Early-life exposure to perfluorinated alkyl substances modulates lipid metabolism in progression to celiac disease

Celiac disease (CD) is a systemic immune-mediated disorder with increased frequency in the developed countries over the last decades implicating the potential causal role of various environmental triggers in addition to gluten. Herein, we apply determination of perfluorinated alkyl substances (PFAS) and combine the results with the determination of bile acids (BAs) and molecular lipids, with the aim to elucidate the impact of prenatal exposure on risk of progression to CD in a prospective series of children prior the first exposure to gluten (at birth and at 3 months of age). Here we analyzed PFAS, BAs and lipidomic profiles in 66 plasma samples at birth and at 3 months of age in the Type 1 Diabetes Prediction and Prevention (DIPP) study (n = 17 progressors to CD, n = 16 healthy controls, HCs). Plasma PFAS levels showed a significant inverse association with the age of CD diagnosis in infants who later progressed to the disease. Associations between BAs and triacylglycerols (TGs) showed different patterns already at birth in CD pmgressors, indicative of different absorption of lipids in these infants. In conclusion, PFAS exposure may modulate lipid and BA metabolism, and the impact is different in the infants who develop CD later in life, in comparison to HCs. The results indicate more efficient uptake of PFAS in such infants. Higher PFAS exposure during prenatal and early life may accelerate the progression to CD in the genetically predisposed children.Peer reviewe

Simultaneous determination of perfluoroalkyl substances and bile acids in human serum using ultra-high-performance liquid chromatography-tandem mass spectrometry

There is evidence of a positive association between per- and polyfluoroalkyl substances (PFASs) and cholesterol levels in human plasma, which may be due to common reabsorption of PFASs and bile acids (BAs) in the gut. Here we report development and validation of a method that allows simultaneous, quantitative determination of PFASs and BAs in plasma, using 150 mu L or 20 mu L of sample. The method involves protein precipitation using 96-well plates. The instrumental analysis was performed with ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS), using reverse-phase chromatography, with the ion source operated in negative electrospray mode. The mass spectrometry analysis was carried out using multiple reaction monitoring mode. The method proved to be sensitive, robust, and with sufficient linear range to allow reliable determination of both PFASs and BAs. The method detection limits were between 0.01 and 0.06 ng mL(-1) for PFASs and between 0.002 and 0.152 ng mL(-1) for BAs, with the exception of glycochenodeoxycholic acid (0.56 ng mL(-1)). The PFAS measured showed excellent agreement with certified plasma PFAS concentrations in NIST SRM 1957 reference serum. The method was tested on serum samples from 20 healthy individuals. In this proof-of-concept study, we identified significant associations between plasma PFAS and BA levels, which suggests that PFAS may alter the synthesis and/or uptake of BAs.Graphica

Early-life exposure to perfluorinated alkyl substances modulates lipid metabolism in progression to celiac disease

Celiac disease (CD) is a systemic immune-mediated disorder with increased frequency in the developed countries over the last decades implicating the potential causal role of various environmental triggers in addition to gluten. Herein, we apply determination of perfluorinated alkyl substances (PFAS) and combine the results with the determination of bile acids (BAs) and molecular lipids, with the aim to elucidate the impact of prenatal exposure on risk of progression to CD in a prospective series of children prior the first exposure to gluten (at birth and at 3 months of age). Here we analyzed PFAS, BAs and lipidomic profiles in 66 plasma samples at birth and at 3 months of age in the Type 1 Diabetes Prediction and Prevention (DIPP) study (n = 17 progressors to CD, n = 16 healthy controls, HCs). Plasma PFAS levels showed a significant inverse association with the age of CD diagnosis in infants who later progressed to the disease. Associations between BAs and triacylglycerols (TGs) showed different patterns already at birth in CD progressors, indicative of different absorption of lipids in these infants. In conclusion, PFAS exposure may modulate lipid and BA metabolism, and the impact is different in the infants who develop CD later in life, in comparison to HCs. The results indicate more efficient uptake of PFAS in such infants. Higher PFAS exposure during prenatal and early life may accelerate the progression to CD in the genetically predisposed children.</p

Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking

Aims: Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function.Methods and results: Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg-/- mice). In 9- to 10-week-old hUgcg-/- mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg-/- mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg-/- mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors.Conclusions: Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function.</p

CHARACTERIZATION OF EARLY LIFE EXPOSURE TO ENVIRONMENTAL CHEMICALS AND ITS IMPACTS ON HEALTH

The exposome is a complex study that includes both endogenous and exogenous markers related to different diseases as part of the research. Connecting both endogenous and exogenous markers can help explain many associations between environmental chemicals and metabolic profiles, which can be stressors for causing different diseases. This study investigates the impact of per- and polyfluorinated alkyl substances (PFAS) exposure during pregnancy on lipid profiles and measures the concentrations in blood and also in infants cord blood at birth. In addition, we are interested in lipids and bile acids (BA) levels in blood and if these three groups of analytes of interest are associated with each other. The infant blood-based samples come from a Chinese cohort and the maternal samples are from a Finnish cohort. The samples were extracted for PFAS and BA and for lipid analysis. Statistical analysis was performed for both cohorts. The main interest was to investigate the interactions between the identified compounds. The results also include concentrations to show the variety of values measured.  Type 2 diabetes (T2D) and non-alcoholic fatty-liver disease (NAFLD) are usually not acquired early in life. Our results show a strong positive correlation between PFASs and triglycerides (TGs), as well as strong correlation between PFASs and conjugated primary and secondary BA particularly in cord blood samples, which can indicate higher risk of developing T2D or NAFLD. In maternal samples, the interactions between PFASs, BAs and lipids were much lower and showed less significant correlation. This indicates that the impact of PFAS exposure is much stronger during fetal development than in adult life.

Simultaneous Determination of Per- and Polyfluoroalkyl Substances and Bile Acids in Human Serum Using Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry

There is evidence of a positive association between per- and polyfluoroalkyl substances (PFAS) and cholesterol levels in human plasma, which may be due to common reabsorption of PFAS and bile acids (BAs) in the gut. Here we report development and validation of a method that allows simultaneous, quantitative determination of PFAS and BAs in plasma, using 150 uL or 20 uL of sample. The method involves protein precipitation using 96-well plates. The instrumental analysis was performed with ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS), using reverse-phase chromatography, with the ion source operated in negative electrospray mode. The mass spectrometry analysis was carried out using multiple reaction monitoring mode. The method proved to be sensitive, robust and with sufficient linear range to allow reliable determination of both PFAS and BAs. The method detection limits were between 0.01 and 0.06 ng⋅mL-1 for PFAS and between 0.002 and 0.152 ng⋅mL-1 for BAs, with the exception of glycochenodeoxycholic acid (0.56 ng⋅mL-1). The PFAS measured showed excellent agreement with certified plasma PFAS concentrations in NIST SRM 1957 reference plasma. The method was tested on serum samples from 20 healthy individuals. In this proof-of-concept study, we identified significant associations between plasma PFAS and BA levels, which suggests that PFAS may alter the synthesis and/or uptake of BAs

Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking

AIMS : Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function. METHODS AND RESULTS : Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg(–/–) mice). In 9- to 10-week-old hUgcg(–/–) mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg(–/–) mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg(–/–) mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors. CONCLUSIONS : Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function