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- Jergil, Måns, 1975-
(författare)
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Pluripotent Stem Cells of Embryonic Origin : Applications in Developmental Toxicology
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- General toxicity evaluation and risk assessment for human exposure is essential when developing new pharmaceuticals and chemicals. Developmental toxicology is an important part of this risk assessment which consumes large resources and many laboratory animals. The prediction of developmental toxicity could potentially be assessed in vitro using embryo-derived pluripotent stem cells for lead characterization and optimization. This thesis explored the potential of short-time assays with pluripotent stem cells of embryonic origin using toxicogenomics. Three established pluripotent stem cell lines; P19 mouse embryonal carcinoma (EC) cells, R1 mouse embryonic stem (mES) cells, and SA002 human embryonic stem (hES) cells were used in the studies. Valproic acid (VPA), an antiepileptic drug which can cause the neural tube defects spina bifida in human and exencephaly in mouse, was used together with microarrays to investigate the global transcriptional response in pluripotent stem cells using short-time exposures (1.5 - 24 h). In addition to VPA, three closely related VPA analogs were tested, one of which was not teratogenic in mice. These analogs also differed in their ability to inhibit histone deacetylase (HDAC) allowing this potential mechanism of VPA teratogenicity to be investigated. The results in EC cells indicated a large number of genes to be putative VPA targets, many of which are known to be involved in neural tube morphogenesis. When compared with data generated in mouse embryos, a number of genes emerged as candidate in vitro markers of VPA-induced teratogenicity. VPA and its teratogenic HDAC inhibiting analog induced major and often overlapping deregulation of genes in mES cells and hES cells. On the other hand, the two non-HDAC inhibiting analogs (one teratogenic and one not) had only minor effects on gene expression. This indicated that HDAC inhibition is likely to be the major mechanism of gene deregulation induced by VPA. In addition, a comparison between human and mouse ES cells revealed an overlap of deregulated genes as well as species specific deregulated genes.
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| 3. |
- Lenters, Virissa, et al.
(författare)
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Prenatal phthalate, perfluoroalkyl acid, and organochlorine exposures and term birth weight in three birth cohorts : Multi-pollutant models based on elastic net regression
- 2016
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Ingår i: Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 124:3, s. 365-372
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Tidskriftsartikel (refereegranskat)abstract
- Background: Some legacy and emerging environmental contaminants are suspected risk factors for intrauterine growth restriction. However, the evidence is equivocal, in part due to difficulties in disentangling the effects of mixtures. Objectives: We assessed associations between multiple correlated biomarkers of environmental exposure and birth weight. Methods: We evaluated a cohort of 1,250 term (≥ 37 weeks gestation) singleton infants, born to 513 mothers from Greenland, 180 from Poland, and 557 from Ukraine, who were recruited during antenatal care visits in 2002‒2004. Secondary metabolites of diethylhexyl and diisononyl phthalates (DEHP, DiNP), eight perfluoroalkyl acids, and organochlorines (PCB-153 and p,p´‑DDE) were quantifiable in 72‒100% of maternal serum samples. We assessed associations between exposures and term birth weight, adjusting for co-exposures and covariates, including prepregnancy body mass index. To identify independent associations, we applied the elastic net penalty to linear regression models. Results: Two phthalate metabolites (MEHHP, MOiNP), perfluorooctanoic acid (PFOA), and p,p´-DDE were most consistently predictive of term birth weight based on elastic net penalty regression. In an adjusted, unpenalized regression model of the four exposures, 2-SD increases in natural log–transformed MEHHP, PFOA, and p,p´-DDE were associated with lower birth weight: –87 g (95% CI: –137, –340 per 1.70 ng/mL), –43 g (95% CI: –108, 23 per 1.18 ng/mL), and –135 g (95% CI: –192, –78 per 1.82 ng/g lipid), respectively; and MOiNP was associated with higher birth weight (46 g; 95% CI: –5, 97 per 2.22 ng/mL). Conclusions: This study suggests that several of the environmental contaminants, belonging to three chemical classes, may be independently associated with impaired fetal growth. These results warrant follow-up in other cohorts.
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| 4. |
- Lenters, Virissa, et al.
(författare)
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Serum concentrations of polybrominated diphenyl ethers (PBDEs) and a polybrominated biphenyl (PBB) in men from Greenland, Poland and Ukraine
- 2013
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Ingår i: Environment International. - : Elsevier BV. - 1873-6750 .- 0160-4120. ; 61, s. 8-16
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Tidskriftsartikel (refereegranskat)abstract
- Many brominated flame retardants (BFRs)-including polybrominated diphenyl ethers (PBDEs)-have been shown to persist in the environment, and some have been associated with adverse health effects. The aim of the present study was to quantify serum concentrations of common brominated flame retardants in Inuit men from across Greenland, and in men from Warsaw, Poland and Kharkiv, Ukraine. Serum was sampled between 2002 and 2004 from men 19 to 50 years of age. 299 samples were analyzed for BDE-28, 47, 99, 100, 153, 154 and 183 and the brominated biphenyl BB-153 using gas chromatography-high resolution mass spectrometry. BDE-47 and BDE-153 were detected in more than 95% of samples from all three populations. All other congeners, except BDE-154, were detected in more than 70% of samples from Greenland; lower detection frequencies were observed in Polish and Ukrainian samples. Concentrations of individual congeners were 2.7 to 15 fold higher in Greenlandic relative to Polish and Ukrainian men. Geometric mean concentrations of the sum of the most abundant PBDEs of the Penta-BDE commercial mixture (BDE-47, 99, 100, 153 and 154) were 6.1, 1.7 and 0.87 ng/g lipids in the Greenlandic, Polish and Ukrainian men, respectively. Furthermore, significant geographical differences in BFR concentrations were observed within Greenland. Principal component analysis revealed distinct clustering of samples by country of origin. The associations between Sigma PBDEs and age were inconsistent, varying from no association in Greenlandic and Polish study populations to a U-shaped relationship in Ukrainians. We report BFR levels for three populations for which sparse biomonitoring data exists. (C) 2013 Elsevier Ltd. All rights reserved.
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| 5. |
- Solecki, Roland, et al.
(författare)
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Scientific principles for the identification of endocrine-disrupting chemicals : a consensus statement
- 2017
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Ingår i: Archives of Toxicology. - : Springer. - 0340-5761 .- 1432-0738. ; 91:2, s. 1001-1006
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Tidskriftsartikel (refereegranskat)abstract
- Endocrine disruption is a specific form of toxicity, where natural and/or anthropogenic chemicals, known as "endocrine disruptors" (EDs), trigger adverse health effects by disrupting the endogenous hormone system. There is need to harmonize guidance on the regulation of EDs, but this has been hampered by what appeared as a lack of consensus among scientists. This publication provides summary information about a consensus reached by a group of world-leading scientists that can serve as the basis for the development of ED criteria in relevant EU legislation. Twenty-three international scientists from different disciplines discussed principles and open questions on ED identification as outlined in a draft consensus paper at an expert meeting hosted by the German Federal Institute for Risk Assessment (BfR) in Berlin, Germany on 11-12 April 2016. Participants reached a consensus regarding scientific principles for the identification of EDs. The paper discusses the consensus reached on background, definition of an ED and related concepts, sources of uncertainty, scientific principles important for ED identification, and research needs. It highlights the difficulty in retrospectively reconstructing ED exposure, insufficient range of validated test systems for EDs, and some issues impacting on the evaluation of the risk from EDs, such as non-monotonic dose-response and thresholds, modes of action, and exposure assessment. This report provides the consensus statement on EDs agreed among all participating scientists. The meeting facilitated a productive debate and reduced a number of differences in views. It is expected that the consensus reached will serve as an important basis for the development of regulatory ED criteria.
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