Using Machine Learning to Construct the Blood-Follicle Distribution Models of Various Trace Elements and Explore the Transport-Related Pathways with Multiomics Data.

Permeabilities of various trace elements (TEs) through the blood-follicle barrier (BFB) play an important role in oocyte development. However, it has not been comprehensively described as well as its involved biological pathways. Our study aimed to construct a blood-follicle distribution model of the concerned TEs and explore their related biological pathways. We finally included a total of 168 women from a cohort of in vitro fertilization-embryo transfer conducted in two reproductive centers in Beijing City and Shandong Province, China. The concentrations of 35 TEs in both serum and follicular fluid (FF) samples from the 168 women were measured, as well as the multiomics features of the metabolome, lipidome, and proteome in both plasma and FF samples. Multiomics features associated with the transfer efficiencies of TEs through the BFB were selected by using an elastic net model and further utilized for pathway analysis. Various machine learning (ML) models were built to predict the concentrations of TEs in FF. Overall, there are 21 TEs that exhibited three types of consistent BFB distribution characteristics between Beijing and Shandong centers. Among them, the concentrations of arsenic, manganese, nickel, tin, and bismuth in FF were higher than those in the serum with transfer efficiencies of 1.19-4.38, while a reverse trend was observed for the 15 TEs with transfer efficiencies of 0.076-0.905, e.g., mercury, germanium, selenium, antimony, and titanium. Lastly, cadmium was evenly distributed in the two compartments with transfer efficiencies of 0.998-1.056. Multiomics analysis showed that the enrichment of TEs was associated with the synthesis and action of steroid hormones and the glucose metabolism. Random forest model can provide the most accurate predictions of the concentrations of TEs in FF among the concerned ML models. In conclusion, the selective permeability through the BFB for various TEs may be significantly regulated by the steroid hormones and the glucose metabolism. Also, the concentrations of some TEs in FF can be well predicted by their serum levels with a random forest model.

Ascertaining sensitive exposure biomarkers of various metal(loid)s to embryo implantation.

Close relationships exist between metal(loid)s exposure and embryo implantation failure (EIF) from animal and epidemiological studies. However, there are still inconsistent results and lacking of sensitive metal(loid) exposure biomarkers associated with EIF risk. We aimed to ascertain sensitive metal(loid) biomarkers to EIF and provide potential biological explanations. Candidate metal(loid) biomarkers were measured in the female hair (FH), female serum (FS), and follicular fluid (FF) with various exposure time periods. An analytical framework was established by integrating epidemiological association results, comprehensive literature searching, and knowledge-based adverse outcome pathway (AOP) networks. The sensitive biomarkers of metal(loid)s along with potential biological pathways to EIF were identified in this framework. Among the concerned 272 candidates, 45 metal(loid)s biomarkers across six time periods and three biomatrix were initially identified by single-metal(loid) analyses. Two biomarkers with counterfactual results according to literature summary results were excluded, and a total of five biomarkers were further determined from 43 remained candidates in mixture models. Finally, four sensitive metal(loid) biomarkers were eventually assessed by overlapping AOP networks information, including Se and Co in FH, and Fe and Zn in FS. AOP networks also identified key GO pathways and proteins involved in regulation of oxygen species biosynthetic, cell proliferation, and inflammatory response. Partial dependence results revealed Fe in FS and Co in FH at their low levels might be potential sensitive exposure levels for EIF. Our study provided a typical framework to screen the crucial metal(loid) biomarkers and ascertain that Se and Co in FH, and Fe and Zn in FS played an important role in embryo implantation.

Cohort-based long-term ozone exposure-associated mortality risks with adjusted metrics: A systematic review and meta-analysis.

Long-term ozone (O3) exposure may lead to non-communicable diseases and increase mortality risk. However, cohort-based studies are relatively rare, and inconsistent exposure metrics impair the credibility of epidemiological evidence synthetization. To provide more accurate meta-estimations, this study updates existing systematic reviews by including recent studies and summarizing the quantitative associations between O3 exposure and cause-specific mortality risks, based on unified exposure metrics. Cross-metric conversion factors were estimated linearly by decadal observations during 1990-2019. The Hunter-Schmidt random-effects estimator was applied to pool the relative risks. A total of 25 studies involving 226,453,067 participants (14 unique cohorts covering 99,855,611 participants) were included in the systematic review. After linearly unifying the inconsistent O3 exposure metrics , the pooled relative risks associated with every 10 nmol mol-1 (ppbV) incremental O3 exposure, by mean of the warm-season daily maximum 8-h average metric, were as follows: 1.014 with 95% confidence interval (CI) ranging 1.009-1.019 for all-cause mortality; 1.025 (95% CI: 1.010-1.040) for respiratory mortality; 1.056 (95% CI: 1.029-1.084) for COPD mortality; 1.019 (95% CI: 1.004-1.035) for cardiovascular mortality; and 1.074 (95% CI: 1.054-1.093) for congestive heart failure mortality. Insignificant mortality risk associations were found for ischemic heart disease, cerebrovascular diseases, and lung cancer. Adjustment for exposure metrics laid a solid foundation for multi-study meta-analysis, and widening coverage of surface O3 observations is expected to strengthen the cross-metric conversion in the future. Ever-growing numbers of epidemiological studies supported the evidence for considerable cardiopulmonary hazards and all-cause mortality risks from long-term O3 exposure. However, evidence of long-term O3 exposure-associated health effects was still scarce, so more relevant studies are needed to cover more populations with regional diversity.

Exposome in human health: Utopia or wonderland?

The current human exposome primarily emphasizes the total environmental exposure during an entire life. The characteristics of "lifelong" and "all environmental factors" make it very challenging to bring the exposomic study into real-life applications. Herein, we mainly discuss the typical application scenarios of exposomics and how to conduct an exposomic study to establish relationships between the exposome and human health. To increase the feasibility and efficiency, we propose that (1) an exposomic study can start with health events during critical-window periods; (2) both data- and hypothesis-driven exposomics should be combined to prioritize the risk of environmental factors; and (3) reliable statistical analysis of high-dimensional data of external and internal exposure factors are urgently needed. With standardization of the exposomic study, it will be critical to build a "wonderland" for human health.

Risk of dietary intake of organochlorine pesticides among the childbearing-age women: A multiple follow-up study in North China.

Exposure to organochlorine pesticides (OCPs) can cause adverse health effects in the female population. We investigated the dietary OCP intake of childbearing-age women living in large agricultural areas of Northern China, as well as their associated health risks. Ten childbearing-age women were recruited during 2015-2016. Their weekly dietary intake diaries and food samples were collected over the course of five visits. The OCP residues of 322 food samples from seven categories (i.e., cereal, vegetable, fruit, fish, meat, egg, and milk) were analyzed by gas chromatography-mass spectrometry. The average concentrations of the total hexachlorocyclohexanes (ΣHCH), dichlorodiphenyltrichloroethanes and their metabolites (ΣDDX), endosulfans (ΣES), and dieldrin and endrin (ΣDrin) in all food categories were, overall, much lower than the maximum residue limits. Relative high mean residues of ΣDrin and ΣES were found in fruits (ΣDrin: 0.687 ng g-1 wet weight (w.w.), ΣES: 2.24 ng g-1 w.w.) and vegetables (ΣDrin: 0.690 ng g-1 w.w., ΣES: 2.11 ng g-1 w.w.). The estimated daily dietary intake (EDI) of these compounds was calculated, with mean levels of 10.6 (ΣES) > 4.37 (ΣDrin) > 1.51 (ΣHCH) > 0.850 (ΣDDX) ng kg-1 day-1. Women during the heating period (from January to March) tended to ingest more ΣHCH, ΣDDX, ΣDrin, and ΣES. Overall, women had no obvious non-carcinogenic and carcinogenic risks due to intake of OCPs, but 83.9% of them has potential carcinogenic risk, with estimated life carcinogenic risk (LCR) exceeding 10-6. Furthermore, women had a higher potential carcinogenic risk during the heating period (mean LCR: 1.33 × 10-5) than during the non-heating period (mean LCR: 8.50 × 10-6). ΣDrin was the dominant OCP responsible for health risks, followed by ΣHCH. We concluded that women in North China still have some dietary OCP intake, especially during the heating period.

Associations between blood heavy metal(loid)s and serum heme oxygenase-1 in pregnant women: Do their distribution patterns matter?

The relationship between heavy metal(loid)s exposure and oxidative stress damage is a matter of research interest. Our study aimed to investigate the distribution patterns of the nine heavy metal(loid)s in blood of pregnant women, including four toxic heavy metal(loid)s [arsenic (As), cadmium (Cd), lead (Pb) and mercury (Hg)] and five typical heavy metal(loid)s [manganese (Mn), cobalt (Co), copper (Cu), zinc (Zn), and selenium (Se)] in blood. Blood samples of 348 women were collected and their concentrations in the serum (sr) and blood cells (bc) were measured, as well as serum heme oxygenase-1 (HO-1) (an oxidative stress marker). Total blood (tb) concentrations of these metal(loid)s and serum-to-blood cell concentration ratios (sr/bc) were further calculated. We found Cu mainly accumulated in the serum compared to the blood cells with Cusr/bc = 2.30, whereas Co, Se, and As evenly distributed between these two fractions. Other metal(loid)s mainly concentrated in the blood cells. Cosr, Cusr, Cubc, Mnbc, Znbc, Cdbc, Cotb, Cutb, Mntb, Zntb, Cdtb, and Cusr/bc were negatively associated with serum HO-1, whereas Assr, Asbc, Astb, Znsr/bc, Cdsr/bc, and Hgsr/bc were positively, indicating of their potential toxicity. We concluded that the distribution patterns of blood heavy metal(loid)s, in particular for Cd, Hg and Zn, which either increased in serum or decreased in blood cells, might be associated with elevated serum oxidative stress, should be considered in environmental health assessments.

Associations of Dietary Exposure to Organochlorine Pesticides from Plant-Origin Foods with Lipid Metabolism and Inflammation in Women: A Multiple Follow-up Study in North China.

This study explored effects of dietary OCP intake from plant-origin foods (cereals, fruits, and vegetables) consumption on lipid metabolism and inflammation of women using a multiple follow-up study. The results showed that dietary intake of p,p'-dichlorodiphenyltrichloroethane (DDT) [ß = - 10.11, 95% confidence interval (95%CI): - 17.32, - 2.905] and o,p'-dichlorodiphenyldichloroethylene (DDE) (ß = - 6.077, 95%CI: - 9.954, - 2.200) were overall negatively associated with serum high-density lipoprotein cholesterol (HDL), whereas other OCPs were not. Serum interleukin (IL)-8 was positively associated with intake of dieldrin (ß = 0.390, 95%CI: 0.105, 0.674), endosulfan-ß (ß = 0.361, 95%CI: 0.198, 0.523), total endosulfan (ß = 0.136, 95%CI: 0.037, 0.234), and total OCPs (ß = 0.084, 95%CI: 0.016, 0.153), and negatively correlated with intake of p,p'-DDE (ß = - 2.692, 95%CI: - 5.185, - 0.198). We concluded that dietary intake of some individual DDT-, DDE- dieldrin-, and endosulfan-class chemicals from plant-origin foods may interfere with lipid metabolism and inflammation responses.

Contribution of Temperature Increase to Restrain the Transmission of COVID-19.

The COVID-19 outbreak has already become a global pandemic and containing this rapid worldwide transmission is of great challenge. The impacts of temperature and humidity on the COVID-19 transmission rate are still under discussion. Here, we elucidated these relationships by utilizing two unique scenarios, repeated measurement and natural experiment, using the COVID-19 cases reported from January 23 - February 21, 2020, in China. The modeling results revealed that higher temperature was most strongly associated with decreased COVID-19 transmission at a lag time of 8 days. Relative humidity (RH) appeared to have only a slight effect. These findings were verified by assessing SARS-CoV-2 infectivity under the relevant conditions of temperature (4°C-37°C) and RH (> 40%). We concluded that temperature increase made an important, but not determined, contribution to restrain the COVID-19 outbreak in China. It suggests that the emphasis of other effective controlling polices should be strictly implemented to restrain COVID-19 transmission in cold seasons.

Internal metal(loid)s are potentially involved in the association between ambient fine particulate matter and blood pressure: A repeated-measurement study in north China.

The effects of ambient fine particulate matter (PM2.5) exposure on blood pressure have been widely reported. However, there remains uncertainty regarding the underlying roles of particulate matter components. We aimed to investigate the association between ambient PM2.5 exposure and blood pressure, as well as the potential effects of trace metal(loid)s, in a repeated-measurement study that enrolled women of childbearing age. Our study included 35 participants from Hebei Province, China, each of whom was visited for five times. During each visit, we conducted questionnaire surveys, measured blood pressure, and collected blood. The daily PM2.5 exposure of participants was estimated according to their residential addresses using a spatiotemporal model that combined monitoring data with satellite measurements and chemical-transport model simulations. This model was used to calculate average PM2.5 concentrations in 1, 3, 7, 15, 30, and 60 days prior to each visit. Serum concentrations of various trace metal(loid)s were measured. A linear mixed-effects model was used to investigate associations among study variables. Overall, the mean (standard deviation) 60 days PM2.5 concentration over all five visits was 108.1(43.3) µg/m3. PM2.5 concentration was positively associated with both systolic and diastolic blood pressures. Likewise, ambient PM2.5 concentration was positively associated with serum concentrations of manganese and arsenic, and negatively associated with serum concentrations of nickel, tin, and chromium. Only the serum concentration of molybdenum was negatively associated with systolic blood pressure. We concluded that ambient PM2.5 exposure may contribute to elevated blood pressure, potentially by interfering with internal intake of various metal(loid)s in the human body.

Potential interference on the lipid metabolisms by serum copper in a women population: A repeated measurement study.

The relationship between excess copper (Cu) intake and lipid metabolic disorders is not well-studied, and most studies on this topic have a cross-sectional design. Here, we investigated the relationship between Cu exposure and blood lipid metabolism in women population, as well as potential mediation effects of oxidative stress and inflammation, using a repeated-measurement study. A total of 35 women in northern China were included, and each individual was visited for five times. Blood samples were collected, and the following serum biomarkers were analyzed: heme oxygenase-1 (HO-1), monocyte chemotactic protein-1 (MCP-1), interleukin (IL)-6, IL-8, and lipids [triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and lipoprotein(a) (Lp(a))]. A linear mixed-effect model was used to analyze the associations between Cu and the individual biomarkers in serum. The results showed that Cu was positively associated with TG (ß = 0.0007, P = 0.01), TC (ß = 0.0006, P = 0.002), LDL (ß = 0.0004, P ≤ 0.001), and Lp(a) (ß = 0.0004, P = 0.01), but not associated with HDL (ß = 0.0001, P = 0.19). Likewise, serum Cu was positively associated with HO-1 (ß = 0.0004, P = 0.03) and negatively associated with MCP-1 (ß = -0.0006, P = 0.003) and IL-8 (ß = -0.002, P = 0.03). Among the biomarkers of oxidative stress, inflammation, and lipids in serum, only IL-8 was negatively associated with HDL (ß = -0.0004, P = 0.009). No other associations were observed. We conclude that high Cu exposure may elevate blood lipid levels as well as disturb processes related to oxidative stress and inflammation responses.

Association between exposure of light rare earth elements and outcomes of in vitro fertilization-embryo transfer in North China.

The adverse health effects of rare earth elements (REEs) on reproductive health remain a subject of debate, and few clinical observations are available. This study investigated the association between light REEs (LREEs) exposure and the outcome of in vitro fertilization-embryo transfer (IVF-ET). We recruited a total of 305 women undergoing IVF-ET in Beijing City and Shandong Province of northern China. Their demographic information and lifestyle characteristics were collected using questionnaires at enrollment. Fasting blood samples were collected on the day before the IVF-ET treatment cycle began. Serum concentrations of the LREEs of concern were analyzed using inductively coupled plasma-mass spectrometry, and four LREEs were measured with a high detection rate, including lanthanum (La), cerium (Ce), praseodymium (Pr), and neodymium (Nd). We found that a higher serum La concentration was associated with a 30% increased likelihood of clinical pregnancy failure [relative risk (RR) = 1.30, 95% confidence interval (CI): 1.00-1.67] and a 230% increased likelihood of preclinical spontaneous abortion (RR = 3.30, 95% CI: 1.57-6.94). There was a negative correlation between serum La concentration and the number of good-quality oocytes. For the other LREEs, no statistically significant associations were observed. We concluded that a high serum La concentration may have an adverse effect on IVF-ET outcomes.

Simultaneous analysis of typical halogenated endocrine disrupting chemicals and metal(loid)s in human hair.

Hair analysis has been an important approach in evaluating population exposure to various environmental factors. To meet the requirements of human environmental epidemiology studies, we aimed to develop an efficient method for simultaneous analysis of various metal(loid)s and some typical environmental halogenated endocrine disrupting chemicals (hEDCs) (i.e., polychlorinated biphenyls, polybrominated diphenyl ethers, and organochlorine pesticides, as well as some of their hydroxyl substituted metabolites) in a single hair sample. The hair was washed successively with surfactant solutions, methanol solvent, and deionized water to remove impurities attached to the hair surface. Efficiency was comprehensively compared among various washing strategies. The hair sample was further pulverized into fine powder with a median diameter (25th-75th percentile) of 8.6 (5.9-13.5) µm. The hair organic components were extracted by acetonitrile solvent and compared with the microwave-assisted extraction method. The hEDCs in the supernatant acetonitrile phase were quantified by gas chromatography-mass spectrometry, and the metal(loid)s in the precipitate hair were further analyzed by inductively coupled plasma mass spectrometry. Our developed method was further applied to analyze the hair samples of 165 pregnant women. The results showed that particles attached to the surface of the hair could not be washed off completely. However, we proposed a protocol framework to wash hair with relatively high efficience, which includes warm water incubation, and use of surfactant and organic solvent. The recoveries of the concerned hEDCs and metal(loid)s were overall in the range of 80% to 120%. For the women population, the method can efficiently recognize the typical exposure characteristics of the concerned hEDCs and metal(loid)s. Our study significantly ameliorated the deficiencies of the traditional hair washing strategy and developed an efficient method for simultaneous analysis of various metal(loid)s and hEDCs in a single hair sample. This method will provide important support for population complex exposure analysis and facilitate environmental exposome studies.