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.

Urinary polycyclic aromatic hydrocarbons and sex hormones in children and adolescents: Evidence from NHANES.

BACKGROUND: Evidences showed that polycyclic aromatic hydrocarbons (PAHs) do harm to human body. However, the association between PAHs and sex hormones in children and adolescents remains unclear. OBJECTIVES: The study aims to investigate the associations between PAHs and sex hormones in the general children and adolescent population. METHODS: 967 participants aged 6-19 with complete data of PAHs exposure biomarkers, covariates and sex hormones [total testosterone (TT), estradiol (E2) and sex hormone binding globulin (SHBG)] were recruited from National Health and Nutrition Examination Survey (NHANES), 2013-2016. Free androgen index (FAI) was calculated with TT/SHBG. Multivariate linear regression models were performed in six subgroups (male children, male adolescents, male late adolescents, female children, female adolescents and female late adolescents) to estimate the associations between sex hormone alterations and PAHs exposure. RESULTS: In male puberty adolescents, weighted multivariate linear regression indicated that negative trends for 2-Hydroxynaphthalene, 1-Hydroxyphenanthrene, 2&3-Hydroxyphenanthrene and E2 (2-Hydroxynaphthalene: ß: -0.104, 95%CI: -0.180, -0.029, P < 0.01; 1-Hydroxyphenanthrene: ß: -0.112, 95%CI: -0.206, -0.018, P = 0.019; 2&3-Hydroxyphenanthrene: ß: -0.125, 95%CI: -0.232, -0.018, P = 0.022), while exposure to 2-Hydroxynaphthalene was related to TT reduction (ß: -0.099, 95%CI: -0.177, -0.020, P = 0.014). Same pattern between 2&3-Hydroxyphenanthrene and E2 alteration (2&3-Hydroxyphenanthrene: ß: -0.139, 95%CI: -0.236, -0.041, P < 0.01) was also observed in male late adolescents. In male children, we determined that 1-Hydroxyphenanthrene was negatively associated with SHBG (ß: -0.121, 95%CI: -0.205, -0.037, P < 0.01), while the same patterns were observed in male puberty children. We did not observe any significant result in female subgroups. All these results above were determined to have q value < 0.05. CONCLUSION: PAHs exposure was associated with the alterations of sex hormones in male adolescents and children. Considering the cross-sectional study design, further large-scale epidemiological study is necessary.

Hypoxia-induced hsa_circ_0000826 is linked to liver metastasis of colorectal cancer.

BACKGROUND: hsa_circ_0000826 has been previously linked to CRC through the competing endogenous RNA network; however, the upstream driver of hsa_circ_0000826 elevation remains unknown. In this study, we aim to elucidate the effect of hypoxia-induced hsa_circ_0000826 on CRC tumorigenesis and metastasis. METHODS: RNA scope assay was used to evaluate the expression of hsa_circ_0000826 in CRC cells under hypoxia condition. The effects of hsa_circ_0000826 on phenotypes of CRC cells were evaluated through cell migration and invasion assay. The nude, AOM-DSS model mice and APCMin /+ mice were used to investigate the relationship between circ_0000826, hypoxia, and CRC in mice. A total of 100 CRC tissue samples, as well as the paired adjacent tissues, were collected, and qRT-PCR assay was used to detect the expression of hsa_circ_0000826 in these samples. RESULTS: Hypoxia-induced hsa_circ_0000826 overexpression can increase the malignant phenotypes, tumor formation, and metastasis capability of CRC cells in vitro. mmu_circ_0000826 levels were significantly increased in the CRC tissues from AOM-DSS and APC mice model under hypoxia conditions. Further, the hypoxia-induced upregulation of mmu_circ_0000826 can also promote CRC tumorigenesis and liver metastasis in vivo. The expression of hsa_circ_0000826 in serum was significantly increased in CRC tissues in 100-pair of CRC and according to the adjacent normal tissues by qRT-PCR assays. Moreover, the expression levels of hsa_circ_0000826 in serum of patient with liver metastasis were significantly increased than those without metastasis. CONCLUSION: Our results suggested that hsa_circ_0000826 was induced by the hypoxia in CRC, which can be a potential biomarker of CRC liver metastasis.

Estimating neighborhood-based mortality risk associated with air pollution: A prospective study.

Effect modification of integrated neighborhood environment on associations of air pollution with mortality remained unclear. We analyzed data from UK biobank prospective study (n = 421,650, median 12.5 years follow-up) to examine disparities of mortality risk associated with air pollution among varied neighborhood settings. Fine particulate matter (PM2.5), PM10 and nitrogen dioxide (NO2) were measured and assigned to each participants' address. Diverse ecological and societal settings of neighborhoods were integrated with principal component analysis and categorized into disadvantaged, intermediate and advantaged levels. We estimated mortality risk associated with air pollution across diverse neighborhoods using Cox regression. We calculated community-level proportions of mortality attributable to air pollutants. There was evidence of higher all-cause and respiratory disease mortality risk associated with PM2.5 and NO2 among those in disadvantaged neighborhoods. In disadvantaged communities, air pollutants explained larger proportions of deaths and such disparities persisted over past decades. Across 2010-2021, reducing PM2.5 and NO2 to 10 µg/m3 (World Health Organization limits) would save 87,000 (52,000-120,000) and 91,000 (37,000-145,000) deaths of populations aged ≥ 40 years, with 150 000 deaths occurred in disadvantaged neighborhood settings. These findings suggested that disadvantaged neighborhoods can exacerbate mortality risk associated with air pollution.

Caloric restriction remodels the hepatic chromatin landscape and bile acid metabolism by modulating the gut microbiota.

BACKGROUND: Caloric restriction (CR) has been known to promote health by reprogramming metabolism, yet little is known about how the epigenome and microbiome respond during metabolic adaptation to CR. RESULTS: We investigate chromatin modifications, gene expression, as well as alterations in microbiota in a CR mouse model. Collectively, short-term CR leads to altered gut microbial diversity and bile acid metabolism, improving energy expenditure. CR remodels the hepatic enhancer landscape at genomic loci that are enriched for binding sites for signal-responsive transcription factors, including HNF4α. These alterations reflect a dramatic reprogramming of the liver transcriptional network, including genes involved in bile acid metabolism. Transferring CR gut microbiota into mice fed with an obesogenic diet recapitulates the features of CR-related bile acid metabolism along with attenuated fatty liver. CONCLUSIONS: These findings suggest that CR-induced microbiota shapes the hepatic epigenome followed by altered expression of genes responsible for bile acid metabolism.

Association between exposure to ambient air pollution and semen quality in adults: a meta-analysis.

Air pollution has become a global concern and may be hazardous to human reproductive capacity, but the impact of exposure to air pollutants on semen quality remains controversial. We performed the meta-analysis to examine the association between air pollution exposure and semen quality. We searched PubMed, Web of Science Core Collection, and Cochrane Library databases (before December 2019). We selected original epidemiological studies on humans, written and published in English, that provided quantitative information to determine the associations between air pollution and sperm parameters. A random-effects model was used when the pooled effect estimates were found to be heterogeneous (I2 > 50% or P < 0.05), otherwise, a fixed-effects model was applied. Publication bias was not evaluated for less than 10 included articles. Our meta-analysis showed that the standardised mean differences (SMDs) (95% confidence interval, 95% CI) of sperm concentration, sperm count, and sperm total motility were -0.17 (-0.20, -0.13), -0.05 (-0.08, -0.02), and -0.33 (-0.54, -0.11), respectively. However, exposure to air pollution was not related to sperm progressive motility (SMD = 0.00, 95% CI: -0.13, 0.12). The results indicated that exposure to air pollutants at a higher level was associated with impaired semen quality, including declined sperm concentration, reduced sperm count, and declined total motility. The results suggested that high level of air pollution exposure had a negative effect on semen quality. Improvement of air quality is important for enhancing semen quality.

Association between exposure to cadmium and risk of all-cause and cause-specific mortality in the general US adults: A prospective cohort study.

BACKGROUND: Cadmium has been suggested to accumulate in the body over a lifetime, posing a great threat to human health. So far, few studies have studied the association between cadmium exposure and long-term health outcomes in adults. OBJECTIVES: To investigate the risk of mortality with blood cadmium level in adults (participants of NHANES, 1999-2014). METHODS: We evaluated the associations between cadmium and risk of mortality. Data on mortality and cadmium exposure were collected in NHANES database including 39,865 participants. Multivariate Cox regression models were established for calculating hazard ratios (HRs) and 95%CI between cadmium exposure and all-cause and specific-cause mortality outcomes. RESULTS: Totally, 39,865 individuals with 19,260 males (48.3%) and 20,605 females (51.7%) were included in the study. During a total of 341,017 person-years of follow-up 5,094 deaths were documented, including 1,067 cardiovascular disease (CVD) and 890 cancers. Compared with the lowest quantile of cadmium exposure level group, the adjusted HRs in the highest quantile cadmium exposure level group were 1.73 (95%CI: 1.52-1.97) for all-cause mortality, 1.72 (95%CI: 1.28-2.30) for CVD mortality and 1.87 (95%CI: 1.49-2.36) for cancer mortality, respectively (P for trend: <0.001). Additionally, significant interactions with smoking status in the stratified analyses of all-cause mortality and cancer mortality, age in the stratified analyses of cancer mortality were found (P for interaction: 0.002, <0.001 and 0.012). CONCLUSIONS: In this nationwide representative sample of the population, we found that higher blood cadmium concentration was associated with increased risks of all-cause and specific-cause mortality. These data further evidence the link between mortality and cadmium concentration. It is of great importance for both policy makers and the public to minimize cadmium exposure, and to reduce long-term adverse health effects.

High-fat diet aggravates prenatal low-dose DEHP exposure induced spermatogenesis disorder: Characterization of testicular metabolic patterns in mouse offspring.

Di-(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer and has been identified as a male prenatal reproductive toxicant. A high fat diet (HFD) has also been suggested as another potential disruptor of male reproductive function. Despite this potential synergism between DEHP exposure and HFD, little is known about the concomitant effects of prenatal DEHP and a subsequent HFD exposure on male offspring reproductive injury. Here we established a mouse model of prenatal exposure to DEHP (0.2 mg/kg/day) to assess the testicular development and spermatogenesis in offspring subjected to obesogenic diet during the pubertal period. Gross phenotype, hormone profiles and the testicular metabolome were analyzed to determine the underlying mechanism. We found that prenatal exposure to low-dose DEHP resulted in decreased sperm density, decreased testosterone (T) levels, increased luteinizing hormone (LH) levels and testicular germ cell apoptosis. Furthermore, these injury phenotypes were aggravated by pubertal HFD treatment. Testicular riboflavin and biotin metabolites were enriched implying their roles in contributing HFD to exacerbate offspring spermatogenesis disorders due to prenatal low-dose DEHP exposure. Our findings suggest that pubertal HFD exacerbates reproductive dysfunction associated with prenatal exposure to low-dose DEHP in male adult offspring.

Association between Blood Manganese Levels and Visceral Adipose Tissue in the United States: A Population-Based Study.

Background: Manganese (Mn) is an essential trace element with a narrow toxic margin for human health. The association between Mn exposure and adverse visceral adipose tissue (VAT) accumulation is unclear. Objective: This study aimed to estimate the associations of blood Mn levels with VAT mass or visceral obesity in the general population in the United States. Method: This cross-sectional study included data of 7297 individuals released by National Health and Nutrition Examination Survey (NHANES). VAT was quantified with dual-energy X-ray absorptiometry, and blood Mn was measured using inductively coupled plasma mass spectrometry. The generalized linear model and generalized additive model (GAM) were applied to estimate the linear and non-linear associations between Mn levels and VAT mass, respectively. Logistic regression was used to estimate the associations between blood Mn levels and the risk of visceral obesity. Results: Fully adjusted generalized linear regression revealed that individuals in the higher quantile of Mn had increased VAT mass compared with those in the lower quantile (ß per quantile change = 0.025; 95% CI of 0.017, 0.033; p < 0.001). Positive associations were also observed in males and females (males: ß per quantile change = 0.012, 95% CI of 0.002, 0.022 (p = 0.020); female: ß per quantile change = 0.036; 95% CI of 0.023, 0.048 (p < 0.001)). The GAM illustrated that the non-linear associations between blood Mn levels and VAT mass were in U-shape patterns (effective degree of freedom >1 in total participants, males, and females). A stratified analysis found significant interactions between Mn and the family income-to-poverty ratio (PIR) in males, with stronger associations in males with a PIR < 1.3 (ß = 0.109; 95% CI of 0.048, 0.170). Additional analyses revealed that individuals in the highest quantile of Mn had a 39% higher risk of visceral obesity (OR = 1.39; 95% CI of 1.15−1.69; p < 0.001). Conclusions: Higher blood Mn levels were positively associated with increased VAT mass and visceral obesity risk. The adverse VAT phenotype associated with excessive blood Mn levels should be further investigated.

Association between per- and polyfluoroalkyl substances and risk of gestational diabetes mellitus.

BACKGROUND: Existing evidence suggests that perfluoroalkyl and polyfluoroalkyl substances (PFASs) exposure might contribute to the incidence of gestational diabetes mellitus (GDM). This study aimed to perform a meta-analysis to identify the association between PFAS and the risk of GDM. METHODS: We systematically searched PubMed, Ovid, Cochrane Library, and Web of Science databases for appropriate articles about the association between PFASs exposure and the risk of GDM before September 28, 2020. Odds ratios (OR) with 95% confidence intervals (CIs) were summarized by Stata 16.0 through fixed effect models according to heterogeneity. We also carried out subgroup analyses by geographic location, blood sampling time of subjects, method of chemical analysis, study design, sample size, and sampling year. In addition, a sensitivity analysis was conducted to explore the robustness of the results. RESULTS: A total of eight studies involving 5654 pregnant women were included in the meta-analysis. Perfluorooctanoic acid (PFOA) exposure was positively and significantly associated with the risk of GDM (OR = 1.27, 95% CI: 1.02-1.59). Exposure to other types of PFASs such as perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA) was not statistically significantly associated with the risk of GDM with the pooled effect estimates of 0.97 (95% CI: 0.86-1.09), 1.03 (95% CI: 0.86-1.24), and 0.80 (95% CI: 0.55-1.16) respectively. CONCLUSION: We conducted a meta-analysis to investigate the association between PFASs exposure and GDM and found that PFOA concentration was significantly associated with a higher risk of GDM, which is of great significance for the prevention and control of GDM in public health. Further studies are needed in order to establish causality and clarify the potential mechanism.

Independent and combined associations of urinary heavy metals exposure and serum sex hormones among adults in NHANES 2013-2016.

Accumulating evidences indicated that heavy metals may disrupt human sex hormones. However, the combined effects of heavy metals on sex hormones remain to be clarified. To explore the independent and combined associations between heavy metal exposure and serum sex hormones among adults, data of 2728 adults from the National Health and Nutrition Examination Survey (NHANES) was applied. We examined independent and combined associations of fourteen urinary heavy metals and three serum sex steroid hormones (total testosterone (TT), estradiol (E2) and sex hormone-binding globulin (SHBG)). Multivariate linear regression was used to evaluate the independent associations between metal exposure and sex hormone alterations. Principle component analysis -weighted quantile sum regression (PCA-WQSR) model was performed to estimate the combined associations in our individuals. In the co-exposure model, we determined that weighted quantile sum (WQS) index of industrial pollutants was negatively associated with E2 in females (WQS Percent change8-metal = -20.6%; 95% CI: -30.1%, -9.96%), while in males WQS index of water pollutants was negatively related to SHBG (WQS Percent change8-metal = -5.35%; 95% CI: -9.88%, -0.598%). Cadmium (Cd), tin (Sn) and lead (Pb) were the dominating metals of female E2-negative association while Ba was the leading contributor related to male SHBG reduction, which was consistent with the results of multivariate linear regression. Additionally, in postmenopausal women, the associations of E2 decrease with heavy metal co-exposure remained significant while Cd and monomethylarsonic acid (MMA) were identified as hazardous metals in the mixture. We concluded that the exposure to heavy metals was associated with human sex hormone alterations in independent or combined manners. Considering the design of NHANES study, further studies from other national-representative surveys are necessary.