Plasma metabolites associated with exposure to perfluoroalkyl substances and risk of type 2 diabetes - A nested case-control study

Perfluoroalkyl substances (PFAS) are widespread persistent environmental pollutants. There is evidence that PFAS induce metabolic perturbations in humans, but underlying mechanisms are still unknown. In this exploratory study, we investigated PFAS-related plasma metabolites for their associations with type 2 diabetes (T2D) to gain potential mechanistic insight in these perturbations.We used untargeted LC-MS metabolomics to find metabolites related to PFAS exposures in a case-control study on T2D (n = 187 matched pairs) nested within the Vasterbotten Intervention Programme cohort. Following principal component analysis (PCA), six PFAS measured in plasma appeared in two groups: 1) perfluorononanoic acid, perfluorodecanoic acid and perfluoroundecanoic acid and 2) perfluorohexane sulfonic acid, perfluorooctane sulfonic acid and perfluorooctanoic acid. Using a random forest algorithm, we discovered metabolite features associated with individual PFAS and PFAS exposure groups which were subsequently investigated for associations with risk of T2D.PFAS levels correlated with 171 metabolite features (0.16 <= vertical bar r vertical bar <= 0.37, false discovery rate (FDR) adjusted p < 0.05). Out of these, 35 associated with T2D (p < 0.05), with 7 remaining after multiple testing adjustment (FDR < 0.05). PCA of the 35 PFAS- and T2D-related metabolite features revealed two patterns, dominated by glycerophospholipids and diacylglycerols, with opposite T2D associations. The glycerophospholipids correlated positively with PFAS and associated inversely with risk for T2D (Odds Ratio (OR) per 1 standard deviation (1-SD) increase in metabolite PCA pattern score = 0.2; 95% Confidence Interval (CI) = 0.1-0.4). The diacylglycerols also correlated positively with PFAS, but they associated with increased risk for T2D (OR per 1-SD = 1.9; 95% CI = 1.3-2.7). These results suggest that PFAS associate with two groups of lipid species with opposite relations to T2D risk

Persistent environmental pollutants and risk of cardiovascular disease

Persistent chemicals emitted in the environment can have a considerable impact on ecosystems and human health, now and in the future. One notorious group of persistent organic pollutants (POPs) is the per- and polyfluoroalkyl substances (PFAS). Since their production in 1940s for household and consumer products, they have accumulated in the environment and in humans via consumption of contaminated drinking water and food. They are hypothesized to induce metabolic disturbances, due to shared chemical similarities with fatty acids. Consequently, PFAS may have high societal and economic impact by increasing risk of obesity, type 2 diabetes (T2D) and cardiovascular disease (CVD). However, reports on these associations are scarce, and the underlying molecular pathways are still unclear. Therefore, in this PhD project, we aimed to i) investigate associations between PFAS and risk of several cardiometabolic diseases and ii) explore potential underlying pathways. In Paper I, we investigated cross-sectional associations between PFAS mixtures and body mass index (BMI) in European teenagers using meta-regression. Results showed a tendency for inverse associations between PFAS and BMI and indicated a potential for diverging contributions between PFAS compounds. In Paper II, using a nested casecontrol study on T2D including metabolomics data in Swedish adults, we found that PFAS correlated positively with glycerophospholipids and diacylglycerols. But whilst glycerophospholipids associated with lower T2D risk, diacylglycerols associated with higher T2D risk. This indicates a potential for diverging effects on disease risk. In Paper III, we investigated whether genetic polymorphisms in peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A), which encodes a master regulator of pathways potentially disrupted by PFAS exposure, associated with secondary cardiovascular events in a large consortium study. However, we did not find clear evidence for such associations. In Paper IV, we assessed associations of PFAS with blood lipids and incident CVD using case-control studies nested in two Swedish adult cohorts. We observed overall null associations with stroke, but a tendency for inverse associations with myocardial infarction as well as associations with higher HDL-cholesterol and lower triglycerides, but also with higher LDL-cholesterol. In Paper V, we included OMICs data (metabolites, proteins and genes), which linked PFAS to lower myocardial infarction risk via lipid and inflammatory pathways. Likewise, a group of ‘old POPs’, the organochlorine compounds (OCs), were linked to higher myocardial infarction risk via the same pathways and to higher stroke risk via mitochondrial pathways. Thus, although we found no evidence for associations between PFAS and increased cardiometabolic disease risk, the overall findings indicate associations of PFAS with metabolic disturbances, particularly lipid metabolism. This is a potential adverse effect on human physiology and warrants further attention

Exposure to persistent organic pollutants alters the serum metabolome in non-obese diabetic mice

Introduction Autoimmune disorders such as type 1 diabetes (T1D) are believed to be caused by the interplay between several genetic and environmental factors. Elucidation of the role of environmental factors in metabolic and immune dysfunction leading to autoimmune disease is not yet well characterized. Objectives Here we investigated the impact of exposure to a mixture of persistent organic pollutants (POPs) on the metabolome in non-obese diabetic (NOD) mice, an experimental model of T1D. The mixture contained organochlorides, organobromides, and per- and polyfuoroalkyl substances (PFAS). Methods Analysis of molecular lipids (lipidomics) and bile acids in serum samples was performed by UPLC-Q-TOF/MS, while polar metabolites were analyzed by GC-Q-TOF/MS. Results Experimental exposure to the POP mixture in these mice led to several metabolic changes, which were similar to those previously reported as associated with PFAS exposure, as well as risk of T1D in human studies. This included an increase in the levels of sugar derivatives, triacylglycerols and lithocholic acid, and a decrease in long chain fatty acids and several lipid classes, including phosphatidylcholines, lysophosphatidylcholines and sphingomyelins. Conclusion Taken together, our study demonstrates that exposure to POPs results in an altered metabolic signature previously associated with autoimmunitypublishedVersio

Persistent organic pollutant exposure as a risk factor of gestational diabetes mellitus:A systematic review and meta-analysis

Background: Findings related to the association between persistent organic pollutants (POPs) and gestational diabetes mellitus (GDM) are inconclusive.Objectives: To estimate the strength of the association between POP exposure and GDM in a systematic review with meta-analysis. Search strategy: MEDLINE, Scopus and Web of Science were searched until July 2023. Selection criteria: Cohort and case–control studies analysing the association between POPs and GDM. Data collection and analysis: We assessed the risk of bias using the Quality in Prognosis Studies scale (QUIPS). Standardised mean differences were pooled using random-effect models. Main results: Sixteen articles including 12 216 participants were selected. The risk of bias was high in four articles (25%), moderate in 11 (68.75%) and low in one (6.25%). Small mean difference between GDM cases and controls was observed for PFHpA (0.26, 95% confidence interval [CI] 0.1–0.35, I2 = 0.0%), PCB180 (0.37, 95% CI 0.19–0.56; I2 = 25.3%), BDE47 (0.23, 95% CI 0.0–0.45, I2 = 0%), BDE99 (0.36, 95% CI 0.14–0.59; I2 = 0%), BDE100 (0.42, 95% CI 0.19–0.64; I2 = 0%) and HCB (0.22, 95% CI 0.01–0.42, I2 = 39.6%). No considerable difference was observed for the rest of POPs. Conclusion: Small mean differences between GDM cases and controls were observed for some POPs. However, evidence shows mostly moderate quality and results were heterogeneous. Improved research methodology is needed to assess POPs and GDM risk.</p

Endocrine Disrupting Chemicals and Type 1 Diabetes

Type 1 diabetes (T1D) is the most common chronic metabolic disease in children and adolescents. The etiology of T1D is not fully understood but it seems multifactorial. The genetic background determines the predisposition to develop T1D, while the autoimmune process against -cells seems to be also determined by environmental triggers, such as endocrine disrupting chemicals (EDCs). Environmental EDCs may act throughout dierent temporal windows as single chemical agent or as chemical mixtures. They could aect the development and the function of the immune system or of the beta-cells function, promoting autoimmunity and increasing the susceptibility to autoimmune attack. Human studies evaluating the potential role of exposure to EDCs on the pathogenesis of T1D are few and demonstrated contradictory results. The aim of this narrative review is to summarize experimental and epidemiological studies on the potential role of exposure to EDCs in the development of T1D.We highlight what we know by animals about EDCs\u2019 eects on mechanisms leading to T1D development and progression. Studies evaluating the EDC levels in patients with T1D were also reported. Moreover, we discussed why further studies are needed and how they should be designed to better understand the causal mechanisms and the next prevention interventions

Persistent Organic Pollutants and Type 2 Diabetes Mellitus. Addressing causality with repeated measurements using novel study designs

Background: Persistent Organic Pollutants (POPs) are chemicals that have negative impacts on the environment and biota and have been investigated as possible risk factors for Type 2 Diabetes Mellitus (T2DM). Other well-established risk factors for T2DM, for example, obesity, increased lipids, and age have been reported to influence human POP concentrations. Previous studies have reported positive associations between single POP measurement and prevalent and incident T2DM, although causality has not been established. Longitudinal studies with repeated pre-diagnostic POP measurements, which may help in addressing causality, are lacking. Aims: This thesis aimed to investigate if the different classes of POPs (perfluoroalkyl acids [PFAAs], polychlorinated biphenyls [PCBs], organochlorine pesticides [OCPs], and polybrominated diphenyl ethers [PBDEs]) are causal factors of T2DM using repeated POP measurements from the same individuals. We also assessed if T2DM status influences the body burden of POPs. Methods: We used questionnaire data and blood samples from two different population-based studies. The Norwegian Women and Cancer study was used to investigate PFAAs-T2DM associations and time trends in PFAAs (2001-2005/06) with two repeated measurements. The Tromsø study was used to study the associations between PCBs, OCPs, PBDEs, and T2DM, and time trends (1986-2016) in cases and controls using three to five repeated POP measurements per individual. Results: Among the PCBs and OCPs, only cis-heptachlor epoxide showed strong pre- and post-diagnostic associations. Further, PCBs and OCPs declined slower in cases compared to controls. PFAAs and PBDEs showed similar time trends in cases and controls, and these POPs were not associated with T2DM before or after diagnosis. Conclusion: The results from this thesis do not support POPs being causal factors of T2DM but suggest that T2DM-related physiological changes may cause retention of certain POPs already years before T2DM diagnosis leading to higher concentrations in prospective cases, and thus, positive associations with T2DM status

A systematic review of evidence that environmental contaminant exposure impedes weight loss and glycemic control during calorie-restricted diets in humans

Calorie-restricted diets cause weight loss and can drive type 2 diabetes remission. However, many patients struggle to achieve clinically relevant weight loss, and the reasons are not well understood. Chemical exposure is associated with obesity and type 2 diabetes development, and some evidence from preclinical experiments suggests it can limit the clinical benefits of calorie restriction. We systematically reviewed the evidence for the effects of environmental chemical exposure on mass loss and glycemic control during diet-induced weight management in humans (PROSPERO: CRD42022339993). Of 222 unique citations, only six papers directly examined this question. Only one targeted people with type 2 diabetes. One linked phthalates and parabens, but not bisphenols, with slower fat loss. Two showed per- and polyfluoroalkyl substances were not associated with mass loss, but with faster subsequent mass regain. One linked impaired adiposity improvements with air pollutants. Two papers reported weight loss-induced elevation in plasma organochlorines associated with altered glycemic control. The risk of bias largely arose from the potential for deviation from the intended diet, and statistics and reporting. The role of chemical exposure in impeding the effectiveness of weight management programs needs to be better understood to provide suitable support to people living with obesity and type 2 diabetes

Endocrine Disrupting Chemicals' Effects in Children: What We Know and What We Need to Learn?

Thousands of natural or manufactured chemicals were defined as endocrine-disrupting chemicals (EDCs) because they can interfere with hormone activity and the endocrine system. We summarize and discuss what we know and what we still need to learn about EDCs' pathogenic mechanisms of action, as well as the effects of the most common EDCs on endocrine system health in childhood. The MEDLINE database (PubMed) was searched on 13 May 2022, filtering for EDCs, endocrine diseases, and children. EDCs are a group of compounds with high heterogeneity, but usually disrupt the endocrine system by mimicking or interfering with natural hormones or interfering with the body's hormonal balance through other mechanisms. Individual EDCs were studied in detail, while humans' "cocktail effect" is still unclear. In utero, early postnatal life, and/or pubertal development are highly susceptible periods to exposure. Human epidemiological studies suggest that EDCs affect prenatal growth, thyroid function, glucose metabolism, obesity, puberty, and fertility through several mechanisms. Further studies are needed to clarify which EDCs can mainly act on epigenetic processes. A better understanding of EDCs' effects on human health is crucial to developing future regulatory strategies to prevent exposure and ensure the health of children today, in future generations, and in the environment

Per and polyfluorinated substances in the Nordic Countries:Use, occurence and toxicology

This Tema Nord report presents a study based on open information and custom market research to review the most common perfluorinated substances (PFC) with less focus on PFOS and PFOA.The study includes three major parts: 1) Identification of relevant per-and polyfluorinated substances and their use in various industrial sectors in the Nordic market by interviews with major players and database information. 2) Emissions to and occurence in the Nordic environment of the substances described in 1). 3) A summary of knowledge of the toxic effects on humans and the environment of substances prioritized in 2). There is a lack of physical chemical data, analystical reference substances, human and environmental occurrence and toxicology data, as well as market information regarding PFCs other than PFOA and PFOS and the current legislation cannot enforce disclosure of specific PFC substance information

New insights on the effects of endocrine-disrupting chemicals on children

Objective: Endocrine disrupting chemicals (EDCs) are present in many areas and materials of the common life, and exposure to these chemicals can occur from products to personal care, from air and food. This review aims to summarize the more recent epidemiological findings for the impact of EDCs on endocrine system health in children, including effects in growth, metabolism, sexual development, and reproduction. Sources: The MEDLINE database (PubMed) was searched on August 24th, 2021, filtering for EDCs, endocrine disruptors, children, and humans. Summary of the findings: Intrauterine exposure of EDCs can have transgenerational effects, thus laying the foundation for disease in later life. The dose-response relationship may not always be predictable as even low-level exposures that may occur in everyday life can have significant effects on a susceptible individual. Although individual compounds have been studied in detail, the effects of a combination of these chemicals are yet to be studied to understand the real-life situation where human beings are exposed to a “cocktail effect” of these EDCs. Epidemiological studies in humans suggest EDCs’ effects on prenatal growth, thyroid function, glucose metabolism, obesity, puberty, and fertility mainly through epigenetic mechanisms. Conclusions: EDCs cause adverse effects in animals, and their effects on human health are now known and irrefutable. Because people are typically exposed to multiple endocrine disruptors, assessing public health effects is difficult. Legislation to ban EDCs and protect especially pregnant women and young children is required and needs to be revised and adjusted to new developments on a regular basis