| 1. |
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| 2. |
- Bjorvang, Richelle D., et al.
(författare)
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Persistent organic pollutants, pre-pregnancy use of combined oral contraceptives, age, and time-to-pregnancy in the SELMA cohort
- 2020
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Ingår i: Environmental Health. - : BMC. - 1476-069X. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background We are exposed to several chemicals such as persistent organic pollutants (POPs) in our everyday lives. Prior evidence has suggested that POPs may have adverse effects on reproductive function by disrupting hormone synthesis and metabolism. While there is age-related decline of fertility, the use of hormonal combined oral contraceptives (COCs) and its association to return of fertility remains controversial. The goal of this study is to investigate the association between exposure to POPs, both individually and as a mixture, and fecundability measured as time-to-pregnancy (TTP) according to pre-pregnancy use of COCs and age. Methods Using the SELMA (Swedish Environmental Longitudinal Mother and Child, Allergy and Asthma) study, we have identified 818 pregnant women aged 18-43 years (mean 29 years) with data on how long they tried to get pregnant and what was their most recently used contraceptive method. These data were collected at enrollment to the study (median week 10 of pregnancy). Concentrations of 22 POPs and cotinine were analyzed in the blood samples collected at the same time as the questions on TTP and pre-pregnancy use of contraceptive. Analyses were done on the association between POPs exposure and TTP measured as continuous (months) and binary (infertile for those with TTP > 12 months). To study the chemicals individually, Cox regression and logistic regression were used to estimate fecundability ratios (FRs) and odds ratios (ORs), respectively. Weighted quantile sum (WQS) regression was used to investigate the chemicals as a mixture where chemicals of concern were identified above the 7.6% threshold of equal weights. To perform the subgroup analysis, we stratified the sample according to use of COCs as the most recent pre-pregnancy contraception method and age (< 29 years, and >= 29 years). The models were adjusted for parity, regularity of menses, maternal body mass index (BMI) and smoking status, and stratified as described above. Results Prior to stratification, none of the POPs were associated with fecundability while increased exposure to HCB, PCB 74 and 118 had higher odds of infertility. Upon stratification, POP exposure was significantly associated with longer TTP in women aged >= 29 years who did not use COC. Specifically, PCBs 156, 180, 183, and 187 were associated with reduced fecundability while PCBs 99, 153, 156, 180, 183, and 187 had higher odds of infertility. As a mixture, we identified the chemicals of concern for a longer TTP include PCBs 118, 156, 183, and 187. Moreover, chemicals of concern identified with increased odds of infertility were PCB 74, 156, 183, 187, and transnonachlor. Conclusion Serum concentrations of selected POPs, both as individual chemicals and as a mixture, were significantly associated with lower fecundability and increased odds of infertility in women aged 29 years and above not using COC as their most recent pre-pregnancy contraceptive. Our findings suggest that pre-pregnancy use of oral contraceptive and age may modify the link between POPs and fecundability. The differences of specific chemicals in the individual analysis and as a mixture support the need to study combination effects of chemicals when evaluating reproductive outcomes.
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| 3. |
- Bornehag, Carl-Gustaf, 1957-, et al.
(författare)
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A Novel Approach to Chemical Mixture Risk Assessment—Linking Data from Population-Based Epidemiology and Experimental Animal Tests
- 2019
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Ingår i: Risk Analysis. - : John Wiley & Sons. - 0272-4332 .- 1539-6924. ; 39:10, s. 2259-2271
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Tidskriftsartikel (refereegranskat)abstract
- Humans are continuously exposed to chemicals with suspected or proven endocrine disrupting chemicals (EDCs). Risk management of EDCs presents a major unmet challenge because the available data for adverse health effects are generated by examining one compound at a time, whereas real-life exposures are to mixtures of chemicals. In this work, we integrate epidemiological and experimental evidence toward a whole mixture strategy for risk assessment. To illustrate, we conduct the following four steps in a case study: (1) identification of single EDCs (“bad actors”)—measured in prenatal blood/urine in the SELMA study—that are associated with a shorter anogenital distance (AGD) in baby boys; (2) definition and construction of a “typical” mixture consisting of the “bad actors” identified in Step 1; (3) experimentally testing this mixture in an in vivo animal model to estimate a dose–response relationship and determine a point of departure (i.e., reference dose [RfD]) associated with an adverse health outcome; and (4) use a statistical measure of “sufficient similarity” to compare the experimental RfD (from Step 3) to the exposure measured in the human population and generate a “similar mixture risk indicator” (SMRI). The objective of this exercise is to generate a proof of concept for the systematic integration of epidemiological and experimental evidence with mixture risk assessment strategies. Using a whole mixture approach, we could find a higher rate of pregnant women under risk (13%) when comparing with the data from more traditional models of additivity (3%), or a compound-by-compound strategy (1.6%).
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| 4. |
- Bornehag, Carl-Gustav, 1957-, et al.
(författare)
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Prenatal exposure to bisphenols and cognitive function in children at 7 years of age in the Swedish SELMA study
- 2021
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 150
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Tidskriftsartikel (refereegranskat)abstract
- Background: Experimental evidence demonstrates that exposure to bisphenol A (BPA), and the recently intro-duced alternatives bisphenol S (BPS) and bisphenol F (BPF) alter normal neurodevelopment. More research is needed to evaluate the associations between exposure to individual BPA alternatives and neurodevelopmental outcomes in humans. Objective: The present study aimed at examining the individual associations between prenatal BPA , BPS and BPF exposure and cognitive outcomes in children at age 7 years. Method: Women were enrolled in the Swedish Environmental Longitudinal Mother and Child, Asthma and Al-lergy (SELMA) study, at gestational median week 10.0, and their children were examined for cognitive function at 7 years of age (N = 803). Maternal urina r y BPA , BPS, and BPF concentrations were measured at enrollment and children?s cognitive function at the age of 7 years was measured using the Wechsler Intelligence Scale for Children IV (WISC-IV). Results: A l l three bisphenols were detected in over 90% of the women, where BPA had the highest geometric mean concentrations (1.55 ng/mL), followed by BPF (0.16 ng/mL) and BPS (0.07 ng/mL). Prenatal BPF exposure was associated with decreased f u l l scale IQ (13 =-1.96, 95%CI;-3.12;-0.80), as we l l as with a decrease in a l l four sub scales covering verbal comprehension, perceptual reasoning, working memor y and processing speed. This association corresponded to a 1.6-point lower IQ score for an inter-quartile-range (IQR) change in prenatal BPF exposure (IQR = 0.054 & ndash;0.350 ng/mL). In sex-stratified analyses, significant associations with f u l l scale IQ were found for boys (13 = - 2.86, 95%CI;-4.54;-1.18), while the associations for girls did not reach significance (13 =-1.38, 95%CI;-2.97; 0.22). No significant associations between BPA nor BPS and cognition were found. Discussion: Prenatal exposure to BPF was significantly associated with children?s cognitive function at 7 years. Since BPF is replacing BPA in numerous consumer products globally, this finding urgently ca l l for further studies.
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| 5. |
- Di Criscio, Michela, et al.
(författare)
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A human-relevant mixture of endocrine disrupting chemicals induces changes in hippocampal DNA methylation correlating with hyperactive behavior in male mice
- 2023
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Ingår i: Chemosphere. - : Elsevier. - 0045-6535 .- 1879-1298. ; 313
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Tidskriftsartikel (refereegranskat)abstract
- Humans are ubiquitously exposed to endocrine disrupting chemicals (EDCs), substances that interfere with endogenous hormonal signaling. Exposure during early development is of particular concern due to the programming role of hormones during this period. A previous epidemiological study has shown association between prenatal co-exposure to 8 EDCs (Mixture N1) and language delay in children, suggesting an effect of this mixture on neurodevelopment. Furthermore, in utero exposure to Mixture N1 altered gene expression and behavior in adult mice. In this study, we investigated whether epigenetic mechanisms could underlie the long term effects of Mixture N1 on gene expression and behavior. To this end, we analyzed DNA methylation at regulatory regions of genes whose expression was affected by Mixture N1 in the hippocampus of in utero exposed mice using bisulfite-pyrosequencing. We show that Mixture N1 decreases DNA methylation in males at three genes that are part of the hypothalamus-pituitary-adrenal (HPA) axis: Nr3c1, Nr3c2, and Crhr1, coding for the glucocorticoid receptor, the mineralocorticoid receptor, and the corticotropin releasing hormone receptor 1, respectively. Furthermore, we show that the decrease in Nr3c1 methylation correlates with increased gene expression, and that Nr3c1, Nr3c2, and Crhr1 methylation correlates with hyperactivity and reduction in social behavior. These findings indicate that an EDC mixture corresponding to a human exposure scenario induces epigenetic changes, and thus programming effects, on the HPA axis that are reflected in the behavioral phenotypes of the adult male offspring.
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| 6. |
- Gennings, Chris, et al.
(författare)
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Incorporating regulatory guideline values in analysis of epidemiology data
- 2018
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 120, s. 535-543
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Tidskriftsartikel (refereegranskat)abstract
- Fundamental to regulatory guidelines is to identify chemicals that are implicated with adverse human health effects and inform public health risk assessors about “acceptable ranges” of such environmental exposures (e.g., from consumer products and pesticides). The process is made more difficult when accounting for complex human exposures to multiple environmental chemicals. Herein we propose a new class of nonlinear statistical models for human data that incorporate and evaluate regulatory guideline values into analyses of health effects of exposure to chemical mixtures using so-called ‘desirability functions’ (DFs). The DFs are incorporated into nonlinear regression models to allow for the simultaneous estimation of points of departure for risk assessment of combinations of individual substances that are parts of chemical mixtures detected in humans. These are, in contrast to published so-called biomonitoring equivalent (BE) values and human biomonitoring (HBM) values that link regulatory guideline values from in vivo studies of single chemicals to internal concentrations monitored in humans. We illustrate the strategy through the analysis of prenatal concentrations of mixtures of 11 chemicals with suspected endocrine disrupting properties and two health effects: birth weight and language delay at 2.5 years. The strategy allows for the creation of a Mixture Desirability Function i.e., MDF, which is a uni-dimensional construct of the set of single chemical DFs; thus, it focuses the resulting inference to a single dimension for a more powerful one degree-of-freedom test of significance. Based on the application of this new method we conclude that the guideline values need to be lower than those for single chemicals when the chemicals are observed in combination to achieve a similar level of protection as was aimed for the individual chemicals. The proposed modeling may thus suggest data-driven uncertainty factors for single chemical risk assessment that takes environmental mixtures into account.
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| 7. |
- Gennings, Chris, et al.
(författare)
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Using Metrics of a Mixture Effect and Nutrition from an Observational Study for Consideration towards Causal Inference
- 2022
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI. - 1661-7827 .- 1660-4601. ; 19:4
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Tidskriftsartikel (refereegranskat)abstract
- Environmental exposures to a myriad of chemicals are associated with adverse health effects in humans, while good nutrition is associated with improved health. Single chemical in vivo and in vitro studies demonstrate causal links between the chemicals and outcomes, but such studies do not represent human exposure to environmental mixtures. One way of summarizing the effect of the joint action of chemical mixtures is through an empirically weighted index using weighted quantile sum (WQS) regression. My Nutrition Index (MNI) is a metric of overall dietary nutrition based on guideline values, including for pregnant women. Our objective is to demonstrate the use of an index as a metric for more causally linking human exposure to health outcomes using observational data. We use both a WQS index of 26 endocrine-disrupting chemicals (EDCs) and MNI using data from the SELMA pregnancy cohort to conduct causal inference using g-computation with counterfactuals for assumed either reduced prenatal EDC exposures or improved prenatal nutrition. Reducing the EDC exposure using the WQS index as a metric or improving dietary nutrition using MNI as a metric, the counterfactuals in a causal inference with one SD change indicate significant improvement in cognitive function. Evaluation of such a strategy may support decision makers for risk management of EDCs and individual choices for improving dietary nutrition.
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| 8. |
- Levin-Schwartz, Yuri, et al.
(författare)
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Exosomal miRNAs in urine associated with children's cardiorenal parameters : A cross-sectional study
- 2021
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Ingår i: Epigenetics. - : Future Medicine Ltd. - 1559-2294 .- 1559-2308. ; 13:7, s. 499-512
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Tidskriftsartikel (refereegranskat)abstract
- Aims: The authors sought to examine associations between urinary exosomal miRNAs (exo-miRs), emerging biomarkers of renal health, and cardiorenal outcomes in early childhood. Materials & Methods: The authors extracted exo-miRs in urine from 88 healthy Mexican children aged 4-6 years. The authors measured associations between 193 exo-miRs and cardiorenal outcomes: systolic/diastolic blood pressure, estimated glomerular filtration rate and urinary sodium and potassium levels. The authors adjusted for age, sex, BMI, socioeconomic status, indoor tobacco smoke exposure and urine specific gravity. Results: Multiple exo-miRs were identified meeting a false discovery rate threshold of q < 0.1. Specifically, three exo-miRs had increased expression with urinary sodium, 17 with urinary sodium-to-potassium ratio and one with decreased estimated glomerular filtration rate. Conclusions: These results highlight urinary exo-miRs as early-life biomarkers of children's cardiorenal health.
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| 9. |
- Lizunkova, Polina, et al.
(författare)
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A Mixture of Endocrine Disrupting Chemicals Associated with Lower Birth Weight in Children Induces Adipogenesis and DNA Methylation Changes in Human Mesenchymal Stem Cells
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 23:4
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Tidskriftsartikel (refereegranskat)abstract
- Endocrine Disrupting Chemicals (EDCs) are man-made compounds that alter functions of the endocrine system. Environmental mixtures of EDCs might have adverse effects on human health, even though their individual concentrations are below regulatory levels of concerns. However, studies identifying and experimentally testing adverse effects of real-life mixtures are scarce. In this study, we aimed at evaluating an epidemiologically identified EDC mixture in an experimental setting to delineate its cellular and epigenetic effects. The mixture was established using data from the Swedish Environmental Longitudinal Mother and child Asthma and allergy (SELMA) study where it was associated with lower birth weight, an early marker for prenatal metabolic programming. This mixture was then tested for its ability to change metabolic programming of human mesenchymal stem cells. In these cells, we assessed if the mixture induced adipogenesis and genome-wide DNA methylation changes. The mixture increased lipid droplet accumulation already at concentrations corresponding to levels measured in the pregnant women of the SELMA study. Furthermore, we identified differentially methylated regions in genes important for adipogenesis and thermogenesis. This study shows that a mixture reflecting human real-life exposure can induce molecular and cellular changes during development that could underlie adverse outcomes.
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| 10. |
- Lizunkova, Polina, et al.
(författare)
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A Mixture of Endocrine Disrupting Chemicals Associated with Lower Birth Weight Induces Adipogenesis and Transcriptional Changes in Human Mesenchymal Stem Cells.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- There are concerns about the involvement of endocrine-disrupting chemicals (EDCs) exposure in the development of metabolic disorders and obesity. Humans are continuously exposed to complex mixtures of EDCs. This study examined effects of a human-relevant EDC mixture on cellular and underlying molecular changes in human mesenchymal stem cells (hMSCs). The EDC mixture consisted of nine chemicals from different classes. Prenatal exposure to this mixture in a previously published epidemiological study was negatively associated with birth weight, an early risk marker for development of metabolic diseases later in life. hMSCs were treated with this mixture in human-relevant concentrations. Adipogenesis was assessed via lipid droplet accumulation assay, while transcriptional changes were assessed by RNA-seq. The exposure to this mixture increased lipid droplet accumulation and gene expression of over 1000 genes, both in dose-dependent manner in hMSCs. The genes that were found to be upregulated by the EDC mixture were associated with cell division. We did not observe upregulation of adipogenesis related genes, however, some of the downregulated genes are known to be involved in osteogenic MSCs differentiation. Additionally, the EDC mixture affected expression of genes that were enriched in corticoid-regulated categories, including some that are known to be involved in osteogenic MSCs differentiation. Our findings demonstrate that a human-relevant EDC exposure can increase adipogenesis as well as possibly alter the balance between adipogenesis and osteogenesis of MSCs. These processes are essential during metabolic programming, hence our results emphasize the role of a human-relevant EDCs as potential metabolic disruptors and potential contributors to the global metabolic disorder epidemic.
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