PFAS and their association with the increased risk of cardiovascular disease in postmenopausal women.

Cardiovascular diseases (CVD) are one of the major causes of death globally. In addition to traditional risk factors such as unhealthy lifestyles (smoking, obesity, sedentary) and genetics, common environmental exposures, including persistent environmental contaminants, may also influence cardiovascular disease risk. Per- and polyfluoroalkyl substances (PFAS) are a class of highly fluorinated chemicals used in household consumer and industrial products known to persist in our environment for years, causing health concerns that are now linked to endocrine disruptions and related outcomes in women, including interference of the cardiovascular and reproductive systems. In postmenopausal women, higher levels of PFAS are observed than in premenopausal women due to the cessation of menstruation, which is crucial for PFAS excretion. Because of these findings, we explored the association between Perfluorooctanoic acid (PFOA), Perfluorooctane sulfonate (PFOS), Perfluorobutanesulfonic acid (PFBS) in postmenopausal women from our previously established CVD study. We used liquid chromatography with tandem mass spectrometry (LC-MS-MS), supported by machine learning approaches, and the detection and quantification of serum metabolites and proteins. Here, we show that PFOS can be a good predictor of coronary artery disease, while PFOA can be an intermediate predictor of coronary microvascular disease. We also found that the PFAS levels in our study are significantly associated with inflammation-related proteins. Our findings may provide new insight into the potential mechanisms underlying the PFAS-induced risk of cardiovascular diseases in this population.

Pathway Preferential Estrogens Prevent Hepatosteatosis Due to Ovariectomy and High-Fat Diets.

About 20-30% of premenopausal women have metabolic syndrome, and the number is almost double in postmenopausal women, and these women have an increased risk of hepatosteatosis. Postmenopausal women with metabolic syndrome are often treated with hormone replacement therapy (HRT), but estrogens in currently available HRTs increase the risk of breast and endometrial cancers and Cardiovascular Disease. Therefore, there is a critical need to find safer alternatives to HRT to improve postmenopausal metabolic health. Pathway preferential estrogen 1 (PaPE-1) is a novel estrogen receptor ligand that has been shown to favorably affect metabolic tissues without adverse effects on reproductive tissues. In this study, we have examined the effects of PaPE-1 on metabolic health, in particular, examining its effects on the liver transcriptome and on plasma metabolites in two different mouse models: diet-induced obesity (DIO) and leptin-deficient (ob/ob) mice. PaPE-1 significantly decreased liver weight and lipid accumulation in both DIO and ob/ob models and lowered the expression of genes associated with fatty acid metabolism and collagen deposition. In addition, PaPE-1 significantly increased the expression of mitochondrial genes, particularly ones associated with the electron transport chain, suggesting an increase in energy expenditure. Integrated pathway analysis using transcriptomics and metabolomics data showed that PaPE-1 treatment lowered inflammation, collagen deposition, and pathways regulating fatty acid metabolism and increased metabolites associated with glutathione metabolism. Overall, our findings support a beneficial metabolic role for PaPE-1 and suggest that PaPE-1 may protect postmenopausal women from fatty liver disease without increasing reproductive cancer risk.

Identification of Circulating Diagnostic Biomarkers for Coronary Microvascular Disease in Postmenopausal Women Using Machine-Learning Techniques.

Coronary microvascular disease (CMD) is a common form of heart disease in postmenopausal women. It is not due to plaque formation but dysfunction of microvessels that feed the heart muscle. The majority of the patients do not receive a proper diagnosis, are discharged prematurely and must go back to the hospital with persistent symptoms. Because of the lack of diagnostic biomarkers, in the current study, we focused on identifying novel circulating biomarkers of CMV that could potentially be used for developing a diagnostic test. We hypothesized that plasma metabolite composition is different for postmenopausal women with no heart disease, CAD, or CMD. A total of 70 postmenopausal women, 26 healthy individuals, 23 individuals with CMD and 21 individuals with CAD were recruited. Their full health screening and tests were completed. Basic cardiac examination, including detailed clinical history, additional disease and prescribed drugs, were noted. Electrocardiograph, transthoracic echocardiography and laboratory analysis were also obtained. Additionally, we performed full metabolite profiling of plasma samples from these individuals using gas chromatography-mass spectrometry (GC-MS) analysis, identified and classified circulating biomarkers using machine learning approaches. Stearic acid and ornithine levels were significantly higher in postmenopausal women with CMD. In contrast, valine levels were higher for women with CAD. Our research identified potential circulating plasma biomarkers of this debilitating heart disease in postmenopausal women, which will have a clinical impact on diagnostic test design in the future.