Biology subjects

Hyotylainen, T.

Publications and source records attributed to Hyotylainen, T..

13 recordsLinked to original sources

bioRxiv2026

Early-life PFAS exposure induces systemic metabolic alterations in plasma and brain in mice

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants associated with adverse health effects, including emerging neurodevelopmental and neurological outcomes. Although PFAS can cross the placental and blood-brain barriers, the metabolic mechanisms underlying their neurotoxicity and potential sex-specific effects remain poorly understood. Here, we investigated the effects of prenatal and early-life exposure to a human-relevant PFAS mixture on plasma and brain metabolism in mice. The mixture contained perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), perfluorodecanoic acid (PFDA), and perfluorononanoic acid (PFNA) at environmentally relevant, subtoxic concentrations. Mass spectrometry-based metabolomics revealed pronounced, sex-dependent metabolic alterations in both plasma and brain. Female brains exhibited more extensive metabolic changes, particularly in lipid and arachidonic acid metabolism, steroid hormone pathways, and carbohydrate and energy metabolism. In contrast, male brains showed more selective perturbations, predominantly involving amino acid and neuroactive signaling pathways related to neurotransmitter metabolism. These distinct metabolic signatures indicate that early-life PFAS exposure affects brain metabolism through sex-dependent mechanisms. Our findings identify the brain metabolome as a sensitive target of early-life PFAS exposure and emphasize the importance of considering sex as a biological variable when assessing the neurotoxicity of persistent environmental contaminants.

pharmacology and toxicology↗

bioRxiv2025

Metabolic effects and biotransformation of perfluorohexyloctane (F6H8) in human hepatocytes

Perfluorohexyloctane (F6H8) is a semifluorinated alkane recently approved for ophthalmic treatment of dry eye disease. Although considered locally safe for topical use, its structural similarity to persistent per- and polyfluoroalkyl substances (PFAS) raises concerns about systemic accumulation and long-term toxicity. To investigate potential hepatic effects, we examined the metabolic impact of F6H8 exposure in human HepaRG hepatocytes across a broad concentration range representing short- and long-term exposure scenarios. Untargeted metabolic profiling by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-OTOFMS) was performed on intracellular extracts and extracellular media. F6H8 induced pronounced, concentration-dependent metabolic alterations, many of which exhibited non-monotonic responses. Low concentrations primarily affected amino acid, fatty acid, and lipid metabolism, while central carbon metabolism was disrupted only at the highest exposures. Notably, a putative biotransformation product, perfluorohexyloctanoic acid, was detected, suggesting metabolic persistence and conversion to a PFAS-like structure. These findings indicate that F6H8 elicits broad metabolic reprogramming and may not be metabolically inert as previously assumed. Given its clinical use and structural similarity to persistent fluorochemicals, the results highlight the need for comprehensive, long-term safety assessment of F6H8 and related semifluorinated alkanes.

pharmacology and toxicology↗

bioRxiv2025

Effects of incrementally increased plant-based protein intake on gut microbiota and inflammatory-metabolic biomarkers in healthy adults

Shifting to a plant-based diet naturally alters protein source choices. In many countries, protein from yellow pea is widely used as main ingredient in meat alternatives. Still, its biological effects, especially regarding gastrointestinal health, remain incompletely understood. The aim of our study was to investigate how a weekly increase in the intake of a well-characterized pea protein isolate affects surrogate markers of health, fecal short-chain fatty acids and gut microbiota composition in healthy individuals. Male and female adults (N=29) participated in this exploratory intervention study. A 4-week pre-intervention period for questionnaires and fecal samples collection was followed by a 4-week supplementation. Participants consumed isolated pea protein in weekly increasing amounts, starting from 0.25 g/kg body mass/day in week 5 to 1.00 g/kg body mass/day in week 8. Questionnaire data, fecal samples as well as fasting blood and 24-h urine samples were collected weekly. Data from biological samples and questionnaires confirmed a healthy study population and compliance. Fecal calprotectin levels significantly increased only in a subset of participants, which was also accompanied by higher fecal water cytotoxicity in vitro. Short-chain fatty acids mainly rose in those subjects with stable calprotectin levels. Relative abundances of Limosilactobacillus frumenti, Odoribacter splanchnicus and Lactobacillus crispatus increased significantly in the total population during the intervention while the relative abundance of Bifidobacterium longum and Bifidobacterium catenulatum decreased. Our results indicate that an increased intake of pea protein isolate affects the growth of certain beneficial bacteria strains and differentially influences markers related to gut inflammation in healthy individuals.

biochemistry↗

bioRxiv2023

Comparative metabolomics and microbiome analysis of Ethanol vs. OMNImet/gene GUT fecal stabilization

Metabolites from feces provide important insights into the functionality of the gut microbiome. As immediate freezing is not always feasible in gut microbiome studies, there is a need for sampling protocols that provide stability of the fecal metabolome and microbiome at room temperature (RT). For this purpose, we investigated the stability of various metabolites and the microbiome (16S ribosomal RNA) in feces collected in 95% ethanol (EtOH) or OMNImet(R)*GUT/ OMNIgene(R)*GUT. To simulate in field-collection scenarios, the samples were stored at different temperatures at varying durations (24h +4{degrees}C, 24h RT, 36h RT, 48h RT, and 7 days RT), and compared to aliquots immediately frozen at -80{degrees}C. We applied several targeted and untargeted metabolomics platforms to measure lipids, polar untargeted metabolites, endocannabinoids, short chain fatty acids (SCFAs), and bile acids (BAs). We found that SCFAs in the non-stabilized samples increased over time, while a stable profile was recorded in sample aliquots stored in 95% EtOH and OMNImet(R)*GUT. When comparing the metabolite levels between fecal aliquots stored at room temperature and at +4{degrees}C, we detected several changes in microbial metabolites, including multiple BAs and SCFAs. Taken together, we found that storing fecal samples at room temperature and stabilizing them in 95% EtOH yielded metabolomic results comparable to flash freezing. We also found that overall composition of the gut microbiome did not vary significantly between different storage types. However, there were notable differences observed in alpha diversity. Taken together, the stability of the metabolome and microbiome in 95 % EtOH provided similar results as the validated commercial collection kits OMNImet(R)*GUT and OMNIgene(R)*GUT, respectively. IMPORTANCEThe analysis of the gut metabolome and microbiome requires the separate collection of fecal specimens using conventional methods or commercial kits. However, these approaches can potentially introduce sampling errors and biases. In addition, the logistical requirements of studying large human cohorts have driven the need for home collection and transport of human fecal specimens at room temperature. By adopting a unified sampling approach at room temperature, we can enhance sampling convenience and practicality, leading to a more precise and comprehensive understanding of gut microbial function. However, the development and applications of such unified sampling systems still face limitations. The results presented in this study aim to address this knowledge gap by investigating the stability of metabolites and the microbiome (16S ribosomal RNA) from fecal samples collected using 95% EtOH, in comparison to well-established commercial collection kits for fecal metabolome (OMNImet(R)*GUT) and microbiome (OMNIgene(R) *GUT) profiling. Additionally, we perform a comparative analysis of various platforms and metabolomic coverage using matrices containing ethanol, evaluating aspects of sensitivity, robustness, and throughput.

biochemistry↗

bioRxiv2022

Dynamics of lipidome in a colon simulator

Current evidence suggests that gut microbiome derived lipids play crucial role in the regulation of host lipid metabolism. However, not much is known about the dynamics of gut microbial lipids within the distinct gut biogeographic. Here we employed targeted and untargeted lipidomics in the in vitro derived feces. Simulated intestinal chyme was collected from in vitro gut vessels (V1-V4), representing proximal to distal parts of the colon after 24 and 48 h with/without PDX treatment. In total 44 simulated chyme samples were collected from the in vitro colon simulator. Factor analysis showed that vessel and time had the strongest impact on the simulated intestinal chyme lipid profiles. We found that levels of phosphatidylcholines, sphingomyelins, triacylglycerols and endocannabinoids were altered in at least one vessel (V1-V4) during simulation. We also found that concentrations of triacylglycerols, diacylglycerols and endocannabinoids changed with time (24 vs. 48 h simulation). Together, we found that the simulated intestinal chyme revealed a wide range of lipids that remained altered in different compartments of the human colon model over time.

biochemistry↗

bioRxiv2021

Perfluorooctanoic Acid Induces Liver and Serum Dyslipidemia in Humanized PPARα Mice Fed an American Diet

Per- and polyfluoroalkyl substances (PFAS) are pervasive in the environment resulting in nearly universal detection in people. Human serum PFAS concentrations are strongly associated with increased serum low-density lipoprotein cholesterol (LDL-C), and growing evidence suggests an association with serum triacylglycerides (TG). Here, we tested the hypothesis that perfluorooctanoic acid (PFOA) dysregulates liver and serum triacylglycerides in human peroxisome proliferator activated receptor (hPPAR)-expressing mice fed an American diet. Mice were exposed to PFOA (3.3 mg/l) in drinking water for 6 weeks resulting in a serum concentration of 48 {+/-} 9 g/ml. In male and female hPPAR mice, PFOA increased total liver TG and TG substituted with saturated and monounsaturated fatty acids. Lack of expression of hPPAR alone also increased total liver TG, and PFOA treatment had little effect on liver TG in null mice. In hPPAR mice, PFOA neither significantly increased nor decreased serum TG; however, there was a modest increase in TG associated with very low-density cholesterol particles in both sexes. Across studies, a non-monotonic effect of PFOA on serum TG is evident, with the serum PFOA concentration in this study falling near the "null point" between increasing and decreasing serum TG. Intriguingly, in female PPAR null mice, PFOA significantly increased serum TG, with a similar trend in males. PFOA also modified fatty acid and TG homeostasis-related gene expression in liver, in a hPPAR-dependent manner, but not in adipose. The results reveal the importance of context (serum concentration and genotype) in determining the effect of PFOA on lipid homeostasis.

pharmacology and toxicology↗

bioRxiv2021

Quantitative analysis and genome-scale modeling of human CD4+ T-cell differentiation reveals subset-specific regulation of glycosphingolipid pathways

T-cells are sentinels of adaptive cell-mediated immune responses. T-cell activation, proliferation and differentiation involves metabolic reprogramming involving the interplay of genes, proteins and metabolites. Here, we aim to understand the metabolic pathways involved in the activation and functional differentiation of human CD4+ T-cell subsets (Th1, Th2, Th17 and iTregs). We combined genome-scale metabolic modeling, gene expression data, targeted and non-targeted lipidomics experiments, together with in vitro gene knockdown experiments and showed that human CD4+ T-cells undergo specific metabolic changes during activation and functional differentiation. In addition, we identified and confirmed the importance of ceramide and glycosphingolipid synthesis pathways in Th17 differentiation and effector functions. Finally, through in vitro gene knockdown experiments, we substantiated the requirement of serine palmitoyl transferase (SPT), a de novo sphingolipid pathway in the expression of proinflammatory cytokine (IL17A and IL17F) by Th17 cells. Our findings may provide a comprehensive resource for identifying CD4+ T-cell-specific targets for their selective manipulation under disease conditions, particularly, diseases characterized by an imbalance of Treg / Th17 cells. Our data also suggest a role for elevated levels of ceramides in conditions comorbid with these diseases, e.g., obesity and insulin resistance.

immunology↗

bioRxiv2019

Targeted Clinical Metabolomics Platform for the Stratification of Diabetic Patients

BackgroundSeveral small molecule biomarkers have been reported in the literature for prediction and diagnosis of (pre)diabetes, its co-morbidities and complications. Here, we report the development and validation of a novel, quantitative, analytical method for use in the diabetes clinic. This method enables the determination of a selected panel of 36 metabolite biomarkers from human plasma.\n\nMethodsBased on a review of the literature and our own data, we selected a panel of metabolites indicative of various clinically-relevant pathogenic stages of diabetes. We combined these candidate biomarkers into a single ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method and optimized it, prioritizing simplicity of sample preparation and time needed for analysis, enabling high-throughput analysis in clinical laboratory settings.\n\nResultsWe validated the method in terms of limit of (a) detection (LOD), (b) limit of quantitation (LOQ), (c) linearity (R2), (d) linear range, and (e) intra- and inter-day repeatability of each metabolite. The methods performance was demonstrated in the analysis of selected samples from a diabetes cohort study. Metabolite levels were associated with clinical measurements and kidney complications in type 1 diabetes (T1D) patients. Specifically, both amino acids and amino acid-related analytes were associated with macro-albuminuria. Additionally, specific bile acids were associated with kidney function, anti-hypertensive medication, statin medication and clinical lipid measurements.\n\nConclusionsThe developed analytical method is suitable for robust determination of selected plasma metabolites in the diabetes clinic.

biochemistry↗

bioRxiv2019

Links between central CB1-receptor availability and peripheral endocannabinoids in patients with first episode psychosis

There is an established, albeit poorly-understood link between psychosis and metabolic abnormalities such as altered glucose metabolism and dyslipidemia, which often precede the initiation of antipsychotic treatment. It is known that obesity-associated metabolic disorders are promoted by peripheral activation of the endocannabinoid system (ECS). Our recent data suggest that ECS dysregulation may also play a role in psychosis. With the aim of characterizing the involvement of the central and peripheral ECSs and their mutual associations, here we performed a combined neuroimaging and metabolomic study in patients with first-episode psychosis (FEP) and healthy controls (HC). Regional brain cannabinoid receptor type 1 (CB1R) availability was quantified in two, independent samples of patients with FEP (n=20 and n=8) and HC (n=20 and n=10), by applying 3D positron emission tomography (PET), using two radiotracers, [11C]MePPEP and [18F]FMPEP-d2. Ten endogenous endocannabinoids or related metabolites were quantified in serum, drawn from these individuals during the same imaging session. Circulating levels of arachidonic acid and oleyl ethanolamide were reduced in FEP individuals, but not in those who were predominantly medication-free. In HC, there was an inverse association between levels of circulating arachidonoyl glycerol, anandamide, oleyl ethanolamide and palmitoyl ethanolamide, and CB1R availability in the posterior cingulate cortex. This phenomenon was, however, not observed in FEP patients. Our data thus provide evidence of cross-talk and dysregulation between peripheral endocannabinoids and central CB1R availability in FEP.

neuroscience↗

bioRxiv2019

Metabolic Alterations in Human Peripheral Blood Mononuclear Cells Associate with Progression to Islet Autoimmunity and Type 1 Diabetes

Previous metabolomics studies suggest that type 1 diabetes (T1D) is preceded by specific metabolic disturbances. Here we asked whether distinct metabolic patterns occur in peripheral blood mononuclear cells (PBMCs) of children later developing pancreatic {beta}-cell autoimmunity or overt T1D. In a longitudinal cohort setting, PBMC metabolomic analysis was applied in children who either (1) progressed to T1D (PT1D, n=34), (2) seroconverted to [≥]1 islet autoantibody without progressing to T1D (P1Ab, n=27), or (3) remained autoantibody negative during follow-up (CTRL, n=10). During the first year of life, levels of most lipids and polar metabolites were lower in PT1D and P1Ab, versus CTRLs. Pathway overrepresentation analysis suggested alanine, aspartate, glutamate, glycerophospholipid and sphingolipid metabolism were overrepresented in PT1D. Genome-scale metabolic models of PBMCs in T1D progression were developed using available transcriptomics data and constrained with metabolomics data from our study. Metabolic modeling confirmed altered ceramide pathways as specifically associated with T1D progression.

molecular biology↗

bioRxiv2019

Prenatal Exposure to Environmental Chemicals Modulates Serum Phospholipids in Newborn Infants, Increasing Later Risk of Type 1 Diabetes

In the last decade, increasing incidence of type 1 diabetes (T1D) stabilized in Finland, a phenomenon that coincides with tighter regulation of perfluoroalkyl substances (PFAS). Here, we quantified PFAS to examine their effects, during pregnancy, on lipid and immune-related markers of T1D risk in children. In a mother-infant cohort (264 dyads), high PFAS exposure during pregnancy associated with decreased cord serum phospholipids and progression to T1D-associated islet autoantibodies in the offspring. This PFAS-lipid association appears exacerbated by increased human leukocyte antigen-conferred risk of T1D in infants. Exposure to a single PFAS compound or a mixture of organic pollutants in non-obese diabetic mice resulted in a lipid profile characterized by a similar decrease in phospholipids, a marked increase of lithocholic acid, and accelerated insulitis. Our findings suggest that PFAS exposure during pregnancy contributes to risk and pathogenesis of T1D in offspring.

molecular biology↗

bioRxiv2018

Circulating Metabolites in Progression to Islet Autoimmunity and Type 1 Diabetes

Previous studies suggest that metabolic dysregulation precedes the onset of type 1 diabetes (T1D). However, these metabolic disturbances and their specific role in disease initiation remain poorly understood. Here we analysed polar metabolites from 415 longitudinal plasma samples in a prospective cohort of children in three study groups: those who progressed to T1D (PT1D), who seroconverted to one islet autoantibody (Ab) but not to T1D (P1Ab), and Ab-negative controls (CTR). In early infancy, PT1D associated with downregulated amino acids, sugar derivatives and fatty acids, including catabolites of microbial origin, as compared to CTR. Methionine remained persistently upregulated in PT1D as compared to CTR and P1Ab. Appearance of islet autoantibodies associated with decreased glutamic and aspartic acids. Our findings suggest that children who progress to T1D have a unique metabolic profile, which is however altered with the onset of islet autoantibodies. Our findings may assist in early prediction of T1D.

biochemistry↗

bioRxiv2018

Dynamics of Plasma Lipidome in Progression to Islet Autoimmunity and Type 1 Diabetes: Type 1 Diabetes Prediction and Prevention Study (DIPP)

Type 1 diabetes (T1D) is one of the most prevalent autoimmune diseases among children in Western countries. Earlier metabolomics studies suggest that T1D is preceded by dysregulation of lipid metabolism. Here we used a lipidomics approach to analyze molecular lipids in a prospective series of 428 plasma samples from 40 children who progressed to T1D (PT1D), 40 children who developed at least a single islet autoantibody but did not progress to T1D during the follow-up (P1Ab) and 40 matched controls (CTR). Sphingomyelins were found to be persistently downregulated in PT1D when compared to the P1Ab and CTR groups. Triacylglycerols and phosphatidylcholines were mainly downregulated in PT1D as compared to P1Ab at the age of 3 months. Our study suggests that children who progressed to islet autoimmunity or overt T1D are characterized by distinct lipidomic signatures, which may be helpful in the identification of at-risk children before the initiation of autoimmunity.

biochemistry↗