Organophosphate esters (OPEs) are widely used synthetic chemicals associated with increased plasma glucose in the general populations; however, evidence regarding their associations among pregnant women remains limited. In the Shanghai-Minhang Birth Cohort Study, urinary concentrations of eight OPE metabolites were measured at 12–16 weeks of gestation. Data on fasting plasma glucose (FPG) and 1 h-plasma glucose (1 h-PG) were obtained from medical records. Women were classified as having elevated glucose levels based on abnormal FPG, 1 h-PG, or a diagnosis of gestational diabetes mellitus (GDM). Multiple linear regression and Bayesian Kernel Machine Regression (BKMR) were employed to estimate associations between individual OPE metabolites or OPE mixtures and plasma glucose levels. Modified Poisson regression assessed the associations of OPE metabolites with the risk of elevated glucose levels. Compared with the lowest exposure group, the highest exposure to bis(1,3-dichloro-2-propyl) phosphate, dibutyl phosphate, and diphenyl phosphate was significantly associated with lower FPG levels. However, 1 h-PG levels tended to increase in the moderate exposure group, with ΣCl-OPEs showing a marginally significant association. Poisson regression results similarly indicated that pregnant women with moderate exposure had an increased risk of elevated glucose levels, though without statistical significance. The BKMR model produced similar findings, indicating that chlorinated-OPE primarily contributed to altered FPG and 1 h-PG, with bis(1,3-dichloro-2-propyl) phosphate and bis(1-chloro-2-propyl) phosphate being the major contributors, respectively. Additionally, associations between OPE exposure and decreased FPG levels were predominantly observed among pregnant women with daily fruit and vegetable intake. The present study observed different association patterns between OPE exposure and FPG or 1 h-PG levels, suggesting potential disruptive effects of OPEs on glucose homeostasis during pregnancy.

Background Long non-coding RNAs (lncRNAs) are increasingly recognized as critical regualtors in cancer biology, including ovarian cancer (OC). Analysis of the OC cohort in the Cancer Genome Atlas (TCGA) revealed that LINC011123 is significantly upregulated in OC compared to normal ovarian tissue. Nonetheless, the functional consequence of this upregulation and the underlying mechanism of LINC01123 in OC remain unclear. We hypothesized that elevated LINC01123 exerts an oncogenic function. Methods RNA sequencing datasets from TCGA were analyzed to identify the RNAs with differential expression in OC tissues relative to standard ovarian tissue. The role of LINC01123 in regulating cell proliferation, migration, and autophagy was defined through functional experiments including wound healing, transwell, and western blotting in vitro, and a xenograft mouse model in vivo. LINC01123 regulation underwent investigation using RNA pulldown and mass spectrometry, RNA immunoprecipitation, luciferase reporter assays, and so on. Results LINC01123 is one of the most highly increased lncRNAs in OC specimens compared to non-cancerous ovarian tissue. Downregulation of LINC01123 functioned to suppress proliferation and cellular migration. RNA pulldown and gene set enrichment analysis suggested that the amount of LINC01123 positively correlated with genes involved in autophagy. LINC01123 promoted autophagy by promoting ATG13 expression. Further mechanistic studies showed that LINC01123 directly binds to p65 to activate ATG13 transcription, promoting autophagy and facilitating OC tumorigenesis. Conclusion Our results uncovered the oncogenic function and mechanism of LINC01123 in OC. LINC01123 associates with p65, augmenting autophagy, which in turn facilitates tumor metastasis within OC cells by increasing ATG13 expression. LINC01123 is a potential therapeutic target for OC patients.

BACKGROUND:Gestational blood pressure (BP) is susceptible to exogenous exposures, including environmental chemicals. However, epidemiological evidence is lacking, particularly for the emerging contaminants. METHODS:We quantified 31 urinary chemicals in early-pregnancy among 815 women from the Jiashan Birth Cohort in Zhejiang Province, China. We applied logistic regression, generalized estimating equation and Bayesian kernel machine regression (BKMR) models to analyze associations between 16 frequently detected compounds and gestational hypertension (GH), trimester-specific BP levels, and BP trajectories throughout pregnancy. RESULTS:Bisphenol A (2,3-dihydroxypropyl) glycidyl ether (BADGE-H2O), bisphenol A-bis(2,3-dihydroxypropyl) ether (BADGE-2H2O), and N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-Q) were consistently associated with an increased risk of GH, elevated BP levels across all trimesters, and a greater likelihood of belonging to BP trajectory groups with a rising pattern. BKMR confirmed that the mixture exposure was associated with higher BP values across all trimesters, identifying BADGE-H2O as the predominant contributor. Bisphenol A (BPA) and 2-methylthio-benzothiazole (2-Me-S-BTH) also showed associations with elevated BP levels and altered BP trajectory membership, whereas inverse associations were preliminarily observed for propyl paraben (PrP), benzyl paraben (BzP), and 2-(Isopropylamino)-5-(phenylamino) cyclohexa-2,5-diene-1,4-dione (IPPD-Q). CONCLUSION:This study reported novel associations between early-pregnancy exposure markers of non-persistent chemicals, especially emerging contaminants (BADGE-H2O, BADGE-2H2O, and 6PPD-Q), and adverse maternal BP outcomes. These findings highlight the potential public health concern posed by these widespread environmental exposures, and underscore the importance of considering real-world mixture exposures. Further research is needed to validate these associations and to elucidate the underlying biological mechanisms.

BACKGROUND:Evidence linking maternal organophosphate ester (OPE) exposure during early gestational weeks with infant birth weight outcomes remains limited. OBJECTIVES:This prospective cohort study examined associations of maternal serum OPE concentrations at 9 to 13+6 weeks of gestation with infant birth weight, large for gestational age (LGA), and small for gestational age (SGA). METHODS:Among 1039 pregnant females in a Qingdao birth cohort, 16 serum OPEs were measured using gas chromatography-tandem mass spectrometry. Individual OPEs were evaluated per interquartile range increase in ln-transformed concentration using multivariable linear regression and modified Poisson regression. Quantile g-computation (Qgcomp), weighted quantile sum (WQS) regression, and Bayesian kernel machine regression assessed OPE mixtures. RESULTS:Tris(isobutyl) phosphate (TIBP) and tris(2-ethylhexyl) phosphate (TEHP) were associated with higher birth weight [TIBP: β = 77 g, 95% confidence interval (CI): 37, 117; TEHP: β = 40 g, 95% CI: 18, 63]. TEHP was associated with higher LGA risk [adjusted risk ratio (aRR) = 1.27, 95% CI: 1.09, 1.48] and lower SGA risk (aRR = 0.71, 95% CI: 0.57, 0.90); p-cresyl diphenyl phosphate was also associated with lower SGA risk (aRR = 0.69, 95% CI: 0.53, 0.91). In Qgcomp models, total OPE mixture exposure was associated with higher LGA risk (aRR = 1.41; 95% CI: 1.10, 1.80). Alkyl-substituted OPE mixture was associated with higher LGA risk in Qgcomp and higher birth weight in WQS; halogenated OPE mixture showed no significant associations. CONCLUSIONS:Maternal serum concentrations of selected OPEs at 9 to 13+6 weeks of gestation, particularly alkyl-substituted OPEs, were associated with higher birth weight and LGA risk. These findings warrant confirmation in studies with repeated exposure assessment and additional longitudinal fetal growth indicators.

Reproductive toxicity of organophosphate esters (OPEs) has been reported, and some animal and human studies suggest that prenatal OPE exposure may alter anogenital distance (AGD) in offspring. However, the long-term effects of prenatal OPE exposure on AGD growth trajectory remain unclear. Based on the Shanghai-Minhang Birth Cohort Study, we examined the effects of prenatal OPE exposure on AGD growth trajectory of children from birth to 48 months. Urine samples from pregnant women were analyzed for eight OPE metabolites. AGD was measured at birth, 6, 12, and 48 months (boys: AGDAP (anus-penis) and AGDAS (anus-scrotum); girls: AGDAC (anus-clitoris) and AGDAF (anus-fourchette)). Group-Based Trajectory Modeling identified two trajectory groups of AGDAC, AGDAF, and AGDAS, which were named as “fast growth” and “slow growth” groups, respectively. Modified Poisson regression models showed a general pattern that higher prenatal OPE exposure increased the probability of AGD being in the “slow growth” trajectory group in both sexes. Statistically or marginally significant associations were found for bis(2-butoxyethyl) phosphate (BBOEP), bis(2-ethylhexyl) phosphate (BEHP), aryl-OPEs, and alkyl-OPEs in girls, and bis(1-chloro-2-propyl) phosphate (BCIPP) and tricresyl phosphate (DCP) in boys. Bayesian Kernel Machine Regression models showed similar results, with significant associations only found in girls, where alkyl-OPEs (especially BBOEP) were identified as major contributors. This study presents the first human evidence of the long-term effects of prenatal OPE exposure on the growth trajectory of AGD, with the magnitude of effects varying by OPE substituents.

Prenatal exposure to bisphenol analogues (BPs) has been suggested to impair fetal growth and increase obesity risk in future life. However, the mechanisms remain unclear. Based on the Shanghai-Minhang Birth Cohort Study, this study aimed to investigate the associations between prenatal exposure to BPs and placental DNA methylation (DNAm) at thyroid hormone (TH)-related genes and explore whether these epigenetic modifications mediated the effects of BPs on offspring adiposity. The participants were recruited between April and December 2012 from the Minhang Maternal and Child Health Hospital in Shanghai, China. The study included 205 mother-child pairs with complete data on exposure, DNAm, and infant skinfold thickness. Maternal BPs concentrations were measured using a single spot urine sample collected in late pregnancy. Placental DNAm levels in the promoter regions were analyzed using bisulfite amplicon sequencing for five TH-related genes: SLC16A2, SLCO1C1, TTR, DIO3 and TRH. We found that prenatal exposure to BPA, BPF and BPS was associated with increased DNAm at SLC16A2, which mediated the associations between these BPs and increased infant skinfold thickness, accounting for 10-16% of the total effects. Additional associations were found between BPS and BPAF and higher methylation levels of SLCO1C1 and TTR. TCBPA was linked to increased DNAm at SLCO1C1 but decreased DNAm at DIO3. These findings suggest that placental DNAm at TH-related genes may serve as a mechanism underlying the effects of prenatal exposure to BPs and a potential mediator linking this exposure to offspring growth.

Maternal per- and polyfluoroalkyl substances (PFAS) exposure has been linked to adverse health effects on offspring, but the mechanisms remain unclear. The present study investigates the relationship between maternal PFAS exposure and the expression of placental cytochrome P450 enzymes (CYP19A1, CYP2J2, and CYP2E1), and explores the potential role of these enzymes in linking maternal PFAS exposure to offspring development. We included 350 mother-infant pairs from the Jiashan birth cohort. Thirteen PFAS compounds were measured in maternal plasma collected at 8–16 weeks of gestation, while the expression levels of the three CYP genes were quantified in placental tissues collected at delivery. Offspring weight and length were measured at birth and at 1, 3, 6, 8, 12, and 24 months of age, and their ponderal index (PI) was computed. Multivariable linear regression was used to examine associations between plasma concentrations of individual PFAS and placental CYP gene expression. Quantile-based g-computation was used to examine the association of the PFAS mixture with placental CYP gene expression. A linear mixed model was used to examine the associations of maternal PFAS and placental CYP expression levels with repeated PI measurements from birth to 24 months. Multilevel mediation analysis was conducted to explore the potential mediating role of CYP genes. Consistent inverse associations between maternal PFAS exposure and the three placental CYP genes expression in female placentas were observed. Specifically, statistically significant decreases were observed in the associations between all PFAS compounds and CYP2J2 expression with β- estimates for the highest exposure versus the lowest from -0.255 to -0.174, as well as between the highest exposure of perfluorotridecanoic acid (PFTrDA) and CYP19A1 expression (β = -0.279, 95

Animal studies have indicated that prenatal depression may affect the reproductive development of offspring. The digit ratio has been proposed as a marker of in utero reproductive development. The aim of this study was to explore the association between prenatal depression and the digit ratio (2nd:4th digit ratio (2D:4D)) in children. This study involved 668 mother-child pairs enrolled in the Shanghai-Minhang birth cohort study (S-MBCS). Prenatal depressive symptoms among pregnant women were evaluated during recruitment and late pregnancy using the validated Chinese version of the Center for Epidemiological Studies Depression Scale (CES-D). Measurements of digit lengths of both hands were conducted during follow-up visits at 4 and 6 years. We observed that mothers with prenatal depressive symptoms tended to have offspring with higher digit ratios at 4 and 6 years of age. For children whose mothers experienced depressive symptoms in the second trimester, the digit ratio of the left hand (2D:4DL) at 4 years of age increased by 0.007 (95% CI: 0.000, 0.015) in the subthreshold group and 0.010 (95% CI: 0.001, 0.019) in the screen-positive group. For those with depressive symptoms in the third trimester, the 2D:4DL in the screen-positive group increased by 0.012 (95% CI: 0.001, 0.023) at 4 years of age and 0.014 (95% CI: 0.003, 0.024) at 6 years of age. A dose-response relationship was established for both the strength and duration of depressive symptoms. Our study suggests that prenatal depressive symptoms may perturb the reproductive development of offspring and predominantly exhibit a feminizing effect.

Urinary exposome analysis faces analytical challenges due to the lack of reference standards for biotransformed products and the wide structural diversity of metabolites. This study developed a chemically labeled exposome analysis (CLEAN) strategy for nontargeted identification of urinary metabolites. The strategy uses dansyl chloride (DnsCl) and N-methylphenylethylamine (MPEA) to label exogenous and endogenous molecules with phenolic hydroxyl, primary amine, and carboxyl groups and develops an integrated screening workflow based on diagnostic fragment ion filtering and machine learning-assisted retention time prediction and structure annotation. We applied the CLEAN strategy to screen for key environmental chemicals in pregnant women associated with small vulnerable newborns (SVN) in a nested case-control study of 80 SVN cases and 160 matched controls. Among 97 identified exogenous substances, 29 were detected in more than 70% samples. The BKMR analysis revealed a significant and positive association between mixed exposure and the SVN risk and identified 1-hydroxypyrene, monoisopropyl phthalate and pentabromophenol as the key exposure markers. Among the identified endogenous metabolites, four amino acids exhibited the strongest mediation effects on the environmental exposure-SVN associations. Collectively, our work demonstrates the ability of CLEAN to achieve high-throughput and accurate urinary exposome characterization, supporting large-scale human biomonitoring and epidemiological studies.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, posing a significant threat to human health. Recently, gambogic acid (GA) has garnered attention for its anticancer properties in GC. However, it remains unclear whether GA can regulate other forms of cell death beyond apoptosis. In this study, we found that GA inhibited proliferation and induced ferroptosis in GC cells. Western blot analysis was employed to assess ferroptosis and endoplasmic reticulum (ER) stress-related proteins, as well as forkhead box A2 (FOXA2) expression. Additionally, malondialdehyde (MDA) and glutathione (GSH) levels were measured following GA treatment, and quantitative real-time polymerase chain reaction (RT-qPCR) was used to evaluate miR-1291 expression. Our findings revealed that GA treatment elevated reactive oxygen species (ROS) levels and promoted intracellular Fe[Formula: see text], MDA, and GSH accumulation. Furthermore, GA upregulated SLC7A11 and ferritin expression while suppressing glutathione peroxidase 4 (GPX4) in AGS and HGC27 cells, suggesting its role in ferroptosis induction. Notably, GA increased miR-1291 levels and downregulated FOXA2 expression. Subsequent analyses showed FOXA2 as a direct target of miR-1291. Functional experiments involving miR-1291 and FOXA2 knockdown or overexpression further suggested that the miR-1291/FOXA2 axis mediates ferroptosis. Finally, tumor xenograft models showed that GA effectively inhibited tumor growth by inducing ferroptosis. In conclusion, our study provides compelling evidence that GA induces ferroptosis in GC through the miR-1291/FOXA2 axis, highlighting its potential as a novel therapeutic strategy and preventive target for gastric cancer treatment.

Emerging chemicals (ECs), including parabens, bisphenols, bisphenol diglycidyl ethers, N,N′-substituted p-phenylenediamines, and benzotriazoles/benzothiazoles (BTH/BTRs), are widely used in industrial and consumer products. This study aimed to determine the urinary concentrations of 33 ECs and three oxidative stress biomarkers in pregnant women from a large birth cohort in Jiashan, China. Among the detected compounds, methyl paraben (MeP), bisphenol A (BPA), bisphenol A bis(2,3-dihydroxypropyl) glycidyl ether (BADGE·2H2O), N-isopropyl-N′-phenyl-1,4-phenylenediamine quinone (IPPDQ), and 1H-benzotriazole (1-H-BTR) were the most prevalent, with median concentrations ranging from 0.51 to 9.02 ng/mL. Notably, BTH/BTRs exhibited the highest exposure levels, approximately 4–16 times greater than those of other ECs. Most ECs showed elevated concentrations in pregnant women who were exposed to secondhand smoke prior to pregnancy. After model analysis, we found that mixtures of ECs were positively associated with both 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 15(R)-prostaglandin F2α (15-PGF2α), while a negative trend was observed between ECs and 8-iso-prostaglandin F2α (8-PGF2α). Specifically, urinary benzyl paraben (BzP), BPA, bisphenol S (BPS), N-(1,3-dimethylbutyl)-N′-phenyl-1,4-phenylenediamine quinone (6PPDQ), IPPDQ, 2(3H)-benzothiazole (2-OH-BTH), and 2-methylthio-benzothiazole (2-Me-S-BTH) or 1-H-BTR were significantly (p < 0.05) associated with 8-OHdG. MeP, 6PPDQ, and 2-Me-S-BTH were linked to 15-PGF2α, while only bisphenol A (2,3-dihydroxypropyl) glycidyl ether (BADGE·H2O) showed a significant positive association with 8-PGF2α. This study provides a comprehensive evaluation of the exposure characteristics of ECs and their associations with oxidative stress biomarkers in pregnant women, offering new insights into the health risks associated with ECs exposure during critical periods of pregnancy.

Organic ultraviolet (UV) filters, chemicals protecting against harmful UV radiation, are extensively incorporated into personal care products and polymers. Evidence regarding the impacts of prenatal UV filter exposure on children's neurodevelopment remains limited. In this study, we included 393 mother-offspring pairs from the Shanghai-Minhang Birth Cohort Study. Maternal urinary concentrations of UV filters in the third trimester of pregnancy were quantified, and children's cognitive and neurobehavioral development was evaluated by the Wechsler Intelligence Scale and Child Behavior Checklist at six years of age. The effects of individual UV filters were examined using linear regression or negative binomial regression, and their combined effect was examined using Bayesian Kernel Machine Regression (BKMR) and Quantile G-Computation (QG-C) models. Our results showed that Oxybenzone (BP-3) exposure in the third tertile was significantly associated with decreased scores in Full Scale Intelligence Quotient (FSIQ), Perceptual Reasoning Index (PRI), and Verbal Comprehension Index (VCI). The BKMR model revealed a higher level of the UV filter mixture was inversely associated with FSIQ and PRI. Notably, the adverse effect of UV filters on cognitive development was modified by sex. In males, a higher level of the UV filter mixture was inversely associated with all three cognitive measures of neurodevelopment whereas no significant associations were observed in females. The results were further supported by the QG-C model. In terms of neurobehavior development, Bumetrizole (UV-326) was associated with higher scores on externalizing problems in the total population. However, no association was observed in BKMR or QG-C models. In conclusion, our results suggest that prenatal exposure to UV filters may be associated with impairment of both cognitive and neurobehavioral development at six years old. Further studies are required to confirm these associations and explore the underlying biological mechanisms, especially regarding sex-specific vulnerabilities.

Ethnopharmacological relevance Myelodysplastic syndrome (MDS) is a hematologic malignancy that presents a unique opportunity for traditional Chinese medicine (TCM) to demonstrate its distinctive value in treatment. Realgar, a component of TCM, has shown notable potential in alleviating clinical symptoms and improving the prognosis of MDS patients. However, the precise mechanisms underlying the treatment of MDS with realgar, particularly its effects on apoptosis-related pathways, remain poorly understood.Aim of the study: This study aimed to investigate the pro-apoptotic effects of realgar on MDS cells and to elucidate the underlying molecular mechanisms. Materials and methods We explored the targets and pathways of realgar’s action on MDS using public databases, network pharmacology, and RNA sequencing. Various techniques were employed, including cell transfection, Cell Counting Kit-8 (CCK8) assay, Cellular Thermal Shift Assay (CETSA), Western blot (WB), quantitative real-time polymerase chain reaction (qRT-PCR), apoptosis and glycolysis assays, extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) measurements, dual-luciferase reporter assays, and immunofluorescence, to investigate the regulatory mechanisms involving STAT3, glycolysis, and apoptosis. Hematoxylin and eosin (HE) staining was utilized to assess realgar’s toxicity. Apoptosis and hemogram changes were analyzed to evaluate the therapeutic effect of realgar on MDS transgenic mice. Results Analysis of public data indicated that apoptosis-related genes are downregulated in MDS patients. Through network pharmacology, CETSA, qRT-PCR, WB, apoptosis assays, and STAT3 overexpression cell transfection, we discovered that realgar inhibits STAT3 expression. Further investigation using RNA sequencing suggested that glycolysis may be involved in this regulatory process. ECAR, OCR, glycolysis assays, WB, apoptosis assays, and glycolysis inhibitor experiments demonstrated that glycolytic function was inhibited. Additionally, GLUT1 expression was significantly decreased, and GLUT1 was found to directly bind to STAT3. In MDS mice, realgar treatment enhanced levels of white blood cells, red blood cells, hemoglobin, and platelets, and increased apoptosis levels. Conclusion Our findings reveal that realgar exerts a significant pro-apoptotic effect on MDS cells in both in vivo and in vitro models. Further analysis demonstrated that realgar regulates the STAT3 pathway, leading to GLUT1-mediated glycolysis alterations that ultimately induce apoptotic pathways, as represented by BCL2. These discoveries hold significant implications for the basic research and clinical diagnosis and treatment of MDS.

Gemcitabine resistance is a critical factor contributing to the recurrence and progression of bladder cancer. In this study, we utilized high-throughput drug screening and bladder cancer organoid models to identify Bavachalcone (Bava) as a sensitizing agent for gemcitabine, thereby inhibiting the progression of bladder cancer. Bava targets transferrin receptor (TFRC) and epidermal growth factor receptor (EGFR), competitively binding to TFRC with transferrin (Tf), which reduces the influx of iron ions and the activity of mitochondrial respiratory chain complexes. Concurrently, Bava inhibits the phosphorylation of TFRC at tyrosine 20 (Y20) by blocking EGFR phosphorylation, thereby stabilizing TFRC on the cell membrane. The combination of Bava and gemcitabine effectively inhibits the repair of DNA damage induced by gemcitabine. Additionally, Bava suppresses the iron-induced ATR-CHEK1-E2F1 signaling pathway and decreases the expression of RRM1, further sensitizing cells to gemcitabine. Studies utilizing patient-derived xenografts of bladder cancer have demonstrated that the Bava-gemcitabine combination significantly inhibits tumor progression. Correlating with clinical data, we found that TFRC and RRM1 may serve as markers of poor prognosis in bladder cancer. In summary, our research has identified specific Chinese medicine monomers that sensitize cells to gemcitabine, elucidated their direct action targets, and highlighted the role of iron ions in tumor development. This work also paves the way for novel drug design strategies that target TFRC to inhibit iron ion influx and mitigate bladder cancer progression.

The human gut microbiome's role in colorectal cancer (CRC) pathogenesis has gained increasing recognition. This study aimed to delineate the microbiome characteristics that distinguish CRC patients from healthy individuals, while also evaluating the influence of aging, through a comprehensive metagenomic approach. The study analyzed a cohort of 80 CRC patients and 80 matched healthy controls, dividing participants into a normal and a CRC group, further categorized by age into young, middle-aged, and old-aged subgroups. Extensive metagenomic sequencing of fecal samples allowed for the exploration of both the structural and functional profiles of the microbiome, with findings validated in an independent cohort to ensure robustness. Our results highlight notable differences in microbiome composition between CRC patients and healthy individuals, which exhibit age-dependent variations. Specifically, a higher prevalence of pathogenic bacteria, such as Bacteroides vulgatus, known to drive inflammation and carcinogenesis, was observed in CRC patients, alongside a reduction in beneficial microbes, including Lactobacillus. Functionally, the CRC-associated microbiome showed an increase in pathways related to DNA repair, cell cycle regulation, and metabolic activities, such as the Citrate cycle and Galactose metabolism, underscoring distinct microbial alterations in CRC patients that could influence disease onset and progression. These insights lay a foundation for future research into microbiome-based diagnostics and treatments for CRC. IMPORTANCE:This study underscores the critical role of the gut microbiome in colorectal cancer (CRC) pathogenesis, particularly in the context of aging. By identifying age-specific microbial biomarkers and functional pathways associated with CRC, our findings provide novel insights into how microbiome composition and metabolic activities influence disease progression. These discoveries pave the way for developing personalized microbiome-based diagnostic tools and therapeutic strategies, potentially improving CRC prevention and treatment outcomes across different age groups. Understanding these microbial dynamics could also inform interventions targeting gut microbiota to mitigate CRC risk and progression.

Early-life exposure to endocrine-disrupting chemicals (EDCs) may contribute to small vulnerable newborns, including conditions such as being small for gestational age (SGA) and preterm birth (PTB), yet evidence remains limited. This study, which is based on 739 mother-infant pairs in the Chinese Jiashan Birth Cohort (2016-2018), including 39 SGA and 38 PTB cases, employed interpretable machine learning to elucidate the isolated effects of 34 EDCs on SGA and PTB risk and sex interactions in a multi-substance exposure context. Extra Trees and CatBoost classifiers performed best for SGA and PTB, respectively, achieving sensitivities of 0.60 and 0.73 and specificities of 0.82 and 0.97. For SGA, key predictors included bisphenol A (2,3-dihydroxypropyl) glycidyl ether (BADGE-H2O), benzophenone (bZp), bisphenol A bis(2,3-dihydroxypropyl) ether (BADGE-2H2O), propyl paraben (PrP), and 2-methylthio-benzothiazole (2-Me-S-BTH). Lower exposures to BADGE-H2O, bZp, and BADGE-2H2O (concentrations below 0.21, 4.22, and 0.93 μg·g-1 creatinine, respectively) and higher exposure to 2-Me-S-BTH (above 0.15 μg·g-1 creatinine) were both associated with increased SGA risk. Notably, BADGE-H2O, BADGE-2H2O, and PrP showed significant interactions with fetal sex. For PTB, key predictors included ethyl paraben (EtP), methyl paraben (MeP), bZp, BADGE-H2O, and 1H-benzotriazole (1-H-BTR). Lower BADGE-H2O and higher EtP and bZp exposures increased PTB risk (< 0.10 and > 0.01 and 0.60 μg·g-1 creatinine, respectively). Male fetuses appeared more susceptible to EtP and MeP, and female fetuses were more susceptible to 1-H-BTR. Bayesian kernel machine regression was performed to compare the results. This study demonstrated the potential of interpretable machine learning in environmental epidemiology.

Background: As a class of synthetic chemicals, organophosphate esters (OPEs) were shown to have thyroid hormones (THs) disrupting potentials in animal studies, while epidemiological evidence on gestational exposure to OPEs and thyroid disruption is limited. Besides, assessment on the safety threshold of OPEs exposure during gestation is especially scarce. Methods: Based on the Shanghai Minhang Birth Cohort Study, we measured maternal urine concentration of 8 OPE metabolites and THs levels in cord plasma and examined their associations using multiple linear regression and quantile g-computation (QGC) models. The benchmark dose (BMD) and its lower limit (BMDL) of urine OPE metabolites concentrations were further estimated via the Bayesian Benchmark Dose Analysis System (BBMD) to reflect the safety threshold of exposure in pregnant women. The corresponding daily intake (DI) of BMDL was then calculated and compared with the current oral reference dose (RfD). Results: A total of 309 mother-newborn pairs were included in this study. Gestational bis (2-butoxyethyl) phosphate (BBOEP) exposure was associated with higher total triiodothyronine (TT3), free triiodothyronine (FT3), total thyroxine (TT4), and free thyroxine (FT4) in cord plasma, while bis(1,3-dichloro-2-propyl) phosphate (BDCPP) was observed to be associated with lower TT3 and FT3/FT4 but higher thyroid stimulating hormone (TSH). In addition, sex-specific effects were observed for bis (2-chloroethyl) phosphate (BCEP), which was associated with lower TT3 in cord plasma of female newborns, and lower TT4 and FT4 in male newborns. Similar results were obtained through QGC model and BBOEP was identified as the main contributor to the higher levels of TT3 and FT3. With benchmark response (BMR) of 10% and background response (P0) of 97.5% for both TT3 and FT3, the BMDL10 of urine BBOEP concentration was 0.50 mu g/L. Further, the corresponding DI of tris (2-butoxyethyl) phosphate (TBOEP), which is the precursor of BBOEP, was 2.53 mu g/kg BW/d. Conclusions: Our findings suggest associations between gestational exposure to OPEs and altered THs biomarkers. According to the estimated BMD10 (BMDL10) of BBOEP and the corresponding DI, the current RfD of 15 mu g/kg BW/d for TBOEP may not protect pregnant women and their newborns from thyroid disruption.

Gemcitabine resistance drives bladder cancer recurrence and progression. Using high-throughput drug screening in bladder cancer cells, we identified Bavachalcone (Bava) as a potent gemcitabine sensitizer. Mechanistically, Bava simultaneously targets transferrin receptor (TFRC) and epidermal growth factor receptor (EGFR). It competes with transferrin (Tf) for TFRC binding, reducing cellular iron influx, and inhibits EGFR-mediated phosphorylation of TFRC at tyrosine 20 (Y20). These actions disrupt mitochondria iron utilization and impairs respiration. The combination of Bava and gemcitabine synergistically inhibits the repair of gemcitabine-induced DNA damage, while suppressing the iron-dependent ATR-CHEK1-E2F1 pathway and downregulating RRM1 expression. Patient-derived xenograft models confirmed the superior antitumor efficacy of the Bava-gemcitabine co-treatment compared to monotherapies. Clinically, elevated TFRC and RRM1 expression correlates with poor prognosis, supporting their utility as biomarkers of bladder cancer. Our study identified Bava as the first small-molecule TFRC inhibitor that overcomes gemcitabine resistance through iron modulation, providing both mechanistic insights and a promising therapeutic strategy for bladder cancer.

Prenatal bisphenols (BPs) exposure may affect infant growth, but the underlying mechanisms remain unclear. Based on Shanghai-Minhang Birth Cohort Study, we examined associations of prenatal BPs exposure with cord blood lipidomics and further explored whether lipid profile alterations mediate the associations between BPs and infant growth. We measured 6 BPs in late-pregnancy maternal urine and infant anthropometry at birth, 6, and 12 months. Cord blood lipid metabolites were measured through lipidomics, including fatty acyls (FA), sterol lipids (SL), and glycerophospholipids (GP). Principal components (PCAs) of FA, SL, and GP metabolites were extracted as FA1-3, SL1, and GP1-3, respectively. Multiple linear regression models showed that BPA, BPF, BPS, and BPAF were associated with decreased concentrations of FA, SL, and several GP metabolites (mainly representing GP1), but increased other GP metabolites (mainly representing GP2), while TCBPA showed opposite patterns. Mediation analysis showed that metabolites in arachidonic acid and phosphatidylinositol metabolism pathways mediated the associations between BPA, BPF, BPS and increased infants' skinfold thickness, with proportions ranging from 18.15 % to 32.47 %. Our findings provide novel evidence that prenatal BPs exposure may disrupt fetal lipid metabolism and highlight the role of arachidonic acid and phosphatidylinositol metabolism in effects of BPs exposure on infant growth.