| 1. |
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| 2. |
- Ali, Imran, et al.
(författare)
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From pure compounds to complex exposure : Effects of dietary cadmium and lignans on estrogen, epidermal growth factor receptor, and mitogen activated protein kinase signaling in vivo.
- 2016
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Ingår i: Toxicology Letters. - : Elsevier BV. - 0378-4274 .- 1879-3169. ; 253
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to environmental endocrine active compounds correlates with altered susceptibility to disease in human populations. Chemical risk assessment is single compound based, although exposure often takes place as heterogeneous mixtures of man-made and natural substances within complex matrices like diet. Here we studied whether the effects of cadmium and enterolactone on endocrine endpoints in dietary exposure can be predicted based on pure compound effects. Ovariectomized estrogen reporter ERE-luciferase (ERE-luc) mice were maintained on diets that intrinsically contain increasing concentrations of cadmium and enterolactone precursors for three and 21 days. The activation of the ERE-luc, epidermal growth factor receptor (EGFR), mitogen activated protein kinase (MAPK)-ERK1/2, and classical estrogen responses were measured. Interactions between the diets and endogenous hormone were evaluated by challenging the animals with 17β-estradiol. Compared to animals on basal purified diet, mice consuming experimental diets were exposed to significantly higher levels of cadmium and enterolactone, yet the exposure remained comparable to typical human dietary intake. Surprisingly, we could not detect effects on endpoints regulated by pure enterolactone, such as ERE-luc activation. However, cadmium accumulation in the liver was accompanied with activation of EGFR and MAPK-ERK1/2 in line with our earlier CdCl2 studies. Further, attenuation of 17β-estradiol-induced ERE-luc response in liver by experimental diets was observed. Our findings indicate that the exposure context can have substantial effects on the activity of endocrine active compounds in vivo. Thus, whenever possible, a context that mimics human exposure should be tested along with pure compounds.
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| 3. |
- Barde, Swapnali, et al.
(författare)
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Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide
- 2016
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Ingår i: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 113:52, s. E8472-E8481
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Tidskriftsartikel (refereegranskat)abstract
- Major depressive disorder (MDD) is a substantial burden to patients, families, and society, but many patients cannot be treated adequately. Rodent experiments suggest that the neuropeptide galanin (GAL) and its three G protein-coupled receptors, GAL(1-3), are involved in mood regulation. To explore the translational potential of these results, we assessed the transcript levels (by quantitative PCR), DNA methylation status (by bisulfite pyrosequencing), and GAL peptide by RIA of the GAL system in postmortem brains from depressed persons who had committed suicide and controls. Transcripts for all four members were detected and showed marked regional variations, GAL and galanin receptor 1 (GALR1) being most abundant. Striking increases in GAL and GALR3 mRNA levels, especially in the noradrenergic locus coeruleus and the dorsal raphe nucleus, in parallel with decreased DNA methylation, were found in both male and female suicide subjects as compared with controls. In contrast, GAL and GALR3 transcript levels were decreased, GALR1 was increased, and DNA methylation was increased in the dorsolateral prefrontal cortex of male suicide subjects, however, there were no changes in the anterior cingulate cortex. Thus, GAL and its receptor GALR3 are differentially methylated and expressed in brains of MDD subjects in a region- and sex-specific manner. Such an epigenetic modification in GALR3, a hyperpolarizing receptor, might contribute to the dysregulation of noradrenergic and serotonergic neurons implicated in the pathogenesis of MDD. Thus, one may speculate that a GAL(3) antagonist could have antidepressant properties by disinhibiting the firing of these neurons, resulting in increased release of noradrenaline and serotonin in forebrain areas involved in mood regulation.
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| 4. |
- Blanc, Mélanie, 1993-, et al.
(författare)
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Environmental chemicals differentially affect epigenetic-related mechanisms in the zebrafish liver (ZF-L) cell line and in zebrafish embryos
- 2019
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Ingår i: Aquatic Toxicology. - : Elsevier. - 0166-445X .- 1879-1514. ; 215
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Tidskriftsartikel (refereegranskat)abstract
- A number of chemicals have been shown to affect epigenetic patterning and functions. Since epigenetic mechanisms regulate transcriptional networks, epigenetic changes induced by chemical exposure can represent early molecular events for long-term adverse physiological effects. Epigenetics has thus appeared as a research field of major interest within (eco)toxicological sciences. The present study aimed at measuring effects on epigenetic-related mechanisms of selected environmental chemicals (bisphenols, perfluorinated chemicals, methoxychlor, permethrin, vinclozolin and coumarin 47) in zebrafish embryos and liver cells (ZFL). Transcription of genes related to DNA methylation and histone modifications was measured and global DNA methylation was assessed in ZFL cells using the LUMA assay. The differences in results gathered from both models suggest that chemicals affect different mechanisms related to epigenetics in embryos and cells. In zebrafish embryos, exposure to bisphenol A, coumarin 47, methoxychlor and permethrin lead to significant transcriptional changes in epigenetic factors suggesting that they can impact early epigenome reprogramming related to embryonic development. In ZFL cells, significant transcriptional changes were observed upon exposure to all chemicals but coumarin 47; however, only perfluorooctane sulfonate induced significant effects on global DNA methylation. Notably, in contrast to the other tested chemicals, perfluorooctane sulfonate affected only the expression of the histone demethylase kdm5ba. In addition, kdm5ba appeared as a sensitive gene in zebrafish embryos as well. Taken together, the present results suggest a role for kdm5ba in regulating epigenetic patterns in response to chemical exposure, even though mechanisms remain unclear. To confirm these findings, further evidence is required regarding changes in site-specific histone marks and DNA methylation together with their long-term effects on physiological outcomes.
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| 5. |
- Blanc, Mélanie, 1993-
(författare)
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How can an organism´s life experience affect their descendants? Insights from epigenetic and transgenerational effects of chemical exposure in zebrafish
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Environmental pollution causes approx. 10% of human diseases, and some develop in the progeny because of parental exposure. Effects passed on to subsequent generations may be a consequence of genetic mutations, or of inherited changes in epigenetic patterns. Epigenetics is the study of mitotically or meiotically heritable changes in gene function that cannot be explained by changes in the DNA sequence. Several chemicals have been suggested to induce epigenetic dysregulation leading to multigenerational and transgenerational effects, i.e. effects that can be observed in completely unexposed generations. However, mechanisms underlying the inheritance of epigenetic changes and their implication in phenotypic adversities are complex and not well-understood. The overall aim of this thesis was to study adverse effects and underlying molecular changes in several generations of zebrafish after parental exposure to selected industrial chemicals. To this end, molecular (lipidomic, transcriptomic, epigenomic) and behavioral analyses were performed. Zebrafish is an acknowledged model for vertebrates in toxicology and biomedicine; as such, the findings can be relevant to many organisms including human. The results from this thesis showed that different types of chemicals, polychlorinated biphenyls, polybromodiphenyl ethers, and permethrin, induced transgenerational effects in concentrations relevant to environmental or human exposures. Impact on anxiety and locomotor activity of zebrafish was observed over several generations. Gene expression and epigenetic (DNA methylation) alterations were partly inherited and suggest stable alteration of specific functions such as glutamatergic/GABAergic neurotransmission and synaptic plasticity. Finally, the findings shed light on experimental limitations and research perspectives, which we expect will contribute to the design of future studies on epigenetically inherited effects of any environmental stress.
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| 6. |
- Blanc, Mélanie, 1993-, et al.
(författare)
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The insecticide permethrin induces transgenerational behavioral changes linked to transcriptomic and epigenetic alterations in zebrafish (Danio rerio)
- 2021
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Ingår i: Science of the Total Environment. - : Elsevier. - 0048-9697 .- 1879-1026. ; 779
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Tidskriftsartikel (refereegranskat)abstract
- The pyrethroid insecticide permethrin is widely used for agricultural and domestic purposes. Previous data indicated that it acts as a developmental neurotoxicant and can induce transgenerational effects in non-target organisms. However, associated underlying mechanisms remain unclear. The aim of this study was to investigate permethrin-related transgenerational effects in the zebrafish model, and to identify possible molecular mechanisms underlying inheritance. Zebrafish (F0) were exposed to permethrin during early-life (2 h post-fertilization up to 28 days). The F1 and F2 offspring generations were obtained by pairing exposed F0 males and females, and were bred unexposed. Locomotor and anxiety behavior were investigated, together with transcriptomic and epigenomic (DNA methylation) changes in brains. Permethrin exposed F0 fish were hypoactive at adulthood, while males from the F1 and F2 generations showed a specific decrease in anxiety-like behavior. In F0, transcriptomic data showed enrichment in pathways related to glutamatergic synapse activity, which may partly underlie the behavioral effects. In F1 and F2 males, dysregulation of similar pathways was observed, including a subset of differentially methylated regions that were inherited from the F0 to the F2 generation and indicated stable dysregulation of glutamatergic signaling. Altogether, the present results provide novel evidence on the transgenerational neurotoxic effects of permethrin, as well as mechanistic insight: a transient exposure induces persistent transcriptional and DNA methylation changes that may translate into transgenerational alteration of glutamatergic signaling and, thus, into behavioral alterations.
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| 7. |
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| 8. |
- Bopp, Stephanie K., et al.
(författare)
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Current EU research activities on combined exposure to multiple chemicals
- 2018
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 120, s. 544-562
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Forskningsöversikt (refereegranskat)abstract
- Humans and wildlife are exposed to an intractably large number of different combinations of chemicals via food, water, air, consumer products, and other media and sources. This raises concerns about their impact on public and environmental health. The risk assessment of chemicals for regulatory purposes mainly relies on the assessment of individual chemicals. If exposure to multiple chemicals is considered in a legislative framework, it is usually limited to chemicals falling within this framework and co-exposure to chemicals that are covered by a different regulatory framework is often neglected. Methodologies and guidance for assessing risks from combined exposure to multiple chemicals have been developed for different regulatory sectors, however, a harmonised, consistent approach for performing mixture risk assessments and management across different regulatory sectors is lacking. At the time of this publication, several EU research projects are running, funded by the current European Research and Innovation Programme Horizon 2020 or the Seventh Framework Programme. They aim at addressing knowledge gaps and developing methodologies to better assess chemical mixtures, by generating and making available internal and external exposure data, developing models for exposure assessment, developing tools for in silico and in vitro effect assessment to be applied in a tiered framework and for grouping of chemicals, as well as developing joint epidemiological-toxicological approaches for mixture risk assessment and for prioritising mixtures of concern. The projects EDC-MixRisk, EuroMix, EUToxRisk, HBM4EU and SOLUTIONS have started an exchange between the consortia, European Commission Services and EU Agencies, in order to identify where new methodologies have become available and where remaining gaps need to be further addressed. This paper maps how the different projects contribute to the data needs and assessment methodologies and identifies remaining challenges to be further addressed for the assessment of chemical mixtures.
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| 9. |
- 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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| 10. |
- 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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| 11. |
- 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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| 12. |
- Cediel Ulloa, Andrea, et al.
(författare)
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Epigenetics of methylmercury
- 2023
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Ingår i: Neurotoxicology. - : Elsevier BV. - 0161-813X .- 1872-9711. ; 97, s. 34-46
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Tidskriftsartikel (refereegranskat)abstract
- Purpose of review: Methylmercury (MeHg) is neurotoxic at high levels and particularly affects the developing brain. One proposed mechanism of MeHg neurotoxicity is alteration of the epigenetic programming. In this review, we summarise the experimental and epidemiological literature on MeHg-associated epigenetic changes.Recent findings: Experimental and epidemiological studies have identified changes in DNA methylation following in utero exposure to MeHg, and some of the changes appear to be persistent. A few studies have evaluated associations between MeHg-related changes in DNA methylation and neurodevelopmental outcomes. Experimental studies reveal changes in histone modifications after MeHg exposure, but we lack epidemiological studies supporting such changes in humans. Experimental and epidemiological studies have identified microRNA-related changes associated with MeHg; however, more research is needed to conclude if these changes lead to persistent and toxic effects.Summary: MeHg appears to interfere with epigenetic processes, potentially leading to persistent changes. However, observed associations of mercury with epigenetic changes are as of yet of unknown relevance to neurodevelopmental outcomes.
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| 13. |
- Cediel Ulloa, Andrea, et al.
(författare)
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Impact of endocrine disrupting chemicals on neurodevelopment : the need for better testing strategies for endocrine disruption-induced developmental neurotoxicity
- 2022
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Ingår i: Expert Review of Endocrinology & Metabolism. - : Taylor & Francis. - 1744-6651 .- 1744-8417. ; 17:2, s. 131-141
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Brain development is highly dependent on hormonal regulation. Exposure to chemicals disrupting endocrine signaling has been associated with neurodevelopmental impairment. This raises concern about exposure to the suspected thousands of endocrine disruptors, and has resulted in efforts to improve regulation of these chemicals. Yet, the causal links between endocrine disruption and developmental neurotoxicity, which would be required for regulatory action, are still largely missing. Areas covered: In this review, we illustrate the importance of two endocrine systems, thyroid hormone and retinoic acid pathways, for neurodevelopment. We place special emphasis on TH and RA synthesis, metabolism, and how endocrine disrupting chemicals known or suspected to affect these systems are associated with developmental neurotoxicity. Expert opinion: While it is clear that neurodevelopment is dependent on proper hormonal functioning, and evidence is increasing for developmental neurotoxicity induced by endocrine disrupting chemicals, this is not grasped by current chemical testing. Thus, there is an urgent need to develop test methods detecting endocrine disruption in the context of neurodevelopment. Key to this development is further mechanistic insights on the involvement of endocrine signaling in neurodevelopment as well as increased support to develop and validate new test methods for the regulatory context.
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| 14. |
- Cediel Ulloa, Andrea, et al.
(författare)
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Methylmercury-induced DNA methylation—From epidemiological observations to experimental evidence
- 2022
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Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Methylmercury (MeHg) is a developmental neurotoxicant, and one potential mechanism of MeHg toxicity is epigenetic dysregulation. In a recent meta-analysis of epigenome-wide association studies (EWAS), associations between prenatal MeHg exposure and DNA methylation at several genomic sites were identified in blood from newborns and children. While EWASs reveal human-relevant associations, experimental studies are required to validate the relationship between exposure and DNA methylation changes, and to assess if such changes have implications for gene expression. Herein, we studied DNA methylation and gene expression of five of the top genes identified in the EWAS meta-analysis, MED31, MRPL19, GGH, GRK1, and LYSMD3, upon MeHg exposure in human SH-SY5Y cells exposed to 8 or 40 nM of MeHg during differentiation, using bisulfite-pyrosequencing and qPCR, respectively. The concentrations were selected to cover the range of MeHg concentrations in cord blood (2–8.5 μg/L) observed in the cohorts included in the EWAS. Exposure to MeHg increased DNA methylation at MED31, a transcriptional regulator essential for fetal development. The results were in concordance with the epidemiological findings where more MED31 methylation was associated with higher concentrations of MeHg. Additionally, we found a non-significant decrease in DNA methylation at GGH, which corresponds to the direction of change observed in the EWAS, and a significant correlation of GGH methylation with its expression. In conclusion, this study corroborates some of the EWAS findings and puts forward candidate genes involved in MeHg’s effects on the developing brain, thus highlighting the value of experimental validation of epidemiological association studies.
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| 15. |
- Cediel-Ulloa, Andrea, 1989-
(författare)
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Novel Endpoints To Unravel Developmental Neurotoxicity : From DNA methylation responses to methylmercury to the in vitro identification of endocrine disruptors
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The developing brain is especially sensitive to environmental stressors due to its dependence on the precise spatiotemporal regulation of multiple signals, and the long time period required for its formation. Some chemicals can interfere with molecular and cellular processes driving brain development, including epigenetic processes such as DNA methylation. Hence, identification of DNA methylation changes induced by chemical exposure may serve as early molecular markers for developmental neurotoxicity (DNT). Chemicals known as endocrine disruptors (EDCs) can produce adverse effects due to their capability to alter the endocrine system. Since brain development is highly dependent on endocrine signals, the potential adverse effects of EDCs on brain development needs to be addressed. Detection of DNT in the regulatory context has been based on in vivo testing, however, the financial costs and time intensive characteristics of these methods have resulted in a limited assessment of the DNT hazard of chemicals. In addition, in order to regulate EDCs, it is paramount to demonstrate that their adverse effects are a product of disruption of endocrine signals. Yet, at the moment, there are no approved methods which address both an endocrine mode of action and adverse neurodevelopmental outcomes. This doctoral thesis had two main aims: Firstly, to identify epigenetic changes, at the level of DNA methylation, underlying DNT induced by exposure to methylmercury (MeHg); and secondly, to develop new approach methods (NAMs) for the detection of DNT induced by endocrine disruption. Epigenetic effects were studied both in epidemiological data and experimentally in vitro. Associations between prenatal MeHg exposure and DNA methylation of GRIN2B and NR3C1 were found in children. In vitro validation of DNA methylation changes found in epigenome-wide association studies of populations exposed to MeHg, uncovered the potential involvement of the Mediator Complex Subunit 31 (MED31) in MeHg DNT. To contribute to the endocrine disruption (ED)-induced DNT field, the applicability of an in vitro model composed of murine neural progenitor cells (the C17.2 cell-line) was evaluated. We found that C17.2 neural differentiation and morphology were sensitive to retinoic acid (RAR), retinoic X (RXR), peroxisome proliferator-activated β/δ (PPARβ/δ), and glucocorticoid (GR) agonism. Furthermore, two out of 25 tested EDCs decreased neurite outgrowth and branching in the C17.2 system. These effects were recovered by co-exposure of the chemicals with antagonists of RAR, RXR, or PPARβ/δ, indicating that their DNT effect is mediated by hormonal disruption. Altogether, this thesis contributed to the development of new methodologies and endpoints for the assessment of DNT induced by MeHg and EDCs.
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| 16. |
- Cediel Ulloa, Andrea, et al.
(författare)
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Prenatal methylmercury exposure and DNA methylation in seven-year-old children in the Seychelles Child Development Study
- 2021
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 147
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundMethylmercury (MeHg) is present in fish and is a neurotoxicant at sufficiently high levels. One potential mechanism of MeHg toxicity early in life is epigenetic dysregulation that may affect long-term neurodevelopment. Altered DNA methylation of nervous system-related genes has been associated with adult mental health outcomes.ObjectiveTo assess associations between prenatal MeHg exposure and DNA methylation (at the cytosine of CG dinucleotides, CpGs) in three nervous system-related genes, encoding brain-derived neurotropic factor (BDNF), glutamate receptor subunit NR2B (GRIN2B), and the glucocorticoid receptor (NR3C1), in children who were exposed to MeHg in utero.MethodsWe tested 406 seven-year-old Seychellois children participating in the Seychelles Child Development Study (Nutrition Cohort 2), who were prenatally exposed to MeHg from maternal fish consumption. Total mercury in maternal hair (prenatal MeHg exposure measure) collected during pregnancy was measured using atomic absorption spectroscopy. Methylation in DNA from the children’s saliva was measured by pyrosequencing. To assess associations between prenatal MeHg exposure and CpG methylation at seven years of age, we used multivariable linear regression models adjusted for covariates.ResultsWe identified associations with prenatal MeHg exposure for DNA methylation of one GRIN2B CpG and two NR3C1 CpGs out of 12 total CpG sites. Higher prenatal MeHg was associated with higher methylation for each CpG site. For example, NR3C1 CpG3 had an expected increase of 0.03-fold for each additional 1 ppm of prenatal MeHg (B = 0.030, 95% CI 0.001, 0.059; p = 0.047). Several CpG sites associated with MeHg are located in transcription factor binding sites and the observed methylation changes are predicted to lead to lower gene expression.ConclusionsIn a population of people who consume large amounts of fish, we showed that higher prenatal MeHg exposure was associated with differential DNA methylation at seven years of age at specific CpG sites that may influence neurodevelopment and mental health.
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| 17. |
- Cediel-Ulloa, Andrea, et al.
(författare)
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The C17.2 cell line as testing system for endocrine disruption-induced developmental neurotoxicity
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Hormone signaling plays an essential role during fetal life and is vital for brain development. Endocrine-disrupting chemicals (EDCs) can interfere with the hormonal milieu in this critical time period, disrupting key neurodevelopmental processes. Hence, there is a need for the development of assays that evaluate developmental neurotoxicity (DNT) induced by an endocrine mode of action. Herein, we evaluated the applicability of the neural progenitor C17. 2 cell-line, as an in vitro test method to aid in the detection of endocrine disruption induced DNT. For this, C17.2 cells were exposed during 10 days of differentiation to (ant)agonists of the thyroid hormone (Thr), glucocorticoid (Gr), retinoic acid (Rar), retinoic x (Rxr), oxysterols (Lxr), estrogen (Er), androgen (Ar), and peroxisome proliferator activated delta (Ppard) receptors, as well as to the agonist of the vitamin D (Vdr) receptor. Upon exposure and differentiation, the cells were incubated with Hoechst (nuclear staining) and subsequently stained for βIII-tubulin (neuronal marker) by immunofluorescence. Automated imaging was carried out with a 10X objective lens using an ImageXpress micro xls system (Molecular Devices) and image analysis was performed with MetaXpress® software (Molecular Devices). The C17.2 cells were responsive to the Rar and Rxr agonists which decreased neurite outgrowth, branching and neuronal differentiation as well as to the Rar antagonist which increased neurite outgrowth and branching. With this approach, we have identified that the C17.2 cells are responsive to Gr, Rar, Rxr, and Pparβ/δ, hence contributing to the development of reliable and transferable test methods for hazard assessment of EDCs.
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| 18. |
- Cediel-Ulloa, Andrea, et al.
(författare)
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The pesticides endosulfan and cypermethrin affect neuronal differentiation via retinoic and peroxisome proliferator receptor activity
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Brain development is highly dependent on hormonal homeostasis, hence developmental exposure to endocrine disrupting chemicals (EDCs) is of high concern. In fact, epidemiological and in vivo studies support associations between exposure to EDCs and impaired neurodevelopment. However, the existing hazard assessment of EDCs does not consider developmental neurotoxicity (DNT) prompting an urgent requirement for innovative testing and screening tools addressing endocrine disruption (ED)-induced DNT. We have previously shown the applicability of the immortalized murine neural progenitor cells, C17.2 cells, for addressing ED-DNT. We evidenced decreased neurite outgrowth and branching when the cells were exposed to the Rar, Rxr or Pparβ/δ agonists, and concluded that this is a suitable model for the evaluation of ED-induced DNT for chemicals disrupting Rar, Rxr or Pparβ/δ signalling. In this study we further validated the C17.2 method by testing the effects of 25 EDCs on the same neuronal morphology endpoints as reported in the previous paper. Out of the tested chemicals, endosulfan and cypermethrin decreased, while benzyl butyl phthalate (BBzP) increased neurite outgrowth and branching. We proceeded to evaluate whether these effects were mediated by Rar, Rxr or Ppar β/δ agonism. The neuronal morphology effects of endosulfan and cypermethrin were rescued by co-exposures Rar and Rxr antagonists, and partially rescued by the Ppar β/δ antagonist indicating a common mechanism. With this approach, we have identified that the C17.2 cells can be used as an in vitro model to address ED-induced DNT.
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| 19. |
- 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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| 20. |
- Cui, Yuan
(författare)
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Single-cell oxygen metabolism: a universal, effect-based marker of chemical toxicity
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Understanding how organisms respond to oxygen (O2) fluctuations in their aquatic microenvironments and studying O2 consumption as an indicator of metabolism is crucial for advancing ecology, toxicology, tissue engineering and environmental sciences. However, despite their importance across scientific disciplines, traditional O2 measurements often lack the sensitivity to capture rapid or localized changes occurring at the microscale. This PhD thesis addresses this challenge by developing novel microfluidic techniques and systems to sense O2.To investigate advective and diffusive O2 fluxes at the microscale, this thesis developed chemical sensing particle image velocimetry (sensPIV), a technique that combines optode microparticles and rapid microscope imaging. Specifically, I contributed by testing the performance of sensPIV particles within O2-permeable polydimethylsiloxane (PDMS) devices. This demonstrated the effectiveness of sensPIV in visualizing microscale O2 fluxes, with potential applications around complex biological structures such as coral segments.To characterize single-cell O2 respiration rates this thesis developed a micro-respiration chamber device. This device consists of gastight microwells that isolate single-cells, allowing for measuring their O2 consumption via immobilized O2-sensitive optodes. When applied to human hepatic cells, this device revealed size-related respiration kinetics in single-cells and adaptively changing respiration rates due to O2 limitations. The micro-respiration device was then refined into SlipO2Chip, a microfluidic platform that quantifies single-cell O2 respiration rates before and after chemical exposures. This was achieved by adding a mechanism for opening and closing microwells via slipping a dedicated channel that introduces chemical solutions. SlipO2Chip demonstrated a dose-dependent decrease in diatom respiration when exposed to the bacterial infochemical 2-Heptyl-4-Quinolone (HHQ), thus enhancing our understanding of toxicological impacts by detailing cell-to-cell heterogeneity. In a final effort, the micro-respiration chamber device was combined with quantitative phase imaging (QPI) to jointly measure respiration rates and dry mass in individual cells from three unicellular diatom species of varying sizes (16 - 300 µm). Preliminary data were integrated into metabolic scaling theory that describes how metabolic rates scale with geometrical size/mass across all species. The results indicated an interspecific scaling exponent similar to published bulk measures, and three intraspecific exponents showing potential morphological and physiological relationships to metabolism. This proof-of-concept study highlighted that combined measurement of metabolism and mass can enhance the resolution of scaling theory by adding crucial information on cell-to-cell variability.Overall, this PhD thesis contributed to ecotoxicology, ecology and bioengineering by providing detailed insights into spatiotemporal O2 dynamics and single-cell O2 metabolism in the presence and absence of chemical perturbations.
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| 21. |
- De Castelbajac, Thalia, et al.
(författare)
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Innovative tools and methods for toxicity testing within PARC work package 5 on hazard assessment
- 2023
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Ingår i: Frontiers in Toxicology. - : Frontiers Media S.A.. - 2673-3080. ; 5
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Forskningsöversikt (refereegranskat)abstract
- New approach methodologies (NAMs) have the potential to become a major component of regulatory risk assessment, however, their actual implementation is challenging. The European Partnership for the Assessment of Risks from Chemicals (PARC) was designed to address many of the challenges that exist for the development and implementation of NAMs in modern chemical risk assessment. PARC's proximity to national and European regulatory agencies is envisioned to ensure that all the research and innovation projects that are initiated within PARC agree with actual regulatory needs. One of the main aims of PARC is to develop innovative methodologies that will directly aid chemical hazard identification, risk assessment, and regulation/policy. This will facilitate the development of NAMs for use in risk assessment, as well as the transition from an endpoint-based animal testing strategy to a more mechanistic-based NAMs testing strategy, as foreseen by the Tox21 and the EU Chemical's Strategy for Sustainability. This work falls under work package 5 (WP5) of the PARC initiative. There are three different tasks within WP5, and this paper is a general overview of the five main projects in the Task 5.2 'Innovative Tools and methods for Toxicity Testing,' with a focus on Human Health. This task will bridge essential regulatory data gaps pertaining to the assessment of toxicological prioritized endpoints such as non-genotoxic carcinogenicity, immunotoxicity, endocrine disruption (mainly thyroid), metabolic disruption, and (developmental and adult) neurotoxicity, thereby leveraging OECD's and PARC's AOP frameworks. This is intended to provide regulatory risk assessors and industry stakeholders with relevant, affordable and reliable assessment tools that will ultimately contribute to the application of next-generation risk assessment (NGRA) in Europe and worldwide.
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| 22. |
- 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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| 23. |
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| 24. |
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| 25. |
- Drakvik, E., et al.
(författare)
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Statement on advancing the assessment of chemical mixtures and their risks for human health and the environment
- 2020
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 134
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Tidskriftsartikel (refereegranskat)abstract
- The number of anthropogenic chemicals, manufactured, by-products, metabolites and abiotically formed transformation products, counts to hundreds of thousands, at present. Thus, humans and wildlife are exposed to complex mixtures, never one chemical at a time and rarely with only one dominating effect. Hence there is an urgent need to develop strategies on how exposure to multiple hazardous chemicals and the combination of their effects can be assessed. A workshop, “Advancing the Assessment of Chemical Mixtures and their Risks for Human Health and the Environment” was organized in May 2018 together with Joint Research Center in Ispra, EU-funded research projects and Commission Services and relevant EU agencies. This forum for researchers and policy-makers was created to discuss and identify gaps in risk assessment and governance of chemical mixtures as well as to discuss state of the art science and future research needs. Based on the presentations and discussions at this workshop we want to bring forward the following Key Messages: • We are at a turning point: multiple exposures and their combined effects require better management to protect public health and the environment from hazardous chemical mixtures. • Regulatory initiatives should be launched to investigate the opportunities for all relevant regulatory frameworks to include prospective mixture risk assessment and consider combined exposures to (real-life) chemical mixtures to humans and wildlife, across sectors. • Precautionary approaches and intermediate measures (e.g. Mixture Assessment Factor) can already be applied, although, definitive mixture risk assessments cannot be routinely conducted due to significant knowledge and data gaps. • A European strategy needs to be set, through stakeholder engagement, for the governance of combined exposure to multiple chemicals and mixtures. The strategy would include research aimed at scientific advancement in mechanistic understanding and modelling techniques, as well as research to address regulatory and policy needs. Without such a clear strategy, specific objectives and common priorities, research, and policies to address mixtures will likely remain scattered and insufficient. © 2019 The Authors
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