Intron Retention of DDX39A Driven by SNRPD2 is a Crucial Splicing Axis for Oncogenic MYC/Spliceosome Program in Hepatocellular Carcinoma.

RNA splicing is a dynamic molecular process in response to environmental stimuli and is strictly regulated by the spliceosome. Sm proteins, constituents of the spliceosome, are key components that mediate splicing reactions; however, their potential role in hepatocellular carcinoma (HCC) is poorly understood. In the study, SNRPD2 (PD2) is found to be the most highly upregulated Sm protein in HCC and to act as an oncogene. PD2 modulates DDX39A intron retention together with HNRNPL to sustain the DDX39A short variant (39A_S) expression. Mechanistically, 39A_S can mediate MYC mRNA nuclear export to maintain high MYC protein expression, while MYC in turn potentiates PD2 transcription. Importantly, digitoxin can directly interact with PD2 and has a notable cancer-suppressive effect on HCC. The study reveals a novel mechanism by which DDX39A senses oncogenic MYC signaling and undergoes splicing via PD2 to form a positive feedback loop in HCC, which can be targeted by digitoxin.

Global, regional, and national burden and quality of care of multiple myeloma, 1990-2019.

Background: Multiple myeloma (MM) is the second most common haematologic malignancy, presenting a great disease burden on the general population; however, the quality of care of MM is overlooked. We therefore assessed gains and disparity in quality of care worldwide from 1990 to 2019 based on a novel summary indicator - the quality of care index (QCI) - and examined its potential for improvement. Methods: Using the Global Burden of Disease 2019 data set, we calculated the QCI of MM for 195 countries and territories. We used the principal component analysis to extract the first principal component of ratios with the combinations of mortality to incidence, prevalence to incidence, disability-adjusted life years to prevalence, and years of life lost to years lived with disability as QCI. We also conducted a series of descriptive and comparative analyses of QCI disparities with age, gender, period, geographies, and sociodemographic development, and compared the QCI among countries with similar socio-demographic index (SDI) through frontier analysis. Results: The age-standardised rates of MM were 1.92 (95% uncertainty interval (UI) = 1.68, 2.12) in incidence and 1.42 (95% UI = 1.24, 1.52) in deaths per 100 000 population in 2019, and were predicted to increase in the future. The global age-standardised QCI increased from 51.31 in 1990 to 64.28 in 2019. In 2019, New Zealand had the highest QCI at 99.29 and the Central African Republic had the lowest QCI at 10.74. The gender disparity of QCI was reduced over the years, with the largest being observed in the sub-Saharan region. Regarding age, QCI maintained a decreasing trend in patients aged >60 in SDI quintiles. Generally, QCI improved with the SDI increase. Results of frontier analysis suggested that there is a potential to improve the quality of care across all levels of development spectrum. Conclusions: Quality of care of MM improved during the past three decades, yet disparities in MM care remain across different countries, age groups, and genders. It is crucial to establish local objectives aimed at enhancing MM care and closing the gap in health care inequality.

National and subnational incidence, mortality and associated factors of colorectal cancer in China: A systematic analysis and modelling study.

Background: Due to their known variation by geography and economic development, we aimed to evaluate the incidence and mortality of colorectal cancer (CRC) in China over the past decades and identify factors associated with CRC among the Chinese population to provide targeted information on disease prevention. Methods: We conducted a systemic review and meta-analysis of epidemiolocal studies on the incidence, mortality, and associated factors of CRC among the Chinese population, extracting and synthesising data from eligible studies retrieved from seven global and Chinese databases. We pooled age-standardised incidence rates (ASIRs) and mortality rates (ASMRs) for each province, subregion, and the whole of China, and applied a joinpoint regression model and annual per cent changes (APCs) to estimate the trends of CRC incidence and mortality. We conducted random-effects meta-analyses to assess the effect estimates of identified associated risk factors. Results: We included 493 articles; 271 provided data on CRC incidence or mortality, and 222 on associated risk factors. Overall, the ASIR of CRC in China increased from 2.75 to 19.39 (per 100 000 person-years) between 1972 and 2019 with a slowed-down growth rate (APC1 = 5.75, APC2 = 0.42), while the ASMR of CRC decreased from 12.00 to 7.95 (per 100 000 person-years) between 1974 and 2020 with a slight downward trend (APC = -0.89). We analysed 62 risk factors with synthesized data; 16 belonging to the categories of anthropometrics factors, lifestyle factors, dietary factors, personal histories and mental health conditions were graded to be associated with CRC risk among the Chinese population in the meta-analysis limited to the high-quality studies. Conclusions: We found substantial variation of CRC burden across regions and provinces of China and identified several associated risk factors for CRC, which could help to guide the formulation of targeted disease prevention and control strategies. Registration: PROSPERO: CRD42022346558.

Association between antibiotic use during early life and early-onset colorectal cancer risk overall and according to polygenic risk and FUT2 genotypes.

Early-onset colorectal cancer (EOCRC) has been increasing worldwide. Potential risk factors may have occurred in childhood or adolescence. We investigated the associations between early-life factors and EOCRC risk, with a particular focus on long-term or recurrent antibiotic use (LRAU) and its interaction with genetic factors. Data on the UK Biobank participants recruited between 2006 and 2010 and followed up to February 2022 were used. We used logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) of the associations between LRAU during early life and EOCRC risk overall and by polygenic risk score (constructed by 127 CRC-related genetic variants) and Fucosyltransferase 2 (FUT2), a gut microbiota regulatory gene. We also assessed the associations for early-onset colorectal adenomas, as precursor lesion of CRC, to examine the effect of LRAU during early-life and genetic factors on colorectal carcinogenesis. A total of 113 256 participants were included in the analysis, with 165 EOCRC cases and 719 EOCRA cases. LRAU was nominally associated with increased risk of early-onset CRC (OR = 1.48, 95% CI = 1.01-2.17, P = .046) and adenomas (OR = 1.40, 95% CI = 1.17-1.68, P < .001). When stratified by genetic polymorphisms of FUT2, LRAU appeared to confer a comparatively greater risk for early-onset adenomas among participants with rs281377 TT genotype (OR = 1.10, 95% CI = 0.79-1.52, P = .587, for CC genotype; OR = 1.75, 95% CI = 1.16-2.64, P = .008, for TT genotype; Pinteraction = .089). Our study suggested that LRAU during early life is associated with increased risk of early-onset CRC and adenomas, and the association for adenomas is predominant among individuals with rs281377 TT/CT genotype. Further studies investigating how LRAU contributes together with genetic factors to modify EOCRC risk, particularly concerning the microbiome-related pathway underlying colorectal carcinogenesis, are warranted.

Cross-cancer pleiotropic analysis identifies three novel genetic risk loci for colorectal cancer.

BACKGROUND: To understand the shared genetic basis between colorectal cancer (CRC) and other cancers and identify potential pleiotropic loci for compensating the missing genetic heritability of CRC. METHODS: We conducted a systematic genome-wide pleiotropy scan to appraise associations between cancer-related genetic variants and CRC risk among European populations. Single nucleotide polymorphism (SNP)-set analysis was performed using data from the UK Biobank and the Study of Colorectal Cancer in Scotland (10 039 CRC cases and 30 277 controls) to evaluate the overlapped genetic regions for susceptibility of CRC and other cancers. The variant-level pleiotropic associations between CRC and other cancers were examined by CRC genome-wide association study meta-analysis and the pleiotropic analysis under composite null hypothesis (PLACO) pleiotropy test. Gene-based, co-expression and pathway enrichment analyses were performed to explore potential shared biological pathways. The interaction between novel genetic variants and common environmental factors was further examined for their effects on CRC. RESULTS: Genome-wide pleiotropic analysis identified three novel SNPs (rs2230469, rs9277378 and rs143190905) and three mapped genes (PIP4K2A, HLA-DPB1 and RTEL1) to be associated with CRC. These genetic variants were significant expressions quantitative trait loci in colon tissue, influencing the expression of their mapped genes. Significant interactions of PIP4K2A and HLA-DPB1 with environmental factors, including smoking and alcohol drinking, were observed. All mapped genes and their co-expressed genes were significantly enriched in pathways involved in carcinogenesis. CONCLUSION: Our findings provide an important insight into the shared genetic basis between CRC and other cancers. We revealed several novel CRC susceptibility loci to help understand the genetic architecture of CRC.

A systematic review of microbial markers for risk prediction of colorectal neoplasia.

BACKGROUND: Substantial evidence indicates that dysbiosis of the gut microbial community is associated with colorectal neoplasia. This review aims to systematically summarise the microbial markers associated with colorectal neoplasia and to assess their predictive performance. METHODS: A comprehensive literature search of MEDLINE and EMBASE databases was performed to identify eligible studies. Observational studies exploring the associations between microbial biomarkers and colorectal neoplasia were included. We also included prediction studies that constructed models using microbial markers to predict CRC and adenomas. Risk of bias for included observational and prediction studies was assessed. RESULTS: Forty-five studies were included to assess the associations between microbial markers and colorectal neoplasia. Nine faecal microbiotas (i.e., Fusobacterium, Enterococcus, Porphyromonas, Salmonella, Pseudomonas, Peptostreptococcus, Actinomyces, Bifidobacterium and Roseburia), two oral pathogens (i.e., Treponema denticola and Prevotella intermedia) and serum antibody levels response to Streptococcus gallolyticus subspecies gallolyticus were found to be consistently associated with colorectal neoplasia. Thirty studies reported prediction models using microbial markers, and 83.3% of these models had acceptable-to-good discrimination (AUROC > 0.75). The results of predictive performance were promising, but most of the studies were limited to small number of cases (range: 9-485 cases) and lack of independent external validation (76.7%). CONCLUSIONS: This review provides insight into the evidence supporting the association between different types of microbial species and their predictive value for colorectal neoplasia. Prediction models developed from case-control studies require further external validation in high-quality prospective studies. Further studies should assess the feasibility and impact of incorporating microbial biomarkers in CRC screening programme.

Long-term risk of colorectal cancer after removal of adenomas during screening colonoscopies in a large community-based population in China.

Patients with conventional adenoma removal are recommended to undergo colonoscopy surveillance to prevent colorectal cancer (CRC). However, evidence supporting the guidelines of colonoscopy surveillance is limited, especially among the Chinese population. We investigated the association between colonoscopy adenoma findings and CRC risk among individuals aged 40 to 74 years who underwent baseline colonoscopy from 2007 to 2016 in Jiashan and Haining, Zhejiang, China; 34 382 participants were categorized into advanced adenoma, nonadvanced adenoma and no adenoma based on adenoma findings. A multivariable Cox regression model was used to estimate the hazard ratio (HR) of CRC incidence with adjustment for potential confounding factors. After a median follow-up time of 7.7 years, 113 incident cases of CRC were identified (18 occurred in 1632 participants with advanced adenoma, 16 in 3973 participants with nonadvanced adenoma and 79 in 28 777 participants with no adenoma). Compared to no adenoma group, the adjusted HR for CRC in advanced adenoma group was 4.01 (95% CI, 2.37-6.77). For nonadvanced adenomas, individuals with ≥3 adenomas showed an increased risk of CRC (HR, 3.65; 95% CI, 1.43-9.31), but no significantly increased risk of CRC was found for 1 to 2 nonadvanced adenomas, compared to those with no adenoma. Our study suggested that the risk of subsequent CRC increased in individuals with high-risk adenoma (at least one advanced adenoma or ≥3 nonadvanced adenomas), but not in those with 1 to 2 nonadvanced adenomas. These results provide the first evidence from the Chinese population for the current surveillance guidelines.

Cohort profile: The National Colorectal Cancer Cohort (NCRCC) study in China.

PURPOSE: The National Colorectal Cancer Cohort (NCRCC) study aims to specifically assess risk factors and biomarkers related to endpoints across the colorectal cancer continuum from the aetiology through survivorship. PARTICIPANTS: The NCRCC study includes the Colorectal Cancer Screening Cohort (CRCSC), which recruited individuals who were at high risk of CRC between 2016 and 2020 and Colorectal Cancer Patients Cohort (CRCPC), which recruited newly diagnosed patients with CRC between 2015 and 2020. Data collection was based on questionnaires and abstraction from electronic medical record. Items included demographic and lifestyle factors, clinical information, survivorship endpoints and other information. Multiple biospecimens including blood, tissue and urine samples were collected. Participants in CRCSC were followed by a combination of periodic survey every 5 years and annual linkage with regional or national cancer and death registries for at least 10 years. In CRCPC, follow-up was conducted with both active and passive approaches at 6, 12, 18, 24, 36, 48 and 60 months after surgery. FINDINGS TO DATE: A total of 19 377 participants and 15 551 patients with CRC were recruited in CRCSC and in CRCPC, respectively. In CRCSC, 48.0% were men, and the average age of participants at enrolment was 58.7±8.3 years. In CRCPC, 61.4% were men, and the average age was 60.3±12.3 years with 18.9% of participants under 50 years of age. FUTURE PLANS: Longitudinal data and biospecimens will continue to be collected. Based on the cohorts, several studies to assess risk factors and biomarkers for CRC or its survivorship will be conducted, ultimately providing research evidence from Chinese population and optimising evidence-based guidelines across the CRC continuum.

Prognostic Risk Model of Immune-Related Genes in Colorectal Cancer.

PURPOSE: We focused on immune-related genes (IRGs) derived from transcriptomic studies, which had the potential to stratify patients' prognosis and to establish a risk assessment model in colorectal cancer. SUMMARY: This article examined our understanding of the molecular pathways associated with intratumoral immune response, which represented a critical step for the implementation of stratification strategies toward the development of personalized immunotherapy of colorectal cancer. More and more evidence shows that IRGs play an important role in tumors. We have used data analysis to screen and identify immune-related molecular biomarkers of colon cancer. We selected 18 immune-related prognostic genes and established models to assess prognostic risks of patients, which can provide recommendations for clinical treatment and follow-up. Colorectal cancer (CRC) is a leading cause of cancer-related death in human. Several studies have investigated whether IRGs and tumor immune microenvironment (TIME) could be indicators of CRC prognoses. This study aimed to develop an improved prognostic signature for CRC based on IRGs to predict overall survival (OS) and provide new therapeutic targets for CRC treatment. Based on the screened IRGs, the Cox regression model was used to build a prediction model based on 18-IRG signature. Cox regression analysis revealed that the 18-IRG signature was an independent prognostic factor for OS in CRC patients. Then, we used the TIMER online database to explore the relationship between the risk scoring model and the infiltration of immune cells, and the results showed that the risk model can reflect the state of TIME to a certain extent. In short, an 18-IRG prognostic signature for predicting CRC patients' survival was firmly established.

Identifying Stage II Colorectal Cancer Recurrence Associated Genes by Microarray Meta-Analysis and Building Predictive Models with Machine Learning Algorithms.

BACKGROUND: Stage II colorectal cancer patients had heterogeneous prognosis, and patients with recurrent events had poor survival. In this study, we aimed to identify stage II colorectal cancer recurrence associated genes by microarray meta-analysis and build predictive models to stratify patients' recurrence-free survival. METHODS: We searched the GEO database to retrieve eligible microarray datasets. The microarray meta-analysis was used to identify universal recurrence associated genes. Total samples were randomly divided into the training set and the test set. Two survival models (lasso Cox model and random survival forest model) were trained in the training set, and AUC values of the time-dependent receiver operating characteristic (ROC) curves were calculated. Survival analysis was performed to determine whether there was significant difference between the predicted high and low risk groups in the test set. RESULTS: Six datasets containing 651 stage II colorectal cancer patients were included in this study. The microarray meta-analysis identified 479 recurrence associated genes. KEGG and GO enrichment analysis showed that G protein-coupled glutamate receptor binding and Hedgehog signaling were significantly enriched. AUC values of the lasso Cox model and the random survival forest model were 0.815 and 0.993 at 60 months, respectively. In addition, the random survival forest model demonstrated that the effects of gene expression on the recurrence-free survival probability were nonlinear. According to the risk scores computed by the random survival forest model, the high risk group had significantly higher recurrence risk than the low risk group (HR = 1.824, 95% CI: 1.079-3.084, p = 0.025). CONCLUSIONS: We identified 479 stage II colorectal cancer recurrence associated genes by microarray meta-analysis. The random survival forest model which was based on the recurrence associated gene signature could strongly predict the recurrence risk of stage II colorectal cancer patients.

FOLFOX treatment response prediction in metastatic or recurrent colorectal cancer patients via machine learning algorithms.

Early identification of metastatic or recurrent colorectal cancer (CRC) patients who will be sensitive to FOLFOX (5-FU, leucovorin and oxaliplatin) therapy is very important. We performed microarray meta-analysis to identify differentially expressed genes (DEGs) between FOLFOX responders and nonresponders in metastatic or recurrent CRC patients, and found that the expression levels of WASHC4, HELZ, ERN1, RPS6KB1, and APPBP2 were downregulated, while the expression levels of IRF7, EML3, LYPLA2, DRAP1, RNH1, PKP3, TSPAN17, LSS, MLKL, PPP1R7, GCDH, C19ORF24, and CCDC124 were upregulated in FOLFOX responders compared with nonresponders. Subsequent functional annotation showed that DEGs were significantly enriched in autophagy, ErbB signaling pathway, mitophagy, endocytosis, FoxO signaling pathway, apoptosis, and antifolate resistance pathways. Based on those candidate genes, several machine learning algorithms were applied to the training set, then performances of models were assessed via the cross validation method. Candidate models with the best tuning parameters were applied to the test set and the final model showed satisfactory performance. In addition, we also reported that MLKL and CCDC124 gene expression were independent prognostic factors for metastatic CRC patients undergoing FOLFOX therapy.

Associations of Trimester-Specific Exposure to Bisphenols with Size at Birth: A Chinese Prenatal Cohort Study.

BACKGROUND: Bisphenol A (BPA) is an endocrine disruptor that affects fetal growth in experimental studies. Bisphenol F (BPF) and bisphenol S (BPS), which have been substituted for BPA in some consumer products, have also shown endocrine-disrupting effects in experimental models. However, the effects of BPF and BPS on fetal growth in humans are unknown. OBJECTIVES: Our goal was to investigate trimester-specific associations of urinary concentrations of BPA, BPF, and BPS with size at birth. METHODS: The present study included 845 pregnant women from Wuhan, China (2013-2015), who provided one urine sample in each of the first, second, and third trimesters. Linear regressions with generalized estimating equations were applied to estimate trimester-specific associations of urinary bisphenol concentrations with birth weight, birth length, and ponderal index. Linear mixed-effects models were used to identify potential critical windows of susceptibility to bisphenols by comparing the exposure patterns of newborns in the 10th percentile of each birth anthropometric measurement to that of those in the 90th percentile. RESULTS: Medians (25th-75th percentiles) of urinary concentrations of BPA, BPF, and BPS were 1.40 (0.19-3.85), 0.65 (0.34-1.39), and 0.38 (0.13-1.11) ng/mL, respectively. Urinary BPA concentrations in different trimesters were inversely, but not significantly, associated with birth weight and ponderal index. Urinary concentrations of BPF and BPS during some trimesters were associated with significantly lower birth weight, birth length, or ponderal index, with significant trend p-values (ptrend<0.05) across quartiles of BPF and BPS concentrations. The observed associations were unchanged after additionally adjusting for other bisphenols. In addition, newborns in the 10th percentile of each birth anthropometry measure had higher BPF and BPS exposures during pregnancy than newborns in the 90th percentile of each outcome. CONCLUSIONS: Prenatal exposure to BPF and BPS was inversely associated with size at birth in this cohort. Replication in other populations is needed. https://doi.org/10.1289/EHP4664.

Variations, Determinants, and Coexposure Patterns of Personal Care Product Chemicals among Chinese Pregnant Women: A Longitudinal Study.

Exposure to mixtures of personal care product chemicals (PCPCs) is commonplace among the Chinese population; yet, limited data are available on the variations, determinants, and coexposure patterns of PCPCs, particularly among pregnant women at multiple time points during gestation. Here, we measured concentrations of 11 most common PCPCs (five parabens, five benzophenones, and triclosan) in 2823 urine samples collected from 941 pregnant women over three trimesters. Based on the quantification results, we calculated the intraclass correlation coefficient (ICC) to assess within-person variability of targeted compounds, applied linear mixed mode models to explore associations between urinary concentrations of PCPCs and exposure-related factors, and used percentile analysis to evaluate exposure to specific or multiple chemicals at one or three trimesters. Seven targeted compounds: methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), 4-hydroxybenzophenone (4-OH-BP), 2,4-dihydroxybenzophenone (BP-1), 2-hydroxy-4-methoxybenzophenone (BP-3), and triclosan (TCS) were detected in over 66% of samples. The median urinary concentrations (ng/mL) of MeP, EtP, PrP, 4-OH-BP, BP-1, BP-3, and TCS were 15.44, 0.49, 0.61, 0.16, 0.25, 0.53, and 0.48, respectively. We observed that benzophenones (ICC: 0.46-0.55) and triclosan (ICC: 0.50) were less variable than parabens (ICC: 0.35-0.40). Urinary levels of parabens were related to physical activity frequency; urinary levels of benzophenones were associated with the refurbishment of homes and household income, and urinary levels of triclosan were contingent upon the personal basic information (prepregnancy body mass index and age). Notably, higher levels of benzophenones and triclosan but lower paraben levels were observed in summer than in winter. Both coexposure to high percentiles of multiple pollutants at one trimester and exposure to one pollutant at high-dose through three trimesters were rare in the study population. Our findings suggest that these exposure-related factors should be taken into consideration, and health risks should be assessed on mixtures of pollutants in future epidemiological studies.

Association between urinary parabens and gestational diabetes mellitus across prepregnancy body mass index categories.

Increasing evidence suggests a potential role of endocrine disrupting chemicals (EDCs) in inducing gestational diabetes mellitus (GDM). However, as far as we know, no study has examined the associations between GDM and exposure to parabens, a kind of EDCs. In this study, we explored the association between urinary parabens of pregnant women and GDM and studied the modification effect of prepregnancy body mass index (BMI). Urine samples were collected from 696 pregnant women and parabens were measured, including four alkyl side chain substituted para-hydroxybenzoic acid ester, substituents varying from methyl to butyl (abbreviates as MeP, EtP, PrP and BuP), and benzyl substituted para-hydroxybenzoic acid ester (BzP). Logistic regression models adjusting for potential confounders were used to study the association of parabens and GDM in the overall population, and further stratified analysis by prepregnancy BMI categories was also performed. The detection rates for the five parabens in the urine samples were 97.70% (MeP), 71.26% (EtP), 96.55% (PrP), 15.80% (BuP) and 2.73% (BzP). No significant association was found between parabens and GDM among the overall population. However, significant non-linear associations of PrP and the summed estrogenic activity of parabens with GDM were found in the stratified analysis by prepregnancy BMI in the overweight/obese population, with adjusted odds ratios (aORs) of 3.47 (95% CI: 1.28, 9.42) and 2.87 (95% CI: 1.07, 7.73) for GDM in the second tertile of urinary PrP and the summed estrogen activity, respectively, when compared to the first tertile. Although no statistically significant association between parabens and GDM was found in the overall population, we found that among the overweight/obese pregnant women, who represent a subgroup more prone to GDM, moderately higher levels of PrP and summed estrogenic activity of parabens were significantly associated with an increasing GDM prevalence.

Perinatal exposure to 4-nonylphenol can affect fatty acid synthesis in the livers of F1 and F2 generation rats.

Objective: To explore the effects of different dosages of 4-nonylphenol (4-NP) on the fatty acid synthesis and estrogen receptor α (ERα) expression in the livers of F1 and F2 rats. Method: Pregnant rats were randomly divided into four groups: control, NP-5 (5 µg per kg per day), NP-25 (25 µg per kg per day) and NP-125 (125 µg per kg per day). 4-NP was gavaged from gestation day (GD) 6 to postnatal day (PND) 21. Some female rats from the experimental groups were mated with male rats from the control group to obtain the F2 rats. F1 generation rats (23 weeks old) and F2 generation rats (13 weeks old) were killed to detect blood biochemistry and the expression of genes and proteins. Results: Compared with the control group, 4-NP (NP-5, NP-25 and NP-125) can increase the liver organ coefficient of the F1 male offspring (P < 0.05 or P < 0.01). The concentration of high density lipoprotein (HDL) in the F1 female NP-5 group was significantly higher than that of the control group (P < 0.01); other indicators had not changed, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC) and low density lipoprotein (LDL). As the dosage of 4-NP increased, more significant changes of blood biochemistry were found, especially in the NP-125 rats (P < 0.05 or P < 0.01). The changes of histopathology by liver biopsy were consistent with biochemical indices of blood (P < 0.05 or P < 0.01). Compared with the control group, the expression of genes involved in fatty acid synthesis increased significantly (P < 0.05 or P < 0.01), and the degrees of increase were proportional to the dose of 4-NP, as measured by lipoprotein lipase (Lpl), fatty acid synthetase (Fas), sterol regulatory element-binding protein 1 (Srebp-1) and peroxisome proliferator-activated receptor (Ppar)-γ. The expression of genes and proteins of ERα were changed significantly, as well (P < 0.05 or P < 0.01). The above changes in the liver tissues of F2 generation rats were consistent with the F1 generation rats. Conclusion: Perinatal exposure to 4-NP can affect the synthesis of fatty acid in the livers of F1 and F2 generation rats. The low expression of ERα may be one of the mechanisms by which 4-NP affected fatty acid synthesis in the livers of rats.

Urinary concentrations of phthalate metabolites associated with changes in clinical hemostatic and hematologic parameters in pregnant women.

BACKGROUND: Exposure to phthalates, one kind of widely used plasticizers, has been demonstrated to be associated with some clinical hematological changes in circulatory system from animal studies and in vitro experiments, but their relations to hemostatic and hematologic changes in human are unknown. OBJECTIVES: We explored the relationships of urinary phthalate metabolites with clinical hemostatic and hematologic parameter changes in pregnant women. METHODS: The present study population included 1482 pregnant women drawn from an ongoing prospective birth cohort study in Wuhan, China. Eight urinary phthalate metabolites and eight blood clinical parameters, including activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen (Fg), total white blood cell counts (WBC), red blood cell counts (RBC), hemoglobin (Hb), and platelet counts (PLT) were measured in the late third trimester. The associations between phthalate metabolites and blood parameters were analyzed using general linear model. The odds ratios (ORs) for anemia during pregnancy associated with phthalates were also explored by using logistic regression models. RESULTS: After adjustment for false discovery rate, a significantly negative association between ln-transformed urinary mono-ethyl phthalate (MEP) concentration and blood Fg, and a positive association between urinary mono-butyl phthalate (MBP) and APTT were found in this study. Higher concentrations of mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) were associated with lower Hb concentrations. In addition, higher levels of MEHP, MEOHP and MECPP were also associated with increased likelihood of anemia. No significant associations were found between phthalates and other hematologic parameters. CONCLUSIONS: Higher urinary phthalate metabolites in late third trimester were associated with prolonged blood clotting time, decreased Hb concentrations, and increased likelihood of anemia in pregnant women. Further research is needed to replicate the observed findings and clarify the potential biological mechanism.

Relationship between maternal exposure to bisphenol S and pregnancy duration.

Bisphenol S (BPS) has been progressively used due to the potential safety problems of bisphenol A (BPA). Thus Human studies are needed to investigate the developmental effects of BPS. In this study, the impact of maternal BPS exposure on birth outcomes was evaluated with linear and logistic regression models. BPS was analyzed in spot urine samples collected from 985 pregnant women at admission to labor. It was found in 93.7% of the urine samples with the specific gravity adjusted geometric mean concentration of 0.17 µg/L. One ln-unit increase in urinary BPS was associated with a 0.72-day increase in pregnancy duration (95% CI: 0.34, 1.09). When stratified by fetal sex, each ln-unit increase in maternal urinary BPS was significantly correlated with increased gestational age [adjusted ß = 1.02, 95% confidence intervals (CI): 0.47, 1.57] and increased odds of late term birth [adjusted odds ratio = 1.29, 95% CI: 1.00, 1.67] for girls, but not significantly for boys. Including maternal urinary BPA and BPS in one model did not change the results. Associations of BPS with birth weight or length were not observed. This is the first report about BPS exposure for pregnant women from China. Higher maternal urinary BPS concentrations were associated with increased gestational age, suggesting maternal BPS exposure may interfere with pregnancy duration. The findings require replication but reveal the probable risks posed by the developmental BPS exposure.

Urinary level of triclosan in a population of Chinese pregnant women and its association with birth outcomes.

Triclosan (TCS) is a suspected endocrine disrupting chemical which is widely used in consumer products as an antibacterial agent. But findings in human studies focusing on the fetal developmental effects of prenatal TCS exposure were rare and inconsistent. This study aimed to determine maternal urinary TCS and investigate its association with birth outcomes. Pregnant women (n = 1006) were randomly selected from the prospective Healthy Baby Cohort (HBC) enrolled in 2014. TCS levels were determined in maternal urine samples collected at delivery and recorded birth outcomes were obtained from the medical records. Multiple linear regressions were applied to evaluate associations of maternal urinary TCS levels with birth outcomes including birth weight, birth length, and gestational age. Logistic regressions were used to evaluate associations with preterm birth, late term birth, and low birth weight. The geometric mean concentrations for TCS and specific gravity (SG) adjusted TCS in maternal urines were 0.73, 0.78 ng/mL, respectively. In the crude model, one ln-unit increase of urinary SG-adjusted TCS concentration was associated with a 0.30-day [95% confidence interval (CI): 0.00, 0.60] increase in gestational age; however, the associations were not statistically significant after adjustment for covariates. No significant associations of SG-adjusted TCS concentrations with birth weight and birth length were observed. Maternal SG-adjusted TCS concentrations were not related to preterm birth, late term birth, and low birth weight (all p > 0.10). Our findings reported a relatively low level of TCS among Chinese pregnant women. With such exposure level, we did not find strong evidence for associations between maternal TCS exposure and birth outcomes. Longitudinal studies concerning about different potential effects of TCS on perinatal health are necessary.

Relationship between maternal phthalate exposure and offspring size at birth.

Research findings on effects of prenatal phthalate exposure on fetal growth were inconsistent. Increasing evidence from animal studies has indicated a potential sex-specific effect of phthalates on fetal growth, but the current human data was limited. In this study, we aimed to estimate the relationships between maternal phthalate exposure and infant birth size. Six major phthalate metabolite levels of urine samples were measured among pregnant women (n=1002) from the Healthy Baby Cohort (HBC), China. The associations between urinary phthalate metabolites levels and birth size (birth weight, birth length, birth weight z-scores and ponderal index) were estimated using linear regression models. In boys, the ln-transformed di-2-ethylhexyl phthalate (DEHP) metabolite levels were significantly associated with increased birth weight and birth weight z-scores. Additionally, each ln-unit increase in mono-(2-ethyl-5-carbox-ypentyl) phthalate (MECPP) was associated with a 0.25kg/m3 [95% confidence interval (CI): 0.03, 0.47] increase in ponderal index in boys. However, we did not observe any significant association of maternal phthalate metabolite levels with any of the outcomes in girls. Our data suggested potential sex-specific associations of maternal phthalate exposure with increased birth weight and ponderal index, which were merely apparent in boys.