Per- and polyfluorinated substances (PFAS) promote osteoclastogenesis and bone loss through PPARα activation.

Per- and polyfluoroalkyl substances (PFAS) are emerging as significant environmental contaminants affecting bone health, with studies linking their exposure to decreased bone mineral density (BMD), enhanced osteoclastogenesis, and disruptions in the bone marrow microenvironment. While current research highlights the effects on bone and BMD, there is a critical gap in understanding the mechanisms behind these effects. Studies presented here investigate the effects of legacy and alternative PFAS, particularly hexafluoropropylene oxide dimer acid (GenX) and perfluorohexane sulfonic acid (PFHxS), on bone health using and models.

Targeted Overexpression of Mitochondrial ALDH2 in Coronary Endothelial Cells Mitigates HFpEF in a Diabetic Mouse Model.

Heart failure (HF) has become an epidemic, with a prevalence of ~7 million cases in the USA. Despite accounting for nearly 50% of all HF cases, heart failure with a preserved ejection fraction (HFpEF) remains challenging to treat. Common pathophysiological mechanisms in HFpEF include oxidative stress, microvascular dysfunction, and chronic unresolved inflammation.

Prenatal per- and polyfluoroalkyl substance exposures and DNA methylation among newborns in the Environmental influences on Child Health Outcomes program.

Gestation is a vulnerable window when exposure to per- and polyfluoroalkyl substances (PFAS) may impact child development and health. Epigenetic modification, including DNA methylation (DNAm), may be one mechanism linking prenatal PFAS exposure to offspring outcomes. We tested associations between prenatal PFAS and newborn DNAm in 1017 participants from 6 cohorts in the US Environmental influences on Child Health Outcomes consortium.

Prenatal PFAS exposure and outcomes related to maternal gut microbiome composition in later pregnancy.

The composition of the gut microbiome is dependent on factors including diet, lifestyle, and exposure to environmental chemicals, and has implications for human health. Per- and polyfluoroalkyl substances (PFAS), a class of man-made chemicals that have nonstick and flame-retardant properties may impact on gut microbiome composition. Our objective was to elucidate links between PFAS and maternal gut microbiome composition in two geographically diverse sites of the Environmental Influences on Child Health Outcomes program.

PFAS Exposure and Male Reproductive Health: Implications for Sperm Epigenetics.

Per- and polyfluoroalkyl substances (PFASs) are persistent environmental contaminants found in human tissues and persist in the environment, posing significant risks to reproductive health. This review examines the impact of PFAS exposure on male reproductive health, with a focus on sperm epigenetics. PFASs disrupt endocrine function by altering key reproductive hormones and impairing sperm motility, quality, and viability.

Exposure of Mice to a PFAS Mixture and Outcomes Related to Circulating Lipids, Bile Acid Excretion, and the Intestinal Transporter ASBT.

Background: Previous epidemiological studies have repeatedly found per- and polyfluoroalkyl substances (PFAS) exposure associated with higher circulating cholesterol, one of the greatest risk factors for development of coronary artery disease. The main route of cholesterol catabolism is through its conversion to bile acids, which circulate between the liver and ileum via enterohepatic circulation. Patients with coronary artery disease have decreased bile acid excretion, indicating that PFAS-induced impacts on enterohepatic circulation may play a critical role in cardiovascular risk.

The long-chain polyfluorinated alkyl substance perfluorohexane sulfonate (PFHxS) promotes bone marrow adipogenesis.

Per- and polyfluoroalkyl substances (PFAS) bioaccumulate in different organ systems, including bone. While existing research highlights the adverse impact of PFAS on bone density, a critical gap remains in understanding the specific effects on the bone marrow microenvironment, especially the bone marrow adipose tissue (BMAT). Changes in BMAT have been linked to various health consequences, such as the development of osteoporosis and the progression of metastatic tumors in bone.

Mixtures of per- and polyfluoroalkyl substances (PFAS) alter sperm methylation and long-term reprogramming of offspring liver and fat transcriptome.

Male fertility has been declining worldwide especially in countries with high levels of endocrine disrupting chemicals (EDCs). Per- and polyfluorinated alkyl Substances (PFAS) have been classified as EDCs and have been linked to adverse male reproductive health. The mechanisms of these associations and their implications on offspring health remain unknown.

Loss of flavin-containing monooxygenase 3 modulates dioxin-like polychlorinated biphenyl 126-induced oxidative stress and hepatotoxicity.

Dioxin-like pollutants (DLPs), such as polychlorinated biphenyl 126 (PCB 126), are synthetic chemicals classified as persistent organic pollutants. They accumulate in adipose tissue and have been linked to cardiometabolic disorders, including fatty liver disease. The toxicity of these compounds is associated with activation of the aryl hydrocarbon receptor (Ahr), leading to the induction of phase I metabolizing enzyme cytochrome P4501a1 (Cyp1a1) and the subsequent production of reactive oxygen species (ROS).

Maternal polychlorinated biphenyl 126 (PCB 126) exposure modulates offspring gut microbiota irrespective of diet and exercise.

The gut microbiota plays an important role throughout the lifespan in maintaining host health, and several factors can modulate microbiota composition including diet, exercise, and environmental exposures. Maternal microbiota is transferred to offspring during early life; thus, environmental exposures before gestation may also modulate offspring microbiota. Here we aimed to investigate the effects of maternal exposure to dioxin-like polychlorinated biphenyls (PCBs) on the microbiota of aged offspring and to determine if lifestyle factors, including maternal exercise or offspring high-fat feeding alter these associations.

Effect of lifestyle-based lipid lowering interventions on the relationship between circulating levels of per-and polyfluoroalkyl substances and serum cholesterol.

Exposure to certain per-and polyfluoroalkyl substances (PFAS) has been shown to be positively associated with total and/or low-density lipoprotein cholesterol. Examining this association in lipid lowering interventions may provide additional evidence linking PFAS to cardiovascular risk. We examined the relationship of 6 PFAS with cholesterol in a 6-month lifestyle-based intervention.

Exposure to a mixture of per-and polyfluoroalkyl substances modulates pulmonary expression of ACE2 and circulating hormones and cytokines.

Genetic and environmental factors impact on the interindividual variability of susceptibility to communicable and non-communicable diseases. A class of ubiquitous chemicals, Per- and polyfluoroalkyl substances (PFAS) have been linked in epidemiological studies to immunosuppression and increased susceptibility to viral infections, but possible mechanisms are not well elucidated. To begin to gain insight into the role of PFAS in susceptibility to one such viral infection, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), male and female C57BL/6 J mice were exposed to control water or a mixture of 5 PFAS (PFOS, PFOA, PFNA, PFHxS, Genx) for 12 weeks and lungs were isolated for examination of expression of SARS-CoV-2-related receptors Angiotensin-Converting Enzyme 2 (ACE2) and others.

Exposure to per- and polyfluoroalkyl substances (PFAS) and type 2 diabetes risk.

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous man-made chemicals found in consumer products including fabrics, food packaging, non-stick coatings, and aqueous film-forming foams. PFAS are stable and extremely resistant to degradation, resulting in high persistence throughout the environment as well as in human blood. PFAS consist of a large family of synthetic chemicals, with over 4000 distinct varieties having been identified and around 250 currently being manufactured at globally relevant levels.

Exposure to the Dioxin-like Pollutant PCB 126 Afflicts Coronary Endothelial Cells via Increasing 4-Hydroxy-2 Nonenal: A Role for Aldehyde Dehydrogenase 2.

Exposure to environmental pollutants, including dioxin-like polychlorinated biphenyls (PCBs), play an important role in vascular inflammation and cardiometabolic diseases (CMDs) by inducing oxidative stress. Earlier, we demonstrated that oxidative stress-mediated lipid peroxidation derived 4-hydroxy-2-nonenal (4HNE) contributes to CMDs by decreasing the angiogenesis of coronary endothelial cells (CECs). By detoxifying 4HNE, aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme, enhances CEC angiogenesis.

Proteomics-Based Identification of Interaction Partners of the Xenobiotic Detoxification Enzyme FMO3 Reveals Involvement in Urea Cycle.

The hepatic xenobiotic metabolizing enzyme flavin-containing monooxygenase 3 (FMO3) has been implicated in the development of cardiometabolic disease primarily due to its enzymatic product trimethylamine-N oxide (TMAO), which has recently been shown to be associated with multiple chronic diseases, including kidney and coronary artery diseases. Although TMAO may have causative roles as a pro-inflammatory mediator, the possibility for roles in metabolic disease for FMO3, irrespective of TMAO formation, does exist. We hypothesized that FMO3 may interact with other proteins known to be involved in cardiometabolic diseases and that modulating the expression of FMO3 may impact on these interaction partners.

Serum concentrations of legacy and emerging per- and polyfluoroalkyl substances in the Anniston Community Health Surveys (ACHS I and ACHS II).

Background: Residents of Anniston Alabama were highly exposed to polychlorinated biphenyls (PCBs) due to longstanding manufacturing in the area. The Anniston Community Health Surveys (ACHS I-2005-2007 and II, 2014) have linked these exposures with a variety of deletereous health outcomes. In addition to PCBs, these individuals were likely simultaneously exposed to other persistent organic pollutants including per and polyfluoroalkyl substances (PFAS), which are an emerging class of ubiquitous industrial chemicals that are measurable in the blood of most individuals and have themselves been linked increased risk of some non communicable diseases.

Exposure to a mixture of legacy, alternative, and replacement per- and polyfluoroalkyl substances (PFAS) results in sex-dependent modulation of cholesterol metabolism and liver injury.

Background: Epidemiological studies have shown Per- and polyfluoroalkyl substances (PFAS) to be associated with diseases of dysregulated lipid and sterol homeostasis such as steatosis and cardiometabolic disorders. However, the majority of mechanistic studies rely on single chemical exposures instead of identifying mechanisms related to the toxicity of PFAS mixtures.

Objectives: The goal of the current study is to investigate mechanisms linking exposure to a PFAS mixture with alterations in lipid metabolism, including increased circulating cholesterol and bile acids.

The transcription factors CREBH, PPARa, and FOXO1 as critical hepatic mediators of diet-induced metabolic dysregulation.

The liver is a critical mediator of lipid and/or glucose homeostasis and is a primary organ involved in dynamic changes during feeding and fasting. Additionally, hepatic-centric pathways are prone to dysregulation during pathophysiological states including metabolic syndrome (MetS) and non-alcoholic fatty liver disease. Omics platforms and GWAS have elucidated genes related to increased risk of developing MetS and related disorders, but mutations in these metabolism-related genes are rare and cannot fully explain the increasing prevalence of MetS-related pathologies worldwide.

Diet as an Exposure Source and Mediator of Per- and Polyfluoroalkyl Substance (PFAS) Toxicity.

Per- and polyfluoroalkyl substances (PFAS) are ubiquitously found in the environment due to their widespread commercial use and high chemical stability. Humans are exposed primarily through ingestion of contaminated water and food and epidemiological studies over the last several decades have shown that PFAS levels are associated with adverse chronic health effects, including cardiometabolic disorders such as hyperlipidemia and non-alcoholic fatty liver disease. Perhaps the most well-established effects, as demonstrated in animal studies and human epidemiological studies, are the metabolic alterations PFAS exposure can lead to, especially on lipid homeostasis and signaling.

A Review of Volatile Organic Compound Contamination in Post-Industrial Urban Centers: Reproductive Health Implications Using a Detroit Lens.

Volatile organic compounds (VOCs) are a group of aromatic or chlorinated organic chemicals commonly found in manufactured products that have high vapor pressure, and thus vaporize readily at room temperature. While airshed VOCs are well studied and have provided insights into public health issues, we suggest that belowground VOCs and the related vapor intrusion process could be equally or even more relevant to public health. The persistence, movement, remediation, and human health implications of subsurface VOCs in urban landscapes remain relatively understudied despite evidence of widespread contamination.

Prebiotic inulin consumption reduces dioxin-like PCB 126-mediated hepatotoxicity and gut dysbiosis in hyperlipidemic Ldlr deficient mice.

Exposure to some environmental pollutants increases the risk of developing inflammatory disorders such as steatosis and cardiometabolic diseases. Diets high in fermentable fibers such as inulin can modulate the gut microbiota and lessen the severity of pro-inflammatory diseases, especially in individuals with elevated circulating cholesterol. Thus, we aimed to test the hypothesis that hyperlipidemic mice fed a diet enriched with 8% inulin would be protected from the pro-inflammatory toxic effects of PCB 126.

High-Throughput UHPLC-MS/MS Measurement of Per- and Poly-Fluorinated Alkyl Substances in Human Serum.

Per- and poly-fluorinated alkyl substances (PFASs) are a large group of synthetic surfactant chemicals with widespread uses in food packaging and textile manufacturing and as the main constituent of aqueous film-forming firefighting foams. PFASs are highly persistent in the environment, and human exposures are extensive with these chemicals detectable in the blood of almost all adult Americans. PFASs exhibit a range of toxic effects in preclinical models.

Dietary inulin decreases circulating ceramides by suppressing neutral sphingomyelinase expression and activity in mice.

Elevated circulating levels of ceramides (Cers) are associated with increased risk of cardiometabolic diseases, and Cers may play a causative role in metabolic dysfunction that precedes cardiac events, such as mortality as a result of coronary artery disease. Although the mechanisms involved are likely complex, these associations suggest that lowering circulating Cer levels could be protective against cardiovascular diseases. Conversely, dietary fibers, such as inulin, have been reported to promote cardiovascular and metabolic health.