31 µg/g), and benzophenone-related chemicals (2.69 µg/g). Urinary concentrations differed between children and mothers, but the pattern of differences varied between chemical groups. Children exhibited greater urinary levels of mono-PAEs than mothers (510 versus 395 ng/mL, p = 0.152), while the latter population exhibited greater levels of parabens and benzophenones. Regression analyses indicate a lack of association between dust and urinary levels for most chemicals, suggesting that other exposure pathways can complicate human exposure scenarios. Indeed, we estimated that the daily intake via dust ingestion only constituted 0.002-0.81% of total daily intake estimated based on urine data for mothers and 0.04-5.61% for children. Future efforts are needed to better characterize source-specific exposure for different populations.

Exposure of children and mothers to organophosphate esters: Prediction by house dust and silicone wristbands.

Ubiquitous human exposure to organophosphorus tri-esters (tri-OPEs) has been reported worldwide. Previous studies investigated the feasibility of using house dust and wristbands to assess human OPE exposure. We hypothesized that these two approaches could differ in relative effectiveness in the characterization of children and adult exposure. In the participants recruited from Guangzhou, South China, urinary levels of major OPE metabolites, including diphenyl phosphate (DPHP) and bis(butoxyethyl) phosphate (BBOEP), were significantly higher in children than their mothers (median 6.6 versus 3.7 ng/mL and 0.11 versus 0.06 ng/mL, respectively). The associations of dust or wristband-associated OPEs with urinary metabolites exhibited chemical-specific patterns, which also differed between children and mothers. Significant and marginally significant associations were determined between dust concentrations of triphenyl phosphate (TPHP), tris(2-butoxyethyl) phosphate (TBOEP), trimethylphenyl phosphate (TMPP), or tris(1-chloro-2-propyl) phosphate (TCIPP) and their metabolites in children urine and between dust tris(1,3-dichloroisopropyl) phosphate (TDCIPP), TPHP or TMPP and urinary metabolites in mothers. By contrast, wristbands exhibited better efficiency of predicting internal exposure to TDCIPP. While both house dust and wristbands exhibited the potential as a convenient approach for assessing long-term OPE exposure, their feasibility requires better investigations via larger-scale studies and standardized sampling protocols.