Profiles and transplacental transfer of per- and polyfluoroalkyl substances in maternal and umbilical cord blood: A birth cohort study in Zhoushan, Zhejiang Province, China.

Per- and polyfluoroalkyl substances (PFAS) can pass through the placental barrier and pose health risks to fetuses. However, exposure and transplacental transfer patterns of emerging PFAS remain unclear. Here, 24 PFAS were measured in paired maternal whole blood (n = 228), umbilical cord whole blood (n = 119) and serum (n = 120). Orthogonal partial least-squares discriminant analysis (OPLS-DA) was used to differentiate PFAS between different matrices. The transplacental transfer (TPT) of PFAS was calculated using cord to maternal whole blood concentration ratios. PFOS and PFOA were still the dominant PFAS in maternal samples. The emerging PFAS had higher TPT than PFOS and PFOA. Moreover, PFAS with the same chain length but different functional groups and C-F bonds showed different TPT, such as PFOS and PFOSA (C8, median: 0.090 vs. 0.305, p < 0.05) and PFHxS and 4:2 FTS (C6, median: 0.220 vs. 1.190, p < 0.05). A significant sex difference in 4:2 FTS (median: boys 1.250, girls 1.010, p < 0.05) were found. Furthermore, we observed a significant U-shaped trend for the TPT of carboxylates with increasing carbon chain length. PFAS showed a compound-specific transfer through placental barrier and a compound-specific distribution between different matrices in this study.

Engineered probiotics introduced to improve intestinal microecology for the treatment of chronic diseases: present state and perspectives.

Purpose: Correcting intestinal microecological imbalance has become one of the core strategies to treat chronic diseases. Some traditional microecology-based therapies targeting intestine, such as prebiotic therapy, probiotic therapy and fecal microbiota transplantation therapy, have been used in the prevention and treatment of clinical chronic diseases, which still facing low safety and poor controllability problems. The development of synthetic biology technology has promoted the development of intestinal microecology-based therapeutics for chronic diseases, which exhibiting higher robustness and controllability, and become an important part of the next generation of microecological therapy. The purpose of this review is to summarize the application of synthetic biology in intestinal microecology-based therapeutics for chronic diseases. Methods: The available literatures were searched to find out experimental studies and relevant review articles on the application of synthetic biology in intestinal microecology-based therapeutics for chronic diseases from year 1990 to 2023. Results: Evidence proposed that synthetic biology has been applied in the intestinal microecology-based therapeutics for chronic diseases, covering metabolic diseases (e.g. diabetes, obesity, nonalcoholic fatty liver disease and phenylketonuria), digestive diseases (e.g. inflammatory bowel disease and colorectal cancer), and neurodegenerative diseases (e.g. Alzheimer's disease and Parkinson's disease). Conclusion: This review summarizes the application of synthetic biology in intestinal microecology-based therapeutics for major chronic diseases and discusses the opportunities and challenges in the above process, providing clinical possibilities of synthetic biology technology applied in microecological therapies.

PM2.5-bound metals and blood metals are associated with pulmonary function and Th17/Treg imbalance: A panel study of asthmatic adults.

Growing research has demonstrated that exposure to fine particulate matter (PM2.5) was associated with decreased pulmonary function and obvious inflammatory response. However, few pieces of research focus on the effects of PM2.5-bound metals on people with asthma. Here, we assessed whether PM2.5 and PM2.5-bound metals exposure could worsen pulmonary function in asthmatic patients and further elucidate the possible mechanisms. Thirty-four asthmatic patients were recruited to follow up for one year with eight visits in 2019-2020 in Taiyuan City, China. The index of pulmonary function was detected and blood and nasal epithelial lining fluid (ELF) samples were acquired for biomarkers measurement at each follow-up. Linear mixed-effect (LME) models were used to evaluate the relations between PM2.5, PM2.5-bound metals, and blood metals with lung function and biomarkers of Th17/Treg balance. The individual PM2.5 exposure concentration varied from 37 µg/m3 to 194 µg/m3 (mean: 59.63 µg/m3) in the present study. An interquartile range (IQR) increment of PM2.5 total mass was associated with a faster decline in maximal mid-expiratory flow (MMEF) and higher interleukin-23 (IL-23). PM2.5-bound metals [e.g. copper (Cu), nickel (Ni), manganese (Mn), titanium (Ti), and zinc (Zn)] were significantly associated with IL-23 (Cu: 5.1126%, 95% CI: 9.3708, 0.8544; Mn: 14.7212%, 95% CI: 27.926, 1.5164; Ni: 1.0269%, 95% CI: 2.0273, 0.0264; Ti: 16.7536%, 95% CI: 31.6203, 1.8869; Zn: 24.5806%, 95% CI: 46.609, 2.5522). Meanwhile, blood lead (Pb) and Cu were associated with significant declines of 0.382-3.895% in MMEF and maximum ventilatory volume (MVV). Blood Pb was associated with descending transforming growth factor ß (TGF-ß). In conclusion, exposure to PM2.5-bound metals and blood metals is a risk factor for decreased pulmonary function, especially in small airways. These alterations might be partially attributed to the imbalance of Th17/Treg.

Metabolic biomarkers linking urinary arsenic species to gestational diabetes mellitus: A cross-sectional study in Chinese pregnant women.

Environmental arsenic (As) exposure has been associated with gestational diabetes mellitus (GDM) risk. Our recent study found that GDM was positively associated with urinary As3+ level while negatively correlated to As5+. However, the mechanisms underlying the association between arsenic species and GDM remain largely unknown. In the present study, through the measurement of urinary arsenic species and metabolome analysis in 399 pregnant women, we aimed to identify the metabolic biomarkers that may link arsenic exposure to GDM based on a novel systems epidemiology strategy termed meet-in-metabolite-analysis (MIMA). The metabolomics analysis revealed that 20 and 16 urinary metabolites were relevant to arsenic exposure and GDM, respectively. Among them, 12 metabolites were identified to be both arsenic- and GDM-related, which are mainly involved in purine metabolism, one­carbon metabolism (OCM) and glycometabolism. Moreover, it was further showed that the regulation of thiosulfate (AOR: 2.52; 95 % CI: 1.33, 4.77) and phosphoroselenoic acid (AOR: 2.35; 95 % CI: 1.31, 4.22) could significantly contribute to the negative association between As5+ and GDM. Considering the biological functions of these metabolites, it is suggested that As5+ may reduce GDM risk by disturbing OCM in the pregnant women. These data will provide novel insights into the mechanism of action of environmental arsenic exposure on GDM incidence from the aspect of metabolism disorder.

Association of urinary metal levels with metabolic syndrome in coal workers.

Studies have indicated that metal exposure is associated with an increased risk of metabolic syndrome (MetS). However, it is unclear whether overexposure to heavy metals occurs in miners and is associated with MetS risk remains unclear. In a cross-sectional study, analysis for metal exposure levels of 3428 participants from three types of workplaces was conducted. Relationships between metals in urine and MetS were characterized using a multivariate binary logistic regression model and restricted cubic spline analysis. The association between urinary metals and workplaces with respect to MetS was studied via mediation analysis and multiplicative interaction analysis. And a sensitivity analysis was performed to assess the robustness of the association between MetS and urinary metals in participants without obesity (n = 2811). Zn, Cu, Fe, Co, and Ni were found to be associated with MetS in the single-metal models, whereas only Zn and Cu showed considerable associations in the multimetal model. The odds ratios (95% CI) for MetS in the highest quartiles were 2.089 (1.611, 2.707) for urinary Zn and 1.394 (1.084, 1.794) for urinary Cu (both false discovery rate for both was < 0.05). Urinary Zn and Cu were positively associated with hypertriglyceridemia. In addition, higher Zn exposure was confirmed in underground workers than ground workers and office workers, and there was a significant association between urinary metal exposure and workplace, which together influenced the occurrence of MetS. These results provided scientific evidence for the relationship between Zn, Cu, workplaces, and MetS in coal workers and indicated that it is critical to reduce occupational metal exposure, especially in underground workers.

The role of reactive astrocytes in neurotoxicity induced by ultrafine particulate matter.

Epidemiological studies have shown that ambient fine particulate matter (PM) can cause various neurodegenerative diseases, including Alzheimer's disease. Reactive astrocytes are strongly induced by ambient fine PM, although their role is poorly understood. Herein, we show that A1 reactive astrocytes (A1s) were induced by neuroinflammatory microglia activated by PM with an aerodynamic diameter ≤ 0.2 µm (PM0.2). The activated-microglia induced A1s by secreting interleukin-1α, tumor necrosis factor-α, and complement 1q, and these cytokines acting together were necessary and sufficient to induce A1s. PM0.2-induced A1s could promote synaptic damage in neurons by secreting complement 3 (C3). SB 290157, a highly selective C3aR nonpeptide antagonist, partially ameliorated glial conditioned medium-induced synaptic injury. In vitro synaptic damage was partially prevented when A1 formation was blocked by minocycline. Finally, this study showed that N-acetyl-L-cysteine ameliorated PM0.2-induced neural damage independent of A1 differentiation. Collectively, these findings explain why central nervous system neurons suffer synaptic damage and neuroinflammation after PM0.2 exposure and suggest that this exposure induces A1s to contribute to synaptic damage of neurons. This study indicates a potential approach for developing improved treatment of these diseases induced by particulate exposure. SYNOPSIS: PM0.2-activated neuroinflammatory microglia induced A1 reactive astrocytes (A1s) by secreting IL-1α, TNF-α, and C1q. PM0.2-induced A1s could promote synaptic damage of neuron by secreting complement 3.

Arsenic metabolism, N6AMT1 and AS3MT single nucleotide polymorphisms, and their interaction on gestational diabetes mellitus in Chinese pregnant women.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in N6AMT1 and AS3MT are associated with arsenic (As) metabolism, and efficient As methylation capacity has been associated with diabetes. However, little is known about the gene-As interaction on gestational diabetes mellitus (GDM). OBJECTIVE: This study aimed to explore the individual and combined effects of N6AMT1 and AS3MT SNPs with As metabolism on GDM. METHODS: A cross-sectional study was performed among 385 Chinese pregnant women (86 GDM and 299 Non-GDM). Four SNPs in N6AMT1 (rs1997605 and rs1003671) and AS3MT (rs1046778 and rs11191453) were genotyped. Urinary inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were determined, and the percentages of As species (iAs%, MMA%, and DMA%) were calculated to assess the efficiency of As metabolism. RESULTS: Pregnant women with N6AMT1 rs1997605 AA genotype had lower iAs% (B: 2.11; 95% CI: 4.08, -0.13) and MMA% (B: 0.21; 95% CI: 0.39, -0.04) than pregnant women with GG genotype. The AS3MT rs1046778 and rs11191453 C alleles were negatively associated with iAs% and MMA% but positively associated with DMA%. Higher urinary MMA% was significantly associated with a lower risk of GDM (OR: 0.54; 95% CI: 0.30, 0.97). The A allele in N6AMT1 rs1997605 (OR: 0.46; 95% CI: 0.26, 0.79) was associated with a decreased risk of GDM. The additive interactions between N6AMT1 rs1997605 GG genotypes and lower iAs% (AP: 0.50; 95% CI: 0.01, 0.99) or higher DMA% (AP: 0.52; 95% CI: 0.04, 0.99) were statistically significant. Similar additive interactions were also found between N6AMT1 rs1003671 GG genotypes and lower iAs% or higher DMA%. CONCLUSIONS: Genetic variants in N6AMT1 and efficient As metabolism (indicated by lower iAs% and higher DMA%) can interact to influence GDM occurrence synergistically in Chinese pregnant women.

Characteristics and pollution risks of potentially toxic elements and nematode community structure on farm soil near coal mines.

As one of the most important coal-producing provinces of China, Shanxi Province has been concerned about soil potentially toxic elements (PTEs) contamination in recent years. The study aimed to determine the status and sources of PTEs contamination and evaluate the quality of the soil ecology. This study investigated the degree of 13 PTEs contamination. The sources and contributions of PTEs were traced by the absolute principal component score followed by a multiple linear regression model (APCS-MLR). And the status of the soil ecosystem was verified by evaluating the soil nematode community around the coal mining areas in Jinzhong. The results showed that the mean PTEs concentration of 5 trace elements were higher than the background values of Shanxi, and safe to considerable was indicated by the pollution and ecological risk values. Soil Hg was the most contaminated element, followed by Cd. The distribution of PTEs was determined by coal mining activities (44.72%) followed by agricultural practice (32.37%) and coal transportation (21.37%). The nematode genera Acrobeloides (4.01%), Aphelenchus (20.30%), Meloidogyne (11.95%) and Aporcelaimus (2.74%) could be regarded as bioindicators of soil PTEs contamination by their tolerance. Concentrations of soil Cr, Mn, Ti and Cd showed remarkable influences on the total nematode abundance, maturity index, enrichment index, structural index, Shannon-Wiener diversity index and Pielou index of soil nematode. It is an appropriate method to evaluate the status of soil PTEs contamination combining the response of a single nematode genus and the nematode community evaluation index.

Association between exposure to perfluoroalkyl substances and uric acid in Chinese adults.

BACKGROUND: A growing body of evidence suggests the deleterious effects of perfluoroalkyl substances (PFASs) on kidney, but little is known on the association between PFASs joint exposure and uric acid. METHODS: Serum PFASs concentrations were measured in 661 participants recruited from Tianjin, China using liquid chromatography/mass spectrometry. The associations of single PFASs exposure with uric acid levels and hyperuricemia were assessed using multivariable linear and logistic regression models, respectively. Restricted cubic spline models were established to investigate the dose-response relationships between PFASs concentrations and uric acid levels. Bayesian Kernel Machine Regression (BKMR) model with a hierarchical variable selection was performed to assess the joint effect of PFASs on uric acid. RESULTS: Potassium perfluoro-1-octanesulfonate (PFOS) and perfluoro-n-octanoic acid (PFOA) were the dominated contributors with median concentrations of 16.80 ng/ml and 9.42 ng/ml, respectively. Increased PFOA concentration (per log2-unit) was associated with elevated uric acid level (ß = 0.088, 95% CI: 0.033-0.143) and higher risk of hyperuricemia (OR = 1.134, 95% CI: 1.006-1.289). Conversely, the estimated change of uric acid associated with log2-unit increment in perfluoro-n-decanoic acid (PFDA) was -0.081 mg/dL (95% CI: -0.154, -0.009). A significant linear dose-response pattern was found between log2-transformed PFOA concentration and uric acid level. BKMR analyses indicated a non-significant overall effect of PFASs mixture on uric acid. CONCLUSIONS: Significant associations between PFOA and PFDA and uric acid, and between PFOA and hyperuricemia were found in the single-pollutant models, but the joint effect of PFASs mixture on uric acid was not observed in the BKMR model, which provided new insights in regulation policies and risk assessment of PFASs.

Heavy metal contamination assessment and probabilistic health risks in soil and maize near coal mines.

Objective: Coal mining activities have continuously introduced heavy metals into the soil-crop system, causing increasing damage to crops. This study integrated the analysis of the heavy metal contamination status and human health risk in soil and maize near coal mines to help formulate control strategies for soil quality, maize production, and safe consumption. Method: This study was carried out on maize agricultural land near a coal mining plant. Heavy metal contamination was assessed by the geo-accumulation index (Igeo), enrichment factor (EF), and bioaccumulation factor (BCF). The Monte Carlo simulation was used to estimate the probabilistic health risk of heavy metals exposure in soil and maize. The relationship between the concentration of heavy metal in the soil and that in maize was further visualized by correlation analysis and random forest analysis. Results: The results revealed that the mean concentrations of soil Ni, Cu, As, Cd, Sn, Zn, Pb, and Hg were all above the local background level. Ni was the most severely polluted heavy metal in maize and had a concentration higher than the risk control standard for corn in China (NY 861-2004). The Igeo values of all heavy metals were low, and EF values showed enrichment in V, Cr, Ti, Ni, and As. The assessment of probabilistic health risk exposed by heavy metals in soil and maize indicated that 1.16 and 1.46% of residents exceeded the carcinogenic risk level due to heavy metal exposure from soil and maize, respectively. Children were the most sensitive to maize and soil heavy metal exposure in the contaminated area. Ingestion of heavy metals was associated with the highest health risk to residents, followed by dermal contact and inhalation. As and Cr in soil and Cr and Ni in maize had the greatest impact on human health risk. Furthermore, maize heavy metals were affected the most by soil Cr, Cd, and V. Conclusion: These results may provide useful information for human carcinogenic risk associated with soil and maize heavy metal exposure due to coal mining activities.

Optimization and application of a method to determine 24 perfluorinated compounds in umbilical cord serum by using liquid chromatography tandem mass spectrometry.

Perfluorinated compounds (PFCs) are a group of widely used synthetic chemicals. Owing to their unique chemical properties, PFCs can accumulate in the environment and living organisms. In vitro and in vivo studies have demonstrated the adverse effects of exposure to PFCs, resulting in increased concern. Therefore, a fast, reliable analytical method is crucial for human biomonitoring and health risk assessment. This study used two isotope internal standards to identify and quantify 24 PFCs in umbilical cord serum samples, based on classical liquid-liquid extraction (LLE) with liquid chromatography tandem mass spectrometry (LC-MS/MS). According to our review of the literature, this study is the first to determine the TFHSA, S4hPDS, S4hPOS, S4hPHS, SPHeS, SPNoS, and SPPeS by using this developed method. The average spiked recoveries of 24 PFCs were acceptable, ranging from approximately 64.0% to 124%; RSDs ranged from 0.74% to 11.2%; LOD and LOQ ranged from 0.013 to 0.248 µg/L and from 0.030 to 0.747 µg/L, respectively. This method was applied to measure the PFCs in umbilical cord serum samples; 24 PFCs were detected in the investigated samples, which are comparable to those reported in the literature. TFHSA, S4hPDS, S4hPOS, S4hPHS, SPHeS, SPNoS, and SPPeS were also detected in the samples, which should be investigated in further research. The sensitivity, accuracy, and precision of the developed method are sufficient for its application in large-scale biomonitoring studies.

Associations of environmental phthalate exposure with male steroid hormone synthesis and metabolism: An integrated epidemiology and toxicology study.

Humans are simultaneously and constantly exposed to various lipophilic chain phthalate acid esters. The association of urinary phthalate metabolites with altered male steroid hormone synthesis and metabolism was examined using epidemiology and toxicology studies. We measured 8 phthalate metabolites [monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), mono-benzyl phthalate (MBzP), mono-n-octylphthalate (MOP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono (2-ethyl-5-oxohexyl) phthalate (MEOHP)] and two sex hormones [testosterone (T) and estradiol (E2)] in single serum and repeated spot urine samples among 451 reproductive-age males. Moreover, in vitro experiments with Leydig cell MLTC-1 steroidogenesis and liver cell HepG2 efflux in response to mixed and individual phthalates were designed to simulate real-world scenarios of human exposure. As a joint mixture, the phthalate metabolite was inversely associated with serum T and E2 concentrations but positively associated with urinary T and E2 concentrations. Combined with in vitro experiments, DEHP metabolites were identified as the predominant contributor to the decline in hormone synthesis, and ATP-binding cassette (ABC) gene activation might be involved in hormone excretion. Exposure to environmentally relevant phthalates was associated with both altered steroid synthesis and excretion, which provides additional insights into the endocrine-disrupting potential of phthalates.

Chronic low-level perfluorooctane sulfonate (PFOS) exposure promotes testicular steroidogenesis through enhanced histone acetylation.

Perfluorooctane sulfonate (PFOS), an artificial perfluorinated compound, has been associated with male reproductive disorders. Histone modifications are important epigenetic mediators; however, the impact of PFOS exposure on testicular steroidogenesis through histone modification regulations remains to be elucidated. In this study, we examined the roles of histone modifications in regulating steroid hormone production in male rats chronically exposed to low-level PFOS. The results indicate that PFOS exposure significantly up-regulated the expressions of StAR, CYP11A1 and 3ß-HSD, while CYP17A1 and 17ß-HSD were down-regulated, thus contributing to the elevated progesterone and testosterone levels. Furthermore, PFOS significantly increased the histones H3K9me2, H3K9ac and H3K18ac while reduced H3K9me3 in rat testis. It is known that histone modifications are closely involved in gene transcription. Therefore, to investigate the association between histone modifications and steroidogenic gene regulation, the levels of these histone marks were further measured in steroidogenic gene promoter regions by ChIP. It was found that H3K18ac was augmented in Cyp11a1 promoter, and H3K9ac was increased in Hsd3b after PFOS exposure, which is proposed to result in the activation of CYP11A1 and 3ß-HSD, respectively. To sum up, chronic low-level PFOS exposure activated key steroidogenic gene expression through enhancing histone acetylation (H3K9ac and H3K18ac), ultimately stimulating steroid hormone biosynthesis in rat testis.

Joint effect of urinary arsenic species and serum one-carbon metabolism nutrients on gestational diabetes mellitus: A cross-sectional study of Chinese pregnant women.

BACKGROUND: Growing evidence indicates that arsenic (As) exposure can increase the risk of gestational diabetes mellitus (GDM). However, little is known about As species and GDM and the combined effect of As and one-carbon metabolism (OCM) on GDM. OBJECTIVES: We aimed to examine the associations between As species and GDM and evaluate the potential interactions of folate, vitamin B12, and homocysteine (Hcy) with As species on GDM prevalence. METHOD: We measured levels of arsenite (As3+), arsenate (As5+), dimethylarsinic acid (DMA), and arsenobetaine (AsB) species in urine and folate, vitamin B12, and Hcy in serum from 396 pregnant women in Tianjin, China. The diagnosis of GDM was based on an oral glucose tolerance test. Associations of As species in urine with GDM were evaluated using generalized linear models (GLMs) and Bayesian kernel machine regression (BKMR). Additive interactions of As and OCM with GDM were estimated by determining the relative excess risk due to interaction (RERI). RESULTS: Of the 396 pregnant women, 89 were diagnosed with GDM. Continuous increases in urinary inorganic As were associated with GDM in the GLMs, with adjusted odds ratios of 2.12 (95% CI: 0.96, 4.71) for As3+, and 0.27 (95% CI: 0.07, 0.98) for As5+. The BKMR in estimating the exposure-response functions showed that As3+ and AsB were positively associated with GDM. However, As5+ showed a negative relationship with GDM. Although the additive interactions between As exposure and OCM indicators were not significant, we found that pregnant women with higher urinary As3+ and total As accompanied by lower serum vitamin B12 were more likely to have higher odds of GDM (3.12, 95% CI: 1.32, 7.38 and 3.10, 95% CI: 1.30, 7.38, respectively). CONCLUSIONS: Our data suggest a positive relation between As3+ and GDM but a negative relation between As5+ and GDM. Potential additive interaction of As and OCM with GDM requires further investigation.

Dynamic recovery after acute single fine particulate matter exposure in male mice: Effect on lipid deregulation and cardiovascular alterations.

Many studies have linked airborne fine particulate matter (PM2.5) exposure to cardiovascular diseases. We performed a time-series analysis to investigate whether the disruption of lipid metabolism recovered or lasted after acute PM2.5 exposure in mice. Targeted lipidomic analysis showed that four major plasma membrane phospholipids along with cholesterol esters (CE) were significantly altered on 7th post-exposure day (PED7), and the alteration reached a peak on PED14. On PED21, the phosphatidylcholine (PC) decrease was more marked than on PED14, and its resurgence was indirectly linked to triglyceride (TG) increase. Homocysteine (HCY), lactate dehydrogenase (LDH), and α-hydroxybutyrate dehydrogenase (α-HBDH) levels increased but glucose levels decreased markedly in a dose- and time-dependent manner throughout the experimental period. Network analysis showed that the lasting lipid deregulation on PED21 correlated to myocardial markers and glucose interruption, during which high-density lipoprotein cholesterol (HDL-C) decreased. The present data implied that the constructional membrane lipids were initially interrupted by PM2.5, and the subsequent rehabilitation resulted in the deregulation of storage lipids; the parallel myocardial and glucose effects may be enhanced by the lasting HDL-C lipid deregulation on PED21. These myocardial and lipidomic events were early indicators of cardiovascular risk, resulting from subsequent exposure to and accumulation of PM2.5.

Phthalate levels in urine of pregnant women and their associated missed abortion risk.

Phthalates are one of the most common environmental endocrine disrupting chemicals (EDCs) in human contact. Prenatal phthalates exposure may adversely affect intrauterine growth, however, little is known about their association. This study aimed to explore the impact of phthalates on the risk of missed abortion. A total of 123 women with missed abortion (cases) and 148 normal pregnant women (controls) were simultaneously collected from Taiyuan, China. Four urinary phthalate metabolites were determined by high-performance liquid chromatography (HPLC). Logistic regression model was used to estimate odds ratios (ORs) and 95 % confidence intervals (95 % CI) of missed abortion associated with phthalate metabolite levels. Four phthalate metabolites, including monomethyl phthalate (MMP), monoethyl phthalate (MEP), monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), were detected in at least 78.97 % of all participants, with the highest geometric mean concentration of 147.19 ng/mL for MEP of the urine samples. Both MMP (Z = -3.898, P < 0.001) and MBP (Z = -2.198, P = 0.028) concentrations were higher in cases than in controls. There were no significant differences for MEP (Z = -0.285, P = 0.076) and MBzP (Z = -0.878, P = 0.380) concentrations between cases and controls. Furthermore, Logistic analysis revealed that each one-unit increase in log-transformed MMP (OR = 1.49, 95 % CI = 1.14-1.95) was positively associated with missed abortion. Increasing risks of missed abortion were observed the third quartile (Q3) and the highest quartile (Q4) of MMP(OR = 2.21, 95 % CI = 1.06-4.60; OR = 2.85, 95 % CI = 1.34-6.05) compared to the lowest quartile (Q1) of MMP concentrations. We concluded that prenatal phthalates exposure may contribute to an increased risk of missed abortion.

Meet-in-metabolite analysis: A novel strategy to identify connections between arsenic exposure and male infertility.

BACKGROUND: Despite a trend in the use of systems epidemiology to fill the knowledge gap between risk-factor exposure and adverse outcomes in the OMICS data, such as the metabolome, seriously hindrances need to be overcome for identifying molecular connections. OBJECTIVES: Using male infertility phenotypes and arsenic exposure, we aimed to identify intermediate biomarkers that reflect both arsenic exposure and male infertility with a meet-in-metabolite analysis (MIMA). METHODS: Urinary arsenic levels and metabolome were measured by using inductively coupled plasma-mass spectrometry (ICP-MS) and HPLC-quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS), respectively. To identify arsenic-related metabolic markers (A-MIMA), the intermediate markers were profiled by orthogonal projections to latent structures (OPLS-DA). To detect infertility-related metabolic markers (I-MIMA), the intermediate markers were investigated by weighted gene co-expression network analysis. The key node markers, related to both A-MIMA and I-MIMA, were determined by O2PLS and defined as MIMA markers. Finally, network analysis was used to construct the MIMA-related metabolic network. RESULTS: Twelve markers each were defined through the significant associations with arsenic exposure (A-MIMA) and/or infertility (I-MIMA), respectively. Seven of them, including acetyl-N-formyl-5-methoxykynurenamine, carnitine, estrone, 2-oxo-4-methylthiobutanoic acid, malonic acid, valine, and LysoPC (10:0), were defined through the associations with both arsenic exposure and male infertility (MIMA markers). These intermediate markers were involved majorly in oxidative stress, one-carbon metabolism, steroid hormone homeostasis, and lipid metabolism pathways. The core correlation network analysis further highlighted that testosterone is a vital link between the effect of arsenic and male infertility. CONCLUSIONS: From arsenic exposure to male infertility, the arsenic methylation that coupled one-carbon metabolism disruption with oxidation stress may have extended its effect to fatty acid oxidation and steroidogenesis dysfunction. Testosterone is at the hub between arsenic exposure and male infertility modules and, along with the related metabolic pathways, may service as a potential surrogate marker in risk assessment for male dysfunction due to arsenic exposure.

Environmental doses of arsenic exposure are associated with increased reproductive-age male urinary hormone excretion and in vitro Leydig cell steroidogenesis.

Humans are ubiquitously exposed to arsenic from multiple sources, and chronic arsenic exposure may be associated with male reproductive health. Although association regarding arsenic exposure and sex hormone secretion in blood has been reported, sex hormone excretion in urine studies is lacking. Urinary sex hormone excretion has emerged as a complementary strategy to evaluate gonadal function. Herein, we determined the associations between environmental exposure to arsenic and urinary sex hormone elimination and in vitro Leydig cell steroidogenesis. Concentrations of arsenic and testosterone (T), estradiol (E2) and progesterone (P) in repeated urine samples were determined among 451 reproductive-age males. Moreover, an in vitro Leydig cell MLTC-1 steroidogenesis experiment was designed to simulate real-world scenarios of low human exposure. Multivariable linear regression models were used to assess the associations of urinary arsenic levels with urinary hormones. Urinary arsenic concentrations were positively associated with urinary sex hormone (T, E2, and P) levels. An in vitro test further demonstrated that a population-based environmental exposure range (0.01-5 µM) of arsenic induced Leydig cell steroidogenesis potency. Our results indicate that low-dose arsenic exposure exhibits an endocrine disrupting effect by stimulating Leydig cell steroidogenesis and accelerating urinary steroid excretion, which extends previous knowledge of the inverse association of high-dose arsenic exposure with sexual steroid production that is assumed to be anti-androgen.

Infantile phthalate metabolism and toxico/pharmacokinetic implications within the first year of life.

BACKGROUND: Infantile development of phthalate metabolism is crucial for risk assessment of endocrine disruption and has important toxico/pharmacokinetic implications. OBJECTIVES: To characterize temporal variability in urinary phthalate metabolites in infants and to examine their growth-dependent detoxification. METHODS: In this cohort study, urine samples (n = 876) from 155 healthy Chinese infants were collected serially at eight time points from birth to one year old. Free and total (i.e., free plus glucuronide conjugated) phthalate metabolites (PMEs) were measured by LC/MS/MS. Time variability in PMEs and PME metabolism capacity was characterized using intraclass correlation coefficients (ICCs) and linear mixed regression models. RESULTS: Concentrations of most PMEs changed significantly, with ICCs ranging from 0.213 to 0.318, and trends increased significantly over time (p < 0.001), while MEHP showed fair reproducibility (ICC = 0.480). Glucuronidation increased considerably (ICC ≤ 0.250; p < 0.001) for most PMEs but not for MMP or MEHP. Ester-chain ω-/ω-1-oxidation and α-/ß-oxidation patterns of MEHP steeply increased from 3 months to 8 months, where they peaked, resulting in a molar percentage of MEHP in ΣDEHP showing the inversion pattern. MEHP detoxification through oxidation of the hydrophobic ester-chain is apparently a priority for carboxyl glucuronidation in infants. CONCLUSIONS: Infant phthalate exposure is prevalent, but they cannot metabolize or eliminate these compounds as efficiently as adults, especially during the first 6 months of life. From an environmental biomonitoring view, age-dependent phthalate metabolism provides crucial implications for infantile ontogeny and health risk assessment within the first year of life.

Elevated bioaccumulation of PFAAs in Oryzias melastigma following the increase of salinity is associated with the up-regulated expression of PFAA-binding proteins.

Perfluoroalkyl acids (PFAAs) are widely detected in the environment, especially in estuarine and coastal areas where fluctuation of salinity occurs. Salinity alteration affected the distribution of PFAAs and even the bioaccumulation in organisms. However, the inner mechanism is still unclear. In this study, the marine medaka (Oryzias melastigma), a euryhaline fish model, was exposed to four PFAAs congeners under three different salinities (0, 15 and 35 psu). Results showed that the bioaccumulation of PFAAs increased in fish as the water salinity increased. PFAAs with longer lengths of carbon­fluorine bond showed higher bioaccumulation in the fish. Salinity did not alter the levels of PFAAs in water media, however, the uptake rate of PFAAs from gills did increase with the salinity. Further analysis of the mechanism showed that PFAA bound to branchial proteins as confirmed by fluorescence spectroscopy. Higher expressions of proteins binding to PFAAs including organic anion transporter 1 (OAT1) and fatty acid-binding protein (FABP) facilitated the uptake of PFAAs through gills in fish culturing under higher salinity. In all, our study showed that elevation of salinity can induce the expression of proteins binding to PFAAs in gills, thus facilitate the uptake of water PFAAs. Salinity fluctuation should be taken into consideration when assessing the chemical risk in the estuarine and coastal areas.