RESUMO
Perfluorooctane sulfonate (PFOS), an endocrine-disrupting chemical pollutant, affects embryonic heart development; however, the mechanisms underlying its toxicity have not been fully elucidated. Here, Single-cell RNA sequencing (scRNA-seq) was used to investigate the overall effects of PFOS on myocardial differentiation from human embryonic stem cells (hESCs). Additionally, apoptosis, mitochondrial membrane potential, and ATP assays were performed. Downregulated cardiogenesis-related genes and inhibited cardiac differentiation were observed after PFOS exposure in vitro. The percentages of cardiomyocyte and cardiac progenitor cell clusters decreased significantly following exposure to PFOS, while the proportion of primitive endoderm cell was increased in PFOS group. Moreover, PFOS inhibited myocardial differentiation and blocked cellular development at the early- and middle-stage. A Gene Ontology analysis and pseudo-time trajectory illustrated that PFOS disturbed multiple processes related to cardiogenesis and oxidative phosphorylation in the mitochondria. Furthermore, PFOS decreased mitochondrial membrane potential and induced apoptosis. These results offer meaningful insights into the cardiogenic toxicity of PFOS exposure during heart formation as well as the adverse effects of PFOS on mitochondria.
Assuntos
Ácidos Alcanossulfônicos , Fluorocarbonos , Células-Tronco Embrionárias Humanas , Doenças Mitocondriais , Humanos , Fluorocarbonos/toxicidade , Fluorocarbonos/metabolismo , Miócitos Cardíacos , Análise de Sequência de RNA , Doenças Mitocondriais/metabolismo , Ácidos Alcanossulfônicos/toxicidade , Ácidos Alcanossulfônicos/metabolismoRESUMO
BACKGROUND: Scanty knowledge prevails regarding the combined impact of multiple plasma trace elements and main contributors on the prevalence of congenital heart defects (CHDs) in offspring. Thus, we performed a nested case-control analysis in a neonates cohort to investigate this important public health issue. METHODS: We selected 164 pairs of cases and non-malformed controls from live births registered in the parent cohort (n = 11,578) at the same hospital. Plasma levels of 14 trace elements were determined by inductively coupled plasma-mass spectrometry. The odds ratios (ORs) of exposure were compared between cases and controls. Bayesian Kernel Machine Regression (BKMR) and Quantile g-Computation (QgC) models were employed to assess the cumulative effect of exposure to trace elements. RESULTS: We found positive associations and linear dose-response relationships between plasma Pb and Sn and CHD. BKMR models indicated that the overall effect of the trace element mixture was associated with CHDs below the 45th percentile or above the 50th percentile, and the combined effect was primarily attributed to Sn and Pb. The QgC model indicated significantly increased odds of CHD with simultaneous exposure to all studied trace elements (OR: 2.19, 95%CI: 1.44-3.33). CONCLUSIONS: This study is the first to report an association between elevated levels of mixed trace elements in maternal plasma with an increased prevalence of fetal CHDs, particularly in the case of Pb and Sn. Findings from this study provide further evidence of the important of heavy metal pollution to human health, and can help stakeholders prioritize policies and develop interventions to target the leading contributors to human exposure.
Assuntos
Cardiopatias Congênitas , Oligoelementos , Feminino , Humanos , Recém-Nascido , Teorema de Bayes , Estudos de Casos e Controles , Cardiopatias Congênitas/epidemiologia , Chumbo , Exposição Materna , Prevalência , GravidezRESUMO
Accumulating evidence strongly suggests that exposure to ambient air pollution is linked with increased frailty. However, little is known about the effect of improved air quality on frailty progression. We aimed to investigate whether improvements in air quality (PM1, PM2.5, PM10, NO2, and O3) can alleviate frailty progression, particularly in the aftermath of implementation of the "Clean Air Action" policy in China. The study involved 12,891 participants with geocoded environmental data from the nationwide China Health and Retirement Longitudinal Study (CHARLS) during the period from May 2011 to August 2015. Multivariate logistic regression models were used to analyze the association of air pollution improvements and frailty progression. The protective effects were noted for PM1, PM2.5, PM10, and NO2 indices, with an aOR (adjusted odds ratio) ranging from 0.72 to 0.79. Air quality improvement in PM1, PM2.5, PM10, and NO2 could alleviate the progression of frailty. The study is the first to examine the association between the improvement of air quality and the progression of frailty, setting a precedent for the importance of a nationwide clean air policy and its impact on healthy ageing.
RESUMO
Prenatal exposure to perfluorooctane sulfonate (PFOS) is associated with adverse health effects, including congenital heart disease, yet the underlying mechanisms remain elusive. Herein, we aimed to evaluate the embryotoxicity of PFOS using C57BL/6 J mice to characterize fetal heart defects after PFOS exposure, with the induction of human embryonic stem cells (hESC) into cardiomyocytes (CMs) as a model of early-stage heart development. We also performed DNA methylation analysis to clarify potential underlying mechanisms and identify targets of PFOS. Our results revealed that PFOS caused septal defects and excessive ventricular trabeculation cardiomyopathy at 5 mg/kg/day in embryonic mice and inhibited the proliferation and pluripotency of ESCs at concentrations >20 µM. Moreover, it decreased the beating rate and the population of CMs during cardiac differentiation. Decreases were observed in the abundances of NPPA+ trabecular and HEY2+ compact CMs. Additionally, DNA methyl transferases and ten-eleven translocation (TET) dioxygenases were regulated dynamically by PFOS, with TETs inhibitor treatment inducing significant decreases similar as PFOS. 850 K DNA methylation analysis combined with expression analysis revealed several potential targets of PFOS, including SORBS2, FHOD1, SLIT2, SLIT3, ADCY9, and HDAC9. In conclusion, PFOS may reprogram DNA methylation, especially demethylation, to induce cardiac toxicity, causing ventricular defects in vivo and abnormal cardiac differentiation in vitro.