An early screening model for preeclampsia: utilizing zero-cost maternal predictors exclusively.

To provide a reliable, low-cost screening model for preeclampsia, this study developed an early screening model in a retrospective cohort (25,709 pregnancies) and validated in a validation cohort (1760 pregnancies). A data augmentation method (α-inverse weighted-GMM + RUS) was applied to a retrospective cohort before 10 machine learning models were simultaneously trained on augmented data, and the optimal model was chosen via sensitivity (at a false positive rate of 10%). The AdaBoost model, utilizing 16 predictors, was chosen as the final model, achieving a performance beyond acceptable with Area Under the Receiver Operating Characteristic Curve of 0.8008 and sensitivity of 0.5190. All predictors were derived from clinical characteristics, some of which were previously unreported (such as nausea and vomiting in pregnancy and menstrual cycle irregularity). Compared to previous studies, our model demonstrated superior performance, exhibiting at least a 50% improvement in sensitivity over checklist-based approaches, and a minimum of 28% increase over multivariable models that solely utilized maternal predictors. We validated an effective approach for preeclampsia early screening incorporating zero-cost predictors, which demonstrates superior performance in comparison to similar studies. We believe the application of the approach in combination with high performance approaches could substantially increase screening participation rate among pregnancies. Machine learning model for early preeclampsia screening, using 16 zero-cost predictors derived from clinical characteristics, was built on a 10-year Chinese cohort. The model outperforms similar research by at least 28%; validated on an independent cohort.

Identification of downstream targets and signaling pathways of long non-coding RNA NR_002794 in human trophoblast cells.

Preeclampsia (PE) is a huge threat to pregnant women. Our previous study demonstrated that long non-coding RNA (lncRNA) NR_002794 was highly expressed in placentas of PE patients and could regulate the phenotypes of trophoblast cells. However, the downstream regulatory mechanisms of NR_002794 remain unknown. In this text, some potential downstream targets or signaling pathways of NR_002794 were identified through RNA sequencing (RNA-seq) and bioinformatics analysis in SWAN71 trophoblast cells. Western blot assay demonstrated that NR_002794 inactivated protein kinase B (AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways and activated cell apoptotic signaling in SWAN71 cells. Both RNA-seq and reverse transcription-quantitative PCR (RT-qPCR) outcomes showed that NR_002794 up-regulation could notably inhibit the expression of C-C motif chemokine ligand 4 like 2 (CCL4L2), interleukin 15 receptor subunit alpha (IL15RA), interleukin 32 (IL32), and tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1), while NR_002794 knockdown induced these gene expressions in SWAN71 cells. CCK-8, BrdU, Transwell, wound healing, and flow cytometry analyses showed that NR_002794 inhibited cell proliferation and migration and induced cell apoptosis through down-regulating TIE1 in SWAN71 cells. In conclusion, lncRNA NR_002794 could exert its functions by regulating AKT and ERK1/2 pathways and TIE1 expression in human trophoblast cells.

Bioaccessibility and bioavailability adjusted dietary exposure of cadmium for local residents from a high-level environmental cadmium region.

The critical health risks caused by cadmium (Cd) via dietary exposure are commonly assessed by detecting Cd concentrations in foods. Differently, in this study, the bioaccessibility and bioavailability of Cd in major local harvests were introduced to assess the dietary exposure of local residents from a high-level environmental Cd region. The results indicated that certain Cd was released into the digestive juice after in vitro digestion with a bioaccessibility of 20-63% for rice and 3-32% for leafy vegetables, and the released portion was partially absorbed by Caco-2 cells with a bioavailability of 2-21% for rice and 0.2-13% for leafy vegetables. The results obtained from the toxicokinetic model revealed that the predicted urinary Cd values from the estimated daily intake (EDI) of Cd, which accounted for bioaccessibility and bioavailability, were consistent with the actual measured values, and the EDIs were considerably lower than the acceptable daily intake. This suggests that the bioaccessibility and bioavailability adjusted dietary Cd exposure should be more precise. The key issues addressed in our study implores that a potential health risk cannot be neglected in people with high consumption of rice from high-level zone.

Association of environmental cadmium exposure and bone remodeling in women over 50 years of age.

Chronic cadmium (Cd) toxicity is a significant health concern, and the mechanism of long-term low-dose Cd exposure on bone has not been fully elucidated yet. This study aimed to assess the association between long-term environmental Cd exposure and bone remodeling in women who aged over 50. A total of 278 non-smoking subjects from Cd-polluted group (n = 191) and non-Cd polluted group (n = 87) were investigated. Bone mineral density (BMD), the levels of three bone turnover markers (BTMs), including total procollagen type 1 amino-terminal propeptide (P1NP), collagen type 1 cross-linked C-telopeptide (ß-CTX), bone-specific alkaline phosphatase (BALP), together with serum soluble receptor activator of nuclear factor-κB ligand (sRANKL) and osteoprotegerin (OPG) were determined. Early markers of renal dysfunction were measured as well. Urinary Cd concentrations ranged from 0.41 to 87.31 µg/g creatinine, with a median of 4.91 µg/g creatinine. Age, BMD, T-score, and prevalence of osteoporosis showed no statistical differences among the quartiles of urinary Cd concentrations, while serum levels of P1NP, ß-CTX, and OPG were higher in the upper quartiles. Multivariate linear regression models indicated significantly positive associations of urinary Cd concentration with serum levels of P1NP, ß-CTX, BALP, sRANKL, and OPG. A ridge regression analysis with T-score and the three BTMs, sRANKL, and OPG, adjusted for age and body mass index (BMI), indicated that except for age and Cd exposure, ß-CTX was a predictor of T-score. These findings demonstrated that Cd may directly accelerate bone remodeling. Serum ß-CTX might be an appropriate biochemical marker for evaluating and monitoring Cd-related bone loss. Capsule: Cadmium (Cd) may directly accelerate bone remodeling and serum ß-CTX is a valuable biochemical marker for evaluating Cd-related bone loss.

AK002210 promotes the proliferation, migration and invasion of trophoblast cell through regulating miR-590/NAIP signal axis.

Preeclampsia (PE) is a pregnancy-related syndrome and has become the leading cause of maternal and neonatal morbidity and mortality. LncRNA has been elucidated to play critical roles in the phenotype of trophoblast cells. However, the effect of AK002210 has not been reported. We aim to investigate the effect of AK002210 on the phenotype of trophoblast cells. Quantitative reverse transcription PCR was used to assess the gene expression. CCK-8 assay was used to evaluate the cell proliferation. Transwell assay was performed to detect the migration and invasion of trophoblast cells. Luciferase assay and rescue experiment were carried out to verify the interaction between miR-590-3p and AK002210 as well as NLR family apoptosis inhibitory protein (NAIP). The results revealed that AK002210 promoted the proliferation, migration and invasion of trophoblast cell while AK002210 knockdown inhibited that. Mechanically, we found that AK002210 was targeted by miR-590-3p. Moreover, miR-590-3p also directly targets NAIP which served as a ceRNA of AK002210. Rescue experiment showed that miR-590-3p reversed the effect of AK002210 which further confirmed their interaction. Moreover, AK002210 was proved to participated in the regulation of ERK/MMP-2 signal axis. In conclusion, we found that AK002210 knockdown may play a critical role in the progression of PE via miR-590-3p/NAIP and ERK/MMP signaling. It has potential to be a novel prognostic or therapeutic marker of PE.

Long non­coding RNA NR_002794 is upregulated in pre­eclampsia and regulates the proliferation, apoptosis and invasion of trophoblast cells.

Pre­eclampsia is a common complication during pregnancy, characterized by hypertension and proteinuria. The pathogenesis of pre­eclampsia is not fully understood. Studies on the maternal spiral artery have led scientists to consider that the ineffective infiltration of placental trophoblast cells may be a primary cause of pre­eclampsia. The present study aimed to investigate the differences in the profiles of long non­coding RNAs (lncRNAs) between the placentas of patients with pre­eclampsia and those of healthy pregnant women. The involvement of the differentially expressed lncRNAs in the biological activity of trophoblast cells was also assessed. A total of 26 differentially expressed lncRNAs were identified between the pre­eclampsia and healthy groups. Upregulation of NR_002794 was found in tissues from patients with pre­eclampsia. In SWAN71 trophoblast cells, NR_002794 had suppressive effects on proliferation and migration, and resulted in an increased rate of apoptosis. Furthermore, lncRNA NR_002794 had no effect on the phagocytosis of trophoblast cells. The present study suggested that abnormal levels of NR_002794 may lead to atypical conditions in trophoblast cells, which may be associated with the failure of maternal spiral artery remodeling during pregnancy and, consequently, with the development of pre­eclampsia.

Prenatal Diagnosis of ß-thalassemia with Cell-free Fetal DNA in Maternal Plasma.

The aim of this study was to explore the feasibility of non-invasive prenatal genetic diagnosis of ß-thalassemia with small fragments of cell-free fetal DNA (cffDNA) in peripheral blood of pregnant women. It was an observational study carried out at Department of Obstetrics, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China, from January 2016 to March 2018. A total of 40 pregnant women, who were likely to give birth to babies with severe ß-thalassemia, were selected, and ß-globin genotype of the fetus was non-invasively detected by cffDNA in peripheral blood of their mothers. Small fragments of cffDNA from all specimens were successfully amplified. Compared with the results of traumatic prenatal diagnosis, 37 cases (92.50%) were diagnosed and 3 cases (7.50%) were misdiagnosed. The cffDNA in maternal plasma can be used for non-invasive prenatal genetic diagnosis of ß-thalassemia, and is worthy of promotion.

A Preliminary Investigation of Naturally Occurring Aluminum in Grains, Vegetables, and Fruits from Some Areas of China and Dietary Intake Assessment.

An investigation of the naturally occurring aluminum contents in grains, fruits and vegetables locally planted in some areas of China was conducted, and the aluminum dietary intake from the investigated food was estimated. A total of 2,469 samples were collected during 2013 to 2014 and tested for aluminum content using ICP-MS method. The results showed that although 77.6% of the samples contained aluminum less than 5 mg/kg, significant variations of aluminum contents were observed in different food groups. Generally, the aluminum contents were found to be relatively high in dried grains and fresh vegetables, and low in fresh fruits. The mean value of aluminum contents in grains was 6.3 mg/kg, with wheat being the highest, followed by soybean and corn. The fresh vegetables had an average aluminum content of 4.7 mg/kg, with leafy vegetables being the highest, followed by bulb and stem vegetables. Most varieties of fresh fruits were low in aluminum, with the mean of 1.3 mg/kg. Based on the food consumption data from the China National Nutrient and Health Survey, the average weekly dietary intake of naturally occurring aluminum from the investigated foods was estimated to be 0.62 mg/kg bw for the general population and 0.55 to 1.00 mg/kg bw for different age groups. Grains and vegetables were the main contributors to the overall intake. Evaluated against the provisional tolerable weekly intake (PTWI) of 2 mg/kg bw, the dietary naturally occurring aluminum intake from the investigated foods was considered to be no safety concern.

Cadmium Exposure and Osteoporosis: A Population-Based Study and Benchmark Dose Estimation in Southern China.

This study aimed to assess the association between osteoporosis and long-term environmental Cd exposure through diet in southern China. A total of 1116 subjects from a Cd-polluted area and a non-Cd-polluted area were investigated. All subjects met the criteria of having been living in the investigated area for more than 15 years and lived on a subsistence diet of rice and vegetables grown in that area. Besides bone mineral density, the levels of urinary markers of early renal impairment, such as urinary N-acetyl-ß-D-glucosaminidase (NAG), α1 -microglobulin, ß2 -microglobulin, and urinary albumin, were also determined. Urinary Cd concentrations of all studied subjects ranged from 0.21 to 87.31 µg/g creatinine, with a median of 3.97 µg/g creatinine. Multivariate linear regression models indicated a significant negative association of urinary Cd concentrations with bone mineral density. In logistic regression models, both categorical and continuous urinary Cd concentrations were positively associated with osteoporosis. Subjects in the second, third, and fourth quartiles of urinary Cd concentration had greater odds of osteoporosis compared with subjects in the first quartile (odds ratio [OR] = 3.07, 95% confidence interval [CI], 1.77 to 5.33; OR = 4.63, 95% CI, 2.68 to 7.98; OR = 9.15, 95% CI, 5.26 to 15.94, respectively). Additional adjustment for levels of urinary markers did not attenuate the associations. No evidence existed of an interaction between urinary Cd concentration and renal function using levels of urinary markers, and estimated glomerular filtration rate (eGFR). In all subjects, the benchmark dose and benchmark dose lower bound were 1.14 (0.61) and 2.73 (1.83) µg/g creatinine, with benchmark response set at 5% and 10%, respectively. The benchmark dose of urinary Cd was lower in women than in men. This study demonstrated an inverse association between the body burden of Cd and osteoporosis. The toxic effect of Cd on bone may occur in parallel to nephrotoxicity. © 2017 American Society for Bone and Mineral Research.

Urine metabolomics of women from small villages exposed to high environmental cadmium levels.

The present study aimed to identify urine metabolites in women exposed to high cadmium (Cd) levels. Twenty-one women exposed to environmental Cd and 12 age-matched controls were categorized as high exposure (urine Cd ≥ 15 µg/g creatinine; n = 9) or low exposure (15 µg/g creatinine > urine Cd > 5 µg/g creatinine; n = 12). Low-molecular weight metabolites in urine were analyzed by gas chromatography and mass spectrometry after derivatization. An orthogonal partial least-squares discriminant analysis model was constructed, and metabolites from the dimensional model were selected according to the variable importance in projection (>1). Metabolites differing significantly in abundance between different exposure groups were identified by searching mass spectral databases, and related pathways were analyzed using the Kyoto Encyclopedia of Genes and Genomes. Approximately 110 significantly different metabolites were detected with variable importance in projection > 1, and 48 of them were found to differ markedly in abundance among the 3 groups. Twenty-seven matched with known metabolites, including 22 significantly increased and 5 markedly decreased in the high-exposure group (p < 0.01). Kyoto Encyclopedia of Genes and Genomes results indicated that carbohydrate, amino acid, bone, and intestinal flora metabolism and the tricarboxylic acid cycle were affected by Cd exposure. The present study identified metabolites that differed in abundance in response to Cd exposure. Further studies may connect these biomarkers to early damage caused by Cd.

Associations between Urinary Excretion of Cadmium and Renal Biomarkers in Nonsmoking Females: A Cross-Sectional Study in Rural Areas of South China.

OBJECTIVES: The aim of this study was to systematically evaluate the relationship between urinary excretion of cadmium (U-Cd) and biomarkers of renal dysfunction. METHODS: One hundred eighty five non-smoking female farmers (aged from 44 to 71 years) were recruited from two rural areas with different cadmium levels of exposure in southern China. Morning spot urine samples were collected for detecting U-Cd, urinary creatinine (U-cre), ß2-microglobulin (ß2-MG), α1-microglobulin (α1-MG), metallothionein (MT), retinol binding protein (RBP), albumin (AB), N-acetyl-ß-D-glucosaminidase (NAG), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT) and kidney injury molecule-1 (KIM-1). Spearman's rank correlation was carried out to assess pairwise bivariate associations between continuous variables. Three different models of multiple linear regression (the cre-corrected, un-corrected and cre-adjusted model) were used to model the dose-response relationships between U-Cd and nine urine markers. RESULTS: Spearman's rank correlation showed that NAG, ALP, RBP, ß2-MG and MT were significantly associated with U-Cd for both cre-corrected and observed data. Generally, NAG correlated best with U-Cd among the nine biomarkers studied, followed by ALP and MT. In the un-corrected model and cre-adjusted model, the regression coefficients and R² of nine biomarkers were larger than the corresponding values in the cre-corrected model, indicating that the use of observed data was better for investigating the relationship between biomarkers and U-Cd than cre-corrected data. CONCLUSIONS: Our results suggest that NAG, MT and ALP in urine were better biomarkers for long-term environmental cadmium exposure assessment among the nine biomarkers studied. Further, data without normalization with creatinine show better relationships between cadmium exposure and renal dysfunction.

[Long-term effect of cadmium exposure on residents' renal dysfunction: An epidemiologic study].

OBJECTIVE: To study long-term effect on renal function exposed to environmental cadmium. METHODS: Stratified random sampling and cluster sampling method of epidemiological investigations were carried out in northern Guangdong province between April, 2011 and August, 2012. A total of 167 residents who lived in high cadmium exposure area for more than 15 years, aged above 40 were selected in exposed group. Moreover, A total of 145 residents who had similar living and economic conditions and lived in local for more than 15 years, aged above 40 were selected in control group. We used health questionnaires and medical examinations in order to acquire their health status. Home-harvested rice and vegetables were collected using quartering method for detection of cadmium level. Urine specimens of residents were collected for detection of cadmium level and creatinine as well as renal dysfunction biomarkers, namely, N-acetyl-beta-D-glucosamidase (NAG), ß2-microglobulin (ß2-MG), and retinol binding protein(RBP), respectively. The analysis of spearman rank correlation and multiple regression were used to investigate the relationships between age, urinary cadmium levels and renal injury biomarkers. RESULTS: The cadmium levels in rice and vegetables of exposed group were 0.75 and 0.10 mg/kg, both were significantly higher than 0.07 and 0.01 mg/kg in the control group (Z values were -6.32 and -7.84, all P values < 0.001). The urinary cadmium level of exposed group was 8.29 µg/g · cr, which was higher than that of the control group 2.03 µg/g · cr with significant difference (Z value was -11.39, P < 0.001). After stratified the total population by age, the urinary cadmium level in 40-49 years, 50-59 years and ≥ 60 years subgroups were 7.22, 8.71, and 13.10 µg/g · cr, which both were significantly higher than 1.80, 2.04, and 2.05 µg/g · cr in the control group (Z values were -5.22, -7.41, and -7.14, all P values < 0.001). After stratified the total population by gender, the urinary cadmium level of male and female were 5.12 and 12.36 µg/g · cr, which both were significantly higher than 1.79 and 2.16 µg/g · cr in the control group (Z values were -7.68 and -9.03, all P values < 0.001). Comparing the differences of renal dysfunction biomarkers (NAG, ß2-MG, RBP) between two groups. The level of urinary ß2-MG and RBP of exposed group were 0.21 and 0.04 µg/g · cr, which were higher than 0.05 and 0.00 µg/g · cr of the control group with significant difference (Z value was -7.08 and -9.65, all P values < 0.001). Pearson correlation analysis showed that NAG, ß2-MG and RBP were positively correlated with urinary cadmium and age, the correlation coefficients were 0.57, 0.49, 0.21 and 0.22, 0.26, 0.23 respectively (all P values < 0.001). After adjusting the effect of age, it was appeared that urinary cadmium levels contributed most to the alteration of NAG, ß2-MG and RBP, the standardized regression coefficients were 0.57, 0.49 and 0.20 (all P values < 0.001), and suggested that the cadmium body burden was one of the most important factors for renal dysfunction. CONCLUSION: Residents, who had cadmium contaminated rice and vegetables for a long time, would take the risk of increasing body burden of cadmium and urinary early biomarkers of renal tubular injury that referred to occurrence of renal dysfunction.

Identifying early urinary metabolic changes with long-term environmental exposure to cadmium by mass-spectrometry-based metabolomics.

Cadmium (Cd) is a common environmental pollutant, and urinary Cd (UCd) is generally used as a marker of exposure; however, our understanding on the related urinary metabolic changes caused by Cd exposure is still not clear. In this study, we applied a mass-spectrometry-based metabolomic approach to assess the urinary metabolic changes in human with long-term environmental Cd exposure, aimed to identify early biomarkers to assess Cd nephrotoxicity. Urine samples from 94 female never smokers aged 44-70 with UCd in the range of 0.20-68.67 µg/L were analyzed by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-ToF-MS) and gas chromatography-mass spectrometry (GC-MS). It was found that metabolites related to amino acid metabolism (L-glutamine, L-cystine, L-tyrosine, N-methyl-L-histidine, L-histidinol, taurine, phenylacetylglutamine, hippurate, and pyroglutamic acid), galactose metabolism (D-galactose and myo-inositol), purine metabolism (xanthine, urea, and deoxyadenosine monophosphate), creatine pathway (creatine and creatinine), and steroid hormone biosynthesis (17-α-hydroxyprogesterone, tetrahydrocortisone, estrone, and corticosterone) were significantly higher among those with a UCd level higher than 5 µg/L. Moreover, we noticed that the level of N-methyl-L-histidine had already started to elevate among individuals with a UCd concentration of ≥2 µg/L. The overall findings illustrate that metabolomics offer a useful approach for revealing metabolic changes as a result of Cd exposure.

Dietary exposure to aluminium of urban residents from cities in South China.

A dietary survey was conducted over three consecutive days by using 24-hour dietary recall in the Pearl River Delta of South China to investigate the dietary consumption status. A total of 1702 food samples, 22 food groups, were collected, and aluminium concentrations of foods were determined by using ICP-MS. Weekly dietary exposure to aluminium of the average urban residents of South China was estimated to be 1.5 mg kg⁻¹ body weight, which amounted to 76% of the provisional tolerable weekly intake. Wheat-made products (53.5%) contributed most to the dietary exposure, followed by vegetables (12.2%). The high-level consumers' weekly exposure to aluminium was 11.1 mg kg⁻¹ body weight, which amounted to 407% of the provisional tolerable weekly intake. The results indicated that the general urban residents in South China might be safe from aluminium exposure, but the high-level consumers might be at some risk of aluminium exposure. The foods contributing to aluminium exposure were processed food with aluminium-containing food additives. It is necessary to take effective measures to control the overuse of aluminium-containing food additives.