Clonal expansion of shared T cell receptors reveals the existence of immune commonality among different lesions of synchronous multiple primary lung cancer.

The increase in the detection rate of synchronous multiple primary lung cancer (MPLC) has posed remarkable clinical challenges due to the limited understanding of its pathogenesis and molecular features. Here, comprehensive comparisons of genomic and immunologic features between MPLC and solitary lung cancer nodule (SN), as well as different lesions of the same patient, were performed. Compared with SN, MPLC displayed a lower rate of EGFR mutation but higher rates of BRAF, MAP2K1, and MTOR mutation, which function exactly in the upstream and downstream of the same signaling pathway. Considerable heterogeneity in T cell receptor (TCR) repertoire exists among not only different patients but also among different lesions of the same patient. Invasive lesions of MPLC exhibited significantly higher TCR diversity and lower TCR expansion than those of SN. Intriguingly, different lesions of the same patient always shared a certain proportion of TCR clonotypes. Significant clonal expansion could be observed in shared TCR clonotypes, particularly in those existing in all lesions of the same patient. In conclusion, this study provided evidences of the distinctive mutational landscape, activation of oncogenic signaling pathways, and TCR repertoire in MPLC as compared with SN. The significant clonal expansion of shared TCR clonotypes demonstrated the existence of immune commonality among different lesions of the same patient and shed new light on the individually tailored precision therapy for MPLC.

Alterations in sperm DNA methylation may as a mediator of paternal air pollution exposure and offspring birth outcomes: Insight from a birth cohort study.

Paternal exposure to environmental risk factors influences the offspring health. This study aimed to evaluate the association between paternal air pollution exposure mediated by sperm DNA methylation and adverse birth outcomes in offspring. We recruited 1607 fertile men and their partners from 2014 to 2016 and collected semen samples to detect sperm DNA methylation. Multivariate linear regression and weighted quantile sum regression models were used to assess the associations between paternal air pollution exposure and offspring birth outcomes. A critical exposure window was identified. Reduced representation bisulfite sequencing was used to detect sperm DNA methylation. The results demonstrated that high paternal exposure to PM2.5 (ß = -211.31, 95% CI: (-386.37, -36.24)), PM10 (ß = -178.20, 95% CI: (-277.13, -79.27)), and NO2 (ß = -84.22, 95% CI: (-165.86, -2.57)) was negatively associated with offspring's birthweight, especially in boys. Additionally, an early exposure window of 15-69 days before fertilization was recognized to be the key exposure window, which increased the risk of low birth weight and small for gestational age. Furthermore, paternal co-exposure to six air pollutants contributed to lower birthweight (ß = -51.91, 95% CI: (-92.72, -11.10)) and shorter gestational age (ß = -1.72, 95% CI: (-3.26, -0.17)) and PM2.5 was the most weighted pollutant. Paternal air pollution exposure resulted in 10,328 differentially methylated regions and the IGF2R gene was the key gene involved in the epigenetic process. These differentially methylated genes were predominantly associated with protein binding, transcriptional regulation, and DNA templating. These findings indicate that spermatogenesis is a susceptible window during which paternal exposure to air pollution affects sperm DNA methylation and the birth outcomes of offspring.

Evaluation of multiple organophosphate insecticide exposure in relation to altered thyroid hormones in NHANES 2007-2008 adult population.

The thyroid gland is susceptible to chemical exposure such as organophosphate insecticides (OPIs). With the ubiquitous nature of these products, humans are simultaneously exposed to a multitude of chemicals. This study aimed to evaluate the association between an individual and a mixture of OPI metabolites and changes in serum thyroid hormone (TH) concentrations. The analyzed data were 1,434 participants from the United States National Health and Nutrition Examination Surveys (NHANES) cycle 2007-2008. Generalized linear model (GLM) regression, weighted quantile sum (WQS), and adaptive least absolute shrinkage and selection operator (adaptive LASSO) regression were used to investigate the associations between urinary OPI metabolites and altered serum THs. In GLM, all of the five urinary OPI metabolites were inversely associated with free triiodothyronine (FT3) among the male subjects; meanwhile, higher thyroglobulin (Tg) was related to dimethylphosphate (DMP). Moreover, in WQS models, the metabolite mixture induced FT3 down-regulation (ß = -0.209 (95% CI: -0.310, -0.114)), and caused an increased Tg concentration (ß = 0.120 (95% CI: 0.024, 0.212)), however, any significant association was observed among female participants. Consistently, the weighted index and LASSO coefficient demonstrated dimethylthiophosphate (DMTP) as the strongest metabolite in the FT3 model (mean weight= 3.449e-01 and ß =-0.022, respectively), and dimethylphosphate (DMP) represented the highest association in the Tg model (mean weight= 9.873e-01 and ß =-0.020, respectively). Further research is required to confirm our results and investigate the clinical impacts of these disruptions.

Maternal Exposure to Trace Elements, Toxic Metals, and Longitudinal Changes in Infancy Anthropometry and Growth Trajectories: A Prospective Cohort Study.

Exploration of stage-specific effects of maternal exposure to trace elements and toxic metals on infancy continuous growth and trajectories is critical for early-life health management. Within a Chinese prospective cohort in 2014-2015, a total of 919 mother-infant pairs were included, and the urinary levels of 17 elements including vanadium (V), chromium (Cr), manganese, iron, cobalt, nickel, copper, zinc, arsenic, molybdenum, palladium, cadmium, tin, gold, mercury, thallium, and lead in early (mean: 11.9 weeks), and late pregnancy (mean: 32.4 weeks) were assessed. Standardized anthropometric assessments of infants were conducted at 1, 3, 6, 8, and 12 months of age. A three-step longitudinal and high-dimensional data analysis procedure was carried out to estimate the impacts of exposome on dynamic growth. Early-pregnancy exposures to V and Cr were positively associated with repeated measurements of length-for-age z-scores (LAZ). Six trajectories were identified based on LAZ. Maternal single exposure to V and Cr as well as mixed exposure to trace elements in early pregnancy were associated with raised odds for the high-stable group. Our results suggested positive associations between maternal trace element exposome and infancy dynamic growth. V and Cr were the key elements and the early pregnancy might be the critical window.

Association of Endocrine-Disrupting Chemicals with All-Cause and Cause-Specific Mortality in the U.S.: A Prospective Cohort Study.

Wide exposure to endocrine-disrupting chemicals (EDCs) poses a great risk on human health. However, few large-scale cohort studies have comprehensively estimated the association between EDCs exposure and mortality risk. This study aimed to investigate the association of urinary EDCs exposure with mortality risk and quantify attributable mortality and economic loss. Multivariable Cox proportional hazards regression models were performed to investigate the association of 38 representative EDCs exposure with mortality risk in the National Health and Nutrition Examination Survey (NHANES). During a median follow-up of 7.7 years, 47,279 individuals were enrolled. All-cause mortality was positively associated with 1-hydroxynaphthalene, 2-hydroxynaphthalene, cadmium, antimony, cobalt, and monobenzyl phthalate. Cancer mortality was positively associated with cadmium. Cardiovascular disease (CVD) mortality was positively associated with 1-hydroxynaphthalene, 2-hydroxynaphthalene, and 2-hydroxyfluorene. Nonlinear U-shaped relationships were found between all-cause mortality and cadmium and cobalt, which was also identified between 2-hydroxyfluorene and CVD mortality. J-shaped association of cadmium exposure with cancer mortality was also determined. EDCs exposure may cause 56.52% of total deaths (1,528,500 deaths) and around 1,897 billion USD in economic costs. Exposure to certain phthalates, polycyclic aromatic hydrocarbons, phytoestrogens, or toxic metals, even at substantially low levels, is significantly associated with mortality and induces high economic costs.

Geographical variation in the effect of ambient temperature on infectious diarrhea among children under 5 years.

Understanding the geographical distribution in the association of temperature with childhood diarrhea can assist in formulating effective localized diarrhea prevention practices. This study aimed to identify the geographical variation in terms of temperature thresholds, lag effects, and attributable fraction (AF) in the effects of ambient temperature on Class C Other Infectious Diarrhea (OID) among children <5 years in Jiangsu Province, China. Daily data of OID cases and meteorological variables from 2015 to 2019 were collected. City-specific minimum morbidity temperature (MMT), increasing risk temperature (IRT), maximum risk temperature (MRT), maximum risk lag day (MRD), and lag day duration (LDD) were identified as risk indicators for the temperature-OID relationship using distributed lag non-linear models. The AF of OID incidence due to temperature was evaluated. Multivariable regression was also applied to explore the underlying modifiers of the AF. The geographical distributions of MMT, IRT, and MRT generally decreased with the latitude increment varying between 22.3-34.7 °C, -2.9-18.1 °C, and -6.8-23.2 °C. Considerable variation was shown in the AF ranging from 0.2 to 8.5%, and the AF significantly increased with latitude (95% confidence interval (CI): -3.458, -0.987) and economic status decrement (95% CI: -0.161, -0.019). Our study demonstrated between-city variations in the association of temperature with OID, which should be considered in the localized clinical and public health practices to decrease the incidence of childhood diarrhea.

The effect of ambient ozone exposure on three types of diabetes: a meta-analysis.

BACKGROUND: Ozone as an air pollutant is gradually becoming a threat to people's health. However, the effect of ozone exposure on risk of developing diabetes, a fast-growing global metabolic disease, remains controversial. OBJECTIVE: To evaluate the impact of ambient ozone exposure on the incidence rate of type 1, type 2 and gestational diabetes mellitus. METHOD: We systematically searched PubMed, Web of Science, and Cochrane Library databases before July 9, 2022, to determine relevant literature. Data were extracted after quality evaluation according to the Newcastle Ottawa Scale (NOS) and the agency for healthcare research and quality (AHRQ) standards, and a meta-analysis was used to evaluate the correlation between ozone exposure and type 1 diabetes mellitus (T1D), type 2 diabetes mellitus (T2D), and gestational diabetes mellitus (GDM). The heterogeneity test, sensitivity analysis, and publication bias were performed using Stata 16.0. RESULTS: Our search identified 667 studies from three databases, 19 of which were included in our analysis after removing duplicate and ineligible studies. Among the remaining studies, three were on T1D, five were on T2D, and eleven were on GDM. The result showed that ozone exposure was positively correlated with T2D [effect size (ES) = 1.06, 95% CI: 1.02, 1.11] and GDM [pooled odds ratio (OR) = 1.01, 95% CI: 1.00, 1.03]. Subgroup analysis demonstrated that ozone exposure in the first trimester of pregnancy might raise the risk of GDM. However, no significant association was observed between ozone exposure and T1D. CONCLUSION: Long-term exposure to ozone may increase the risk of T2D, and daily ozone exposure during pregnancy was a hazard factor for developing GDM. Decreasing ambient ozone pollution may reduce the burden of both diseases.

Preimplantation triclosan exposure alters uterine receptivity through affecting tight junction protein†.

Triclosan is a broad-spectrum antibacterial agent and widely exists in environmental media and organisms. Triclosan exposure has been reported to have adverse effects on reproduction including embryo implantation disorder. During the embryo implantation window, it is vital that the endometrium develops into a receptive state under the influence of ovarian hormones. However, the effect of triclosan on embryo implantation and endometrial receptivity remains unclear. In the current study, we found a decreased embryo implantation rate, serum estrogen, and progesterone levels in mice exposed to triclosan from gestation days 0.5 to 5.5. Through RNA sequencing (RNA-seq), we identified nearly 800 differentially expressed genes, which were enriched in various pathways, including uterus development, inflammatory response, and immune system processes. Among those enriched pathways, the tight junction pathway is essential for the establishment of the receptive state of the endometrium. Then, genes involved in the tight junction pathway, including Cldn7, Cldn10, and Crb3, were validated by quantitative real-time polymerase chain reaction and the results were consistent with those from RNA-seq. Through immunofluorescence staining and western blotting, we confirmed that the tight junction protein levels of CLDN7 and CRB3 were increased. All these findings suggest that preimplantation triclosan exposure reduces the rate of embryo implantation through upregulating the expression of the tight junction genes and affecting the receptivity of the endometrium. Our data could be used to determine the sensitive time frame for triclosan exposure and offer a new strategy to prevent implantation failure.

Associations between antenatal corticosteroid exposure and neurodevelopment in infants.

BACKGROUND: It has been well recognized that antenatal administration of dexamethasone to pregnant women at risk of preterm delivery may markedly accelerate fetal maturation and reduce the risk of adverse perinatal outcomes in their preterm infants, particularly for births before 34 weeks of gestation. Since 2015, antenatal corticosteroid administration has been extended beyond 34 weeks of gestation by clinical guidelines, as it might have beneficial effects on fetal maturation and perinatal outcomes. However, concerns regarding the potential influence of antenatal corticosteroid treatment on offspring neurodevelopment have been raised. OBJECTIVE: This study aimed to investigate whether maternal antenatal corticosteroid administration was associated with neurodevelopment in infants at 1 year of age. STUDY DESIGN: In this prospective and longitudinal birth cohort study, women were followed up throughout gestation, and their infants underwent a Bayley Scales of Infant and Toddler Development, Third Edition, screening test at 1 year of age between December 2018 and September 2020. Finally, 1609 pregnant women and 1759 infants were included in the current study. Using a generalized linear mixed model, we examined the association between antenatal corticosteroid exposure and infant neurodevelopment in cognitive, receptive communication, expressive communication, fine motor, and gross motor functions. RESULTS: Of the 1759 infants eligible for this study, 1453 (82.6%) were singletons. A total of 710 infants were exposed to antenatal corticosteroids, among whom 415 were dexamethasone exposed and 483 were prednisone exposed. Dexamethasone was prescribed most often in late pregnancy, whereas prednisone was often used before 8 weeks of gestation among women who conceived through assisted reproductive technology. Compared with those who had no exposure, antenatal corticosteroid exposure was associated with an increased risk of infants being noncompetent in the cognitive development domain after adjusting for conventional risk factors (adjusted risk ratio, 1.53; 95% confidence interval, 1.08-2.18; P=.017). For medication-specific exposure, those exposed vs not exposed to antenatal dexamethasone were 1.62-fold (95% confidence interval, 1.10-2.38; P=.014) more likely to be noncompetent in the cognitive development domain at 1 year. The association did not vary markedly between preterm and term infants, singletons and twins, or assisted reproductive technology-conceived and spontaneously conceived infants (all P>.05 for heterogeneity). In contrast, a null association was observed for the risk of being noncompetent in any domain of neurodevelopment with antenatal prednisone exposure at early pregnancy. CONCLUSION: Here, antenatal corticosteroid, particularly dexamethasone exposure, was markedly associated with an increased risk of infants being noncompetent in the cognitive development domain at 1 year of age. These findings may provide new information when weighing the benefits and potential risks of maternal antenatal corticosteroid administration.

Association between ambient particulate matter exposure and semen quality in fertile men.

BACKGROUND: Several studies have suggested adverse effects of particulate matter (PM) exposure on male reproductive health; few have investigated the association between PM exposure and semen quality in a large population of fertile men. METHODS: We evaluated 14 parameters of semen quality in 1554 fertile men in Nanjing from 2014 to 2016. Individual exposure to particular matter ≤10 µm in diameter (PM10) and ≤ 2.5 µm in diameter (PM2.5) during key periods of sperm development (0-90, 0-9, 10-14, 15-69, and 70-90 days before semen collection) were estimated by inverse distance weighting interpolation. Associations between PM exposure and semen quality were estimated using multivariable linear regression. RESULTS: Higher 90-days average PM2.5 was in association with decreased sperm motility (2.21% for total motility, 1.93% for progressive motility per 10 µg/m3 increase, P <  0.001) and four quantitative aspects of sperm motion (curvilinear velocity (VCL), straight line velocity (VSL), average path velocity (VAP), and amplitude of lateral head displacement (ALH), P <  0.01). The association between PM2.5 exposure and semen quality were generally stronger for the earlier exposure window (70-90 days prior to ejaculation) than for recent exposure (0-9, 10-14, or 15-69 days). In the subgroup of men who had normal sperm parameters (n = 1019), similar results were obtained. Ninety-days PM10 exposure was associated only with decreased VCL and VAP and was not related to sperm concentration. CONCLUSIONS: Exposure to PM2.5 adversely affects semen quality, specifically lower sperm motility, in fertile men.

Human X chromosome exome sequencing identifies BCORL1 as contributor to spermatogenesis.

BACKGROUND: Infertility affects approximately 15% of couples worldwide with male infertility being responsible for approximately 50% of cases. Although accumulating evidence demonstrates the critical role of the X chromosome in spermatogenesis during the last few decades, the expression patterns and potential impact of the X chromosome, together with X linked genes, on male infertility are less well understood. METHODS: We performed X chromosome exome sequencing followed by a two-stage independent population validation in 1333 non-obstructive azoospermia cases and 1141 healthy controls to identify variant classes with high likelihood of pathogenicity. To explore the functions of these candidate genes in spermatogenesis, we first knocked down these candidate genes individually in mouse spermatogonial stem cells (SSCs) using short interfering RNA oligonucleotides and then generated candidate genes knockout mice by CRISPR-Cas9 system. RESULTS: Four low-frequency variants were identified in four genes (BCORL1, MAP7D3, ARMCX4 and H2BFWT) associated with male infertility. Functional studies of the mouse SSCs revealed that knocking down Bcorl1 or Mtap7d3 could inhibit SSCs self-renewal and knocking down Armcx4 could repress SSCs differentiation in vitro. Using CRISPR-Cas9 system, Bcorl1 and Mtap7d3 knockout mice were generated. Excitingly, Bcorl1 knockout mice were infertile with impaired spermatogenesis. Moreover, Bcorl1 knockout mice exhibited impaired sperm motility and sperm cells displayed abnormal mitochondrial structure. CONCLUSION: Our data indicate that the X-linked genes are associated with male infertility and involved in regulating SSCs, which provides a new insight into the role of X-linked genes in spermatogenesis.

Prothioconazole induces cell cycle arrest by up-regulation of EIF4EBP1 in extravillous trophoblast cells.

Prothioconazole (PTC) is a new broad-spectrum triazole antibacterial agent that is being widely used in agriculture. PTC has been linked to a number of reproductive outcomes including embryo implantation disorder; however, the exact mechanism underlying this relationship has yet to be determined. Proper trophoblast proliferation and migration is a prerequisite for successful embryo implantation. To elucidate the underlying molecular perturbations, we detect the effect of PTC on extravillous trophoblast cells proliferation and migration, and investigate its potential mechanisms. Exposure to different concentrations of PTC (0-500 µM) significantly inhibited the cell viability and migration ability (5 µM PTC exposure), and also caused the cell cycle arrest at the lowest dose (1 µM PTC exposure). Transcriptome analysis revealed that PTC exposure disturbed multiple biological processes including cell cycle and apoptosis, consistent with cell phenotype. Specifically, eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1, 4E-BP1) was identified as up-regulated in PTC exposure group and knockdown of EIF4EBP1, and attenuated the G1 phase arrest induced by PTC exposure. In summary, our data demonstrated that 4E-BP1 participated in PTC-induced cell cycle arrest in extravillous trophoblast cells by regulating cyclin D1. These findings shed light on the potential adverse effect of PTC exposure on the embryo implantation.

Estimating the effects of policies on infertility prevalence worldwide.

BACKGROUND: Infertility has troubled millions of people worldwide while always being an ignored issue. The high cost of treatment or lack of services placed a barrier to the alleviation of infertility status. Governments play a significant role to promote infertility-related policies for better access to infertility services and comprehensive supports for infertile people. METHODS: Data of infertility status indicators and infertility-related policies in ten representative countries were collected. An infertility-related policy system was established, then classification and quantification were processed according to specific criteria, and different policy implementation patterns were identified. The effectiveness of specific infertility-related policy and various patterns on infertility prevalence relief between 1990 and 2017 were evaluated via generalized linear models and analyses of covariance for the first time. RESULTS: Economic support policies would be less prioritized compared with social security policies, while economic support policy had a significant positive role in the decline of female infertility prevalence (ß = -2·16, p = 0·042). In detail, insurance coverage and economic reward policies were crucial (ß = -3·31, p = 0·031; ß = -4·10, p = 0·025) with adjusted with covariates. The effect of economic support-oriented pattern was relatively better than other patterns for both male and female infertility prevalence relief. Nevertheless, the effectiveness of gradual-promotion pattern seemed preferable for male infertility prevalence relief while was similar with simultaneous-promotion pattern for females. CONCLUSIONS: Our data-driven analysis revealed that insurance coverage and economic reward policies played the pivotal role in moderation of female infertility status. Economic support-oriented pattern and gradual-promotion pattern were preferable when promoting infertility-related policies.

Gender difference in hepatic AMPK pathway activated lipid metabolism induced by aged polystyrene microplastics exposure.

Microplastics (MPs) pollution becomes an increasing concern and researchers keep exploring the health effects caused by MPs exposure. The ageing process in the environment significantly alters the physicochemical characteristics of MPs and subsequently affects their toxicities. The health effects of aged MPs exposure and the mechanism underlying are worthy of exploration. Polystyrene microplastics (PS-MPs) (with size less than 50 µm) were obtained by grinding and screening polystyrene materials. PS-MPs continued to be aged by ozone treatment (0.4 mg/min, 9 h). Both male and female C57BL/6 mice were orally exposed to 0 or 2 mg/kg/d aged PS-MPs for 28 days. Results showed that PS-MPs were found in liver, ovary and spleen of females and liver, testis and spleen of males in the aged PS-MPs group. Exposure to aged PS-MPs significantly decreased abdominal fat/body coefficient, the adipocyte size and the serum LDL-C level in females. Compared to the control, serum estradiol (E2) level, the mRNA expression levels of genes regulating E2 production (17ß-hsd, 3ß-hsd and Star) in ovary and the protein expression levels of E2 receptors (ERα, ERß), AMPKα and p-AMPKα1 in liver increased significantly, and the mRNA expression levels of AMP-activated protein kinase (AMPK) downstream genes (Srebp-1c, Fas and Scd1) in liver decreased significantly in the female aged PS-MPs group. Liver metabolomic profiling showed that differential metabolites between female aged PS-MPs group and female control group were enriched in biotin metabolism and the level of biotin increased significantly in the female aged PS-MPs group. However, no significant changes were detected in males. These results indicated that aged PS-MPs exposure increased ovarian E2 production and activated the AMPK pathway in the liver which might inhibit liver lipid synthesis only in females. Our findings provide new insights into the potential sex-specific health effects of environmental MPs pollution.

Association between triclosan exposure and obesity measures among 7-year-old children in northern China.

BACKGROUND: Triclosan (TCS) is a widely used synthetic antibacterial compound with ubiquitous human exposure. Animal studies have suggested the obesogenic effect of TCS exposure, but knowledge regarding its impacts on childhood obesity was limited. OBJECTIVE: To investigate the associations of TCS exposure with childhood obesity in northern China. METHODS: This study included 423 children who participated in the 7-year-old follow-up visits of Laizhou Wan Birth Cohort in Shandong, northern China. Children's TCS exposure were determined in spot urine samples via high performance liquid chromatography-tandem mass. Their height, weight, waist circumference, body fat percentage, body mass index (BMI), and waist-to-height ratio (WHtR) were measured or calculated. BMI z-score ≥ 85th percentile was defined as overweight/obesity, and WHtR ≥ 0.5 was considered to be abdominal obesity. Multivariable linear regressions, generalized linear models (GLMs), and multivariable logistic regressions were performed to examine the associations between TCS exposure and obesity measures in children. RESULTS: Linear regressions showed that TCS concentrations, when treated as continuous variables, were positively associated with BMI z-score (ß = 0.12, 95% CI: 0.01, 0.24) and body fat percentage (ß = 0.82, 95% CI: 0.13, 1.52). When TCS concentrations were categorized as a four-level ordinal variable, the results of GLMs were similar those of continuous variables and both of the positive trends were significant (p-trend = 0.049 for BMI z-score; p-trend = 0.023 for body fat percentage). Moreover, the higher TCS levels versus reference group were associated with an approximate 2-3 fold increased risk of abdominal obesity (p-trend = 0.044). CONCLUSION: Exposure to TCS was positively associated with obesity measures among 7-year-old children in northern, China. Given to the cross-sectional study design, a large prospective study is warranted to confirm our findings.

Chemical mixture exposure patterns and obesity among U.S. adults in NHANES 2005-2012.

BACKGROUND: The effect of chemical exposure on obesity has raised great concerns. Real-world chemical exposure always imposes mixture impacts, however their exposure patterns and the corresponding associations with obesity have not been fully evaluated. OBJECTIVES: To discover obesity-related mixed chemical exposure patterns in the general U.S. METHODS: Sparse Decompositional Regression (SDR), a model adapted from sparse representation learning technique, was developed to identify exposure patterns of chemical mixtures with exclusion (non-targeted model) and inclusion (targeted model) of health outcomes. We assessed the relationships between the identified chemical mixture patterns and obesity-related indexes. We also conducted a comprehensive evaluation of this SDR model by comparing to the existing models, including generalized linear regression model (GLM), principal component analysis (PCA), and Bayesian kernel machine regression (BKMR). RESULTS: Eight core exposure patterns were identified using the non-targeted SDR model. Patterns of high levels of MEP, high levels of naphthalene metabolites (ΣOH-Nap), and a pattern of high exposure levels of MCOP, MCNP, and MCPP were positively associated with obesity. Patterns of high levels of BP3, and a pattern of higher mixed levels of MPB, PPB, and MEP were found to have negative associations. Associations were strengthened using the targeted SDR model. In the single chemical analysis by GLM, BP3, MBP, PPB, MCOP, and MCNP showed significant associations with obesity or body indexes. The SDR model exceeded the performance of PCA in pattern identification. Both SDR and BKMR identified a positive contribution of ΣOH-Nap and MCOP, as well as a negative contribution of BP3 and PPB to obesity. CONCLUSION: Our study identified five core exposure patterns of chemical mixtures significantly associated with obesity using the newly developed SDR model. The SDR model could open a new avenue for assessing health effects of environmental mixture contaminants.

A metabolomic study on the effect of prenatal exposure to Benzophenone-3 on spontaneous fetal loss in mice.

Benzophenone-3 (BP-3) is widely used in a variety of cosmetics and is prevalent in drinking water or food, and women were under notable high exposure burden of BP-3. Reports show the associations between prenatal exposure to BP-3 and the risk of fetal loss, but its underlying mechanism remains largely unknown. Pregnant ICR mice were gavaged with BP-3 from gestational day (GD) 0 to GD 6 at doses of 0.1, 10 and 1000 mg/kg/day. The samples were collected on GD 12. Ultra-performance liquid chromatography coupled with mass spectrometry-based metabolomics was used to detect metabolome changes in fetal mice, the uterus and the placenta to identify the underlying mechanism. The results showed that the body weight and relative organ weights of the liver, brain and uterus of pregnant mice were not significantly changed between the control group and the treatment group. BP-3 increased fetal loss, and induced placental thrombosis and tissue necrosis with enhancement of platelet aggregation. Metabolomic analysis revealed that fructose and mannose metabolism, the TCA cycle, arginine and proline metabolism in the fetus, arginine and proline metabolism and biotin metabolism in the uterus, and arginine biosynthesis and pyrimidine metabolism in the placenta were the key changed pathways involved in the above changes. Our study indicates that exposure to BP-3 can induce placental thrombosis and fetal loss via the disruption of maternal and fetal metabolism in mice, providing novel insights into the influence of BP-3 toxicity on the female reproductive system.

Gestational diabetes mellitus is associated with the neonatal gut microbiota and metabolome.

BACKGROUND: Gestational diabetes mellitus (GDM) is a metabolic disease that occurs in pregnant women and increases the risk for the development of diabetes. The relationship between GDM and meconium microbiota and metabolome remains incompletely understood. METHODS: Four hundred eighteen mothers (147 women with GDM and 271 normal pregnant women) and their neonates from the GDM Mother and Child Study were included in this study. Meconium microbiota were profiled by 16S rRNA gene sequencing. Meconium and maternal serum metabolome were examined by UPLC-QE. RESULTS: Microbial communities in meconium were significantly altered in neonates from the GDM mothers. A reduction in alpha diversity was observed in neonates of GDM mothers. At the phylum level, the abundance of Firmicutes and Proteobacteria changed significantly in neonates of GDM mothers. Metabolomic analysis of meconium showed that metabolic pathways including taurine and hypotaurine metabolism, pyrimidine metabolism, beta-alanine metabolism, and bile acid biosynthesis were altered in GDM subjects. Several changed metabolites varying by the similar trend across the maternal serum and neonatal meconium were observed. CONCLUSION: Altogether, these findings suggest that GDM could alter the serum metabolome and is associated with the neonatal meconium microbiota and metabolome, highlighting the importance of maternal factors on early-life metabolism.

Immunity and coagulation and fibrinolytic processes may reduce the risk of severe illness in pregnant women with coronavirus disease 2019.

BACKGROUND: There are specific physiological features regarding the immunity and coagulation among pregnant women, which may play important roles in the development of coronavirus disease 2019. OBJECTIVE: This study aimed to determine the key factors associated with the deterioration of patients with coronavirus disease 2019 and the differentiating clinical characteristics of pregnant women with coronavirus disease 2019 to interfere with the progression of coronavirus disease 2019. STUDY DESIGN: A retrospective study of 539 Chinese Han adult patients with coronavirus disease 2019 was conducted, of which 36 cases were pregnant women. In addition, 36 pregnant women without coronavirus disease 2019 were recruited as the control. The characteristics of severe and critical illnesses, which were differentiated from mild and moderate illnesses in patients with coronavirus disease 2019, were analyzed using a machine learning algorithm. In addition, major differences between pregnant women with coronavirus disease 2019 and age-matched nonpregnant women with severe or critical coronavirus disease 2019, paired with pregnant women without coronavirus disease 2019, were explored to identify specific physiological features of pregnant women with coronavirus disease 2019. RESULTS: For the total patient population, the lymphocyte, CD3+, CD4+, CD8+, CD19+, and CD16+CD56+ cell counts were significantly lower, and white blood cell count, neutrophil count, and neutrophil-to-lymphocyte ratio were higher in those with severe or critical illness than those with mild or moderate illness (P<.001). The plasma levels of interleukin-6, interleukin-10, and interleukin-6-to-interleukin-10 ratio were significantly increased in patients with critical illness compared with patients with mild, moderate, and severe illnesses (P<.001). The above immunologic coclusters achieved an area under the receiver operating characteristic curve of 0.801 (95% confidence interval, 0.764-0.838), and its combined model with the coagulation and fibrinolysis indices (prothrombin time, D-dimer) achieved an area under the receiver operating characteristic curve of 0.815 (95% confidence interval, 0.779-0.851) using the random forest regression model to predict severe or critical illness. For pregnant women with coronavirus disease 2019, none had preexisting diseases. Compared with nonpregnant women with mild or moderate coronavirus disease 2019, pregnant women with coronavirus disease 2019 displayed increased white blood cell count, neutrophil count, neutrophil-to-lymphocyte ratio, and levels of D-dimer and fibrinogen, along with decreased lymphocyte and interleukin-4 levels (P<.05). Although they presented similar changes of immunologic markers of lymphocyte; white blood cell count; neutrophil-to-lymphocyte ratio; CD3+, CD4+, CD8+, and CD16+CD56+ cell counts; and interleukin-6-to-interleukin-10 ratio, compared with nonpregnant women with severe or critical coronavirus disease 2019, none of the pregnant women with coronavirus disease 2019 deteriorated into severe or critical illness. There was no significant difference in white blood cell count, lymphocyte count, neutrophil count, neutrophil-to-lymphocyte ratio, immunologic markers, or coagulation and fibrinolysis markers between pregnant women with coronavirus disease 2019 and pregnant women without coronavirus disease 2019. As for the discrepancy of pathophysiological features between pregnant women with coronavirus disease 2019 and nonpregnant women with severe or critical coronavirus disease 2019, the immunologic markers achieved an area under the receiver operating characteristic curve of 0.875 (95% confidence interval, 0.773-0.977), and its combined model with coagulation and fibrinolysis indices achieved an area under the receiver operating characteristic curve of 0.931 (95% confidence interval, 0.850-1.000). CONCLUSION: Immune dysregulation was identified as a crucial feature of patients with coronavirus disease 2019, which developed severe or critical illness, and pregnant women with coronavirus disease 2019 presented with similar immune responses but rarer incidences of severe or critical illness. Immune dysregulation is related to the risks of deterioration into severe or critical illness. The specific coagulation and fibrinolysis systems of pregnancy may reduce the risk of pregnant women with coronavirus disease 2019 without preexisting disease from developing severe illness.

Differences of blood cells, lymphocyte subsets and cytokines in COVID-19 patients with different clinical stages: a network meta-analysis.

BACKGROUND: Due to the rapid spread of coronavirus disease 2019 (COVID-19) worldwide, it is necessary to ascertain essential immune inflammatory parameters that describe the severity of the disease and provide guidance for treatment. We performed network meta-analyses to determine differences in blood cells, lymphocyte subsets, and cytokines in COVID-19 patients with different clinical stages. METHODS: Databases were systematically searched to May 2, 2020, and updated on June 1, 2020. Network meta-analyses were conducted via Stata 15.0, and the mean difference (MD) and its 95% CI were used as the effect values of the pooled analysis. RESULTS: Seventy-one studies were included involving 8647 COVID-19 patients, White blood cell (WBC), neutrophil (NEUT), IL-6, and IL-10 counts increased significantly with worsening of the COVID-19, while lymphocyte (LYM) counts decreased. The levels of platelet (PLT), CD3+, CD4+, CD8+, and CD19+ cells in severe and critical patients were significantly lower than those in mild patients. IL-1ß count was significantly elevated in critical patients. CONCLUSIONS: Immune suppression and inflammatory injury play crucial roles in the progression of COVID-19, and the identification of susceptible cells and cytokines provide guidance for the early and accurate treatment of COVID-19 patients.