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| 2. |
- 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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| 3. |
- 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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| 4. |
- Caporale, N., et al.
(författare)
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From cohorts to molecules: Adverse impacts of endocrine disrupting mixtures
- 2022
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 375:6582
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Tidskriftsartikel (refereegranskat)abstract
- Convergent evidence associates exposure to endocrine disrupting chemicals (EDCs) with major human diseases, even at regulation-compliant concentrations. This might be because humans are exposed to EDC mixtures, whereas chemical regulation is based on a risk assessment of individual compounds. Here, we developed a mixture-centered risk assessment strategy that integrates epidemiological and experimental evidence. We identified that exposure to an EDC mixture in early pregnancy is associated with language delay in offspring. At human-relevant concentrations, this mixture disrupted hormone-regulated and disease-relevant regulatory networks in human brain organoids and in the model organisms Xenopus leavis and Danio rerio, as well as behavioral responses. Reinterrogating epidemiological data, we found that up to 54% of the children had prenatal exposures above experimentally derived levels of concern, reaching, for the upper decile compared with the lowest decile of exposure, a 3.3 times higher risk of language delay. © 2022 American Association for the Advancement of Science. All rights reserved.
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| 5. |
- Cotgreave, Ian, et al.
(författare)
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Pyriproxifen and microcephaly: an investigation of potential ties to the ongoing "Zika epidemic"
- 2016
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- As part of the Swetox mission to react to emerging concerns in chemical health and environmental safety, a preliminary litterature investigation was undertaken to gather all readily available scientific information on PPF with respect to safety assessment, in order to better understand potential links between chemical exposure and the devopment of microcephaly in affected areas. Therefore the contents of the report do not constitute an attempt at either questioning the use of existing regulatory data in the manner prescribed by international regulatory proceedures, or as a new risk assessment, based on the scientific information and concepts discussed. Here we report our findings, with particular emphasis on exisiting regulatory information, potential for lack of translation of results from regulatory animal testing to humans, lack of human exposure data and suggestions on plausible mode(s) of action of PPF in human neurodevelopmental adversities such as microcephaly.
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| 6. |
- Engdahl, Elin, et al.
(författare)
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DNA methylation at GRIN2B partially mediates the association between prenatal bisphenol F exposure and cognitive functions in 7-year-old children in the SELMA study
- 2021
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 156
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Tidskriftsartikel (refereegranskat)abstract
- Background: Accumulating evidence suggests that prenatal chemical exposure triggers epigenetic modifications that could influence health outcomes later in life. In this study, we investigated whether DNA methylation (DNAm) levels at the glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B) gene underlies the association between prenatal exposure to an endocrine disrupting chemical (EDC), bisphenol F (BPF), and lower cognitive functions in 7-year-old children. Methods: Data from 799 children participating in the Swedish Environmental Longitudinal Mother and child Asthma and allergy (SELMA) pregnancy cohort was analyzed. Prenatal BPF exposure was assessed by measuring BPF levels in maternal urine. At age 7, DNAm of three CpG sites in a regulatory region of the GRIN2B gene was analyzed from buccal swabs using bisulfite-Pyrosequencing. Cognitive functions, including full-scale IQ and four subscales, were evaluated using the Wechsler Intelligence Scale for Children (WISC-IV). Associations between prenatal BPF exposure and GRIN2B DNAm, as well as between GRIN2B DNAm and cognitive functions, were determined using regression models adjusted for potential confounders. Generalized structural equation models (gSEM) were used to evaluate if GRIN2B DNAm mediates the association between prenatal BPF exposure and cognitive functions at 7 years of age. Results: Prenatal BPF exposure was positively associated with GRIN2B DNAm levels at the third CpG site (CpG3), while CpG3 methylation was inversely associated with cognitive test scores. Mediation analyses showed that CpG3 methylation exerted 6–9% of the association between BPF exposure and full-scale IQ, as well as verbal comprehension and perceptual reasoning in boys, while not significant in girls. Conclusions: This study is the first to identify locus-specific DNAm as a mediating factor underlying an epidemiological association between prenatal EDC exposure and cognitive functions in childhood. It also confirms previous findings, that GRIN2B DNAm is responsive to environmental exposures.
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| 7. |
- Faure, Quentin, et al.
(författare)
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Tomonaga-Luttinger Liquid Spin Dynamics in the Quasi-One-Dimensional Ising-Like Antiferromagnet BaCo2V2O8
- 2019
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Ingår i: Physical Review Letters. - : American Physical Society. - 0031-9007 .- 1079-7114. ; 123:2
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Tidskriftsartikel (refereegranskat)abstract
- Combining inelastic neutron scattering and numerical simulations, we study the quasi-one-dimensional Ising anisotropic quantum antiferromagnet BaCo2V2O8 in a longitudinal magnetic field. This material shows a quantum phase transition from a Neel ordered phase at zero field to a longitudinal incommensurate spin density wave at a critical magnetic field of 3.8 T. Concomitantly, the excitation gap almost closes and a fundamental reconfiguration of the spin dynamics occurs. These experimental results are well described by the universal Tomonaga-Luttinger liquid theory developed for interacting spinless fermions in one dimension. We especially observe the rise of mainly longitudinal excitations, a hallmark of the unconventional low-field regime in Ising-like quantum antiferromagnetic chains.
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| 8. |
- 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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| 9. |
- 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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| 10. |
- Lizunkova, Polina, et al.
(författare)
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Additivity provides a good approximation for the effect of a complex, human-relevant chemical mixture on metabolic outcomes
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Humans and the environment are exposed to complex mixtures of numerous synthetic chemicals. This study investigated whether the additivity model could predict effects of a human-relevant complex chemical mixture. The additivity model analysis was conducted on toxicological data from two experimental models exposed to the mixture and its individual compounds. The chemical mixture was previously identified in an epidemiological study to be associated with lower birth weight. This mixture consisted of 14 fourteen chemicals from different classes. Gompertz nonlinear function was used for individual compound and mixture analysis. We showed that the additivity model provided an adequate and larger estimate for mixture effects for both experimental assays in comparison to the measured effects, despite for one of the assays the test for additivity was rejected. Our results underscore dose addition model applicability for regulatory risk assessment of complex human-relevant chemical mixtures.
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