| 1. |
- Bergman, Åke, et al.
(författare)
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Manufacturing doubt about endocrine disrupter science : A rebuttal of industry-sponsored critical comments on the UNEP/WHO report "State of the Science of Endocrine Disrupting Chemicals 2012"
- 2015
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Ingår i: Regulatory toxicology and pharmacology. - : Academic Press. - 0273-2300 .- 1096-0295. ; 73:3, s. 1007-1017
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Tidskriftsartikel (refereegranskat)abstract
- We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO, 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption is based on incomplete and misleading quoting of the report through omission of qualifying statements and inaccurate description of study objectives, results and conclusions. Lamb et al. define extremely narrow standards for synthesizing evidence which are then used to dismiss the UNEP/WHO 2013 report as flawed. We show that Lamb et al. misuse conceptual frameworks for assessing causality, especially the Bradford-Hill criteria, by ignoring the fundamental problems that exist with inferring causality from empirical observations. We conclude that Lamb et al.'s attempt of deconstructing the UNEP/WHO (2013) report is not particularly erudite and that their critique is not intended to be convincing to the scientific community, but to confuse the scientific data. Consequently, it promotes misinterpretation of the UNEP/WHO (2013) report by non-specialists, bureaucrats, politicians and other decision makers not intimately familiar with the topic of endocrine disruption and therefore susceptible to false generalizations of bias and subjectivity.
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| 2. |
- Bergman, Åke, et al.
(författare)
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Science and policy on endocrine disrupters must not be mixed : a reply to a "common sense" intervention by toxicology journal editors
- 2013
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Ingår i: Environmental Health. - : BioMed Central (BMC). - 1476-069X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- The "common sense" intervention by toxicology journal editors regarding proposed European Union endocrine disrupter regulations ignores scientific evidence and well-established principles of chemical risk assessment. In this commentary, endocrine disrupter experts express their concerns about a recently published, and is in our considered opinion inaccurate and factually incorrect, editorial that has appeared in several journals in toxicology. Some of the shortcomings of the editorial are discussed in detail. We call for a better founded scientific debate which may help to overcome a polarisation of views detrimental to reaching a consensus about scientific foundations for endocrine disrupter regulation in the EU.
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| 3. |
- Castellanos, Cesilie Granum, et al.
(författare)
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Differential effects of the persistent DDT metabolite methylsulfonyl-DDE in nonstimulated and LH-stimulated neonatal porcine Leydig cells
- 2013
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 267:3, s. 247-255
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Tidskriftsartikel (refereegranskat)abstract
- 3-Methylsulfonyl-DDE (MeSO2-DDE) is a potent adrenal toxicant formed from the persistent insecticide DDT. MeSO2-DDE is widely present in human plasma, milk and fat, and in tissues of marine mammals. In the present study, we investigated endocrine-disrupting properties of MeSO2-DDE in primary neonatal porcine Leydig cells. Unstimulated and LH-stimulated cells were exposed to MeSO2-DDE at concentrations ranging from 0.6 to 20 mu M for 48 h. Cell viability, hormone secretion and expression of steroidogenesis related genes were recorded. Secretion of testosterone and estradiol was increased in a concentration-dependent fashion in unstimulated Leydig cells, while in LH-stimulated cells, secretion of testosterone, estradiol and progesterone was decreased. The expression of important steroidogenic genes was down-regulated both in unstimulated and LH-stimulated cells. Notably, no significant impairment of cell viability occurred at any exposure except the highest concentration (20 mu M) in LH-stimulated cells. This indicated that the effects on hormone secretion and gene expression were not caused by cytotoxicity. We conclude that the adrenal toxicant MeSO2-DDE disrupts hormone secretion in a complex fashion in neonatal porcine Leydig cells. The different endocrine responses in unstimulated and LH-stimulated cells imply that the endocrine disruptive activity of MeSO2-DDE is determined by the physiological status of the Leydig cells.
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| 4. |
- Gutleb, Arno C., et al.
(författare)
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Effects on bone tissue in ewes (Ovies aries) and their foetuses exposed to PCB 118 and PCB 153
- 2010
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Ingår i: Toxicology Letters. - : Elsevier BV. - 0378-4274 .- 1879-3169. ; 192:2, s. 126-133
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to investigate whether low levels of mono-ortho PCB 118 and di-ortho PCB 153, affect bone composition and strength in ewes (Dala breed) and their foetuses following exposure starting at conception and ending a week before expected delivery. In male foetuses, trabecular bone mineral content at the metaphysis was almost 30% lower in the PCB 118 (49mug/kg body wt/day) group compared to the control group (corn oil) (ANCOVA, P<0.05). In female foetuses of the PCB 153 (98mug/kg body wt/day) group trabecular cross-sectional area at the metaphysis was 19% smaller than in the controls (ANCOVA, P<0.05). At the diaphysis a smaller marrow cavity area (up to 24% reduction) was observed in female and male foetuses exposed to PCB 153 compared with controls (ANCOVA, P<0.05). There were also significant differences at the mid diaphyseal measure point between the PCB 153 and the control group females (ANCOVA, P<0.05). Cortical and total bone mineral density, cortical thickness were significantly higher, endosteal circumference shorter and marrow cavity significantly smaller in the PCB 153 group (ANCOVA, P<0.05). In conclusion there were gender dependent effects on bone tissue and cortical bone was more affected than trabecular bone.
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| 5. |
- Gutleb, Arno C., et al.
(författare)
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In Vitro Assay Shows That PCB Metabolites Completely Saturate Thyroid Hormone Transport Capacity in Blood of Wild Polar Bears (Ursus maritimus)
- 2010
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 44:8, s. 3149-3154
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Tidskriftsartikel (refereegranskat)abstract
- Persistent chemicals accumulate in the arctic environment due to their chemical reactivity and physicochemical properties and polychlorinated biphenyls (PCBs) are the most concentrated pollutant class in polar bears (Ursus maritimus). Metabolism of PCB and polybrominated biphenyl ether (PBDE) flame-retardants alter their toxicological properties and these metabolites are known to interfere with the binding of thyroid hormone (TH) to transthyretin (TTR) in rodents and humans. In polar bear plasma samples no binding of [I-125]-T-4 to TTR was observed after incubation and PAGE separation. Incubation of the plasma samples with (C-14)-4-OH-CB107, a compound with a higher binding affinity to TTR than the endogenous ligand T-4 resulted in competitive binding as proven by the appearance of a radio labeled TTR peak in the gel. Plasma incubation with T-4 up to 1 mM, a concentration that is not physiologically relevant anymore did not result in any visible competition. These results give evidence that the binding sites on TTR for T-4 in wild living polar bears are completely saturated. Such saturation of binding sites can explain observed lowered levels of THs and could lead to contaminant transport into the developing fetus.
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| 6. |
- Kalayou, Shewit, et al.
(författare)
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Label-free based quantitative proteomics analysis of primary neonatal porcine Leydig cells exposed to the persistent contaminant 3-methylsulfonyl-DDE
- 2016
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Ingår i: Journal of Proteomics. - : Elsevier BV. - 1874-3919 .- 1876-7737. ; 137, s. 68-82
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Tidskriftsartikel (refereegranskat)abstract
- Evidence that persistent environmental pollutants may target the male reproductive system is increasing. The male reproductive system is regulated by secretion of testosterone by testicular Leydig cells, and perturbation of Leydig cell function may have ultimate consequences. 3-Methylsulfonyl-DDE (3-MeSO2-DDE) is a potent adrenal toxicants formed from the persistent insecticide DDT. Although studies have revealed the endocrine disruptive effect of 3-MeSO2-DDE, the underlying mechanisms at cellular level in steroidogenic Leydig cells remains to be established. The current study addresses the effect of 3-MeSO2-DDE on viability, hormone production and proteome response of primary neonatal porcine Leydig cells. The AlamarBlue (TM) assay was used to evaluate cell viability. Solid phase radioimmunoassay was used to measure concentration of hormones produced by both unstimulated and Luteinizing hormone (LH)-stimulated Leydig cells following 48 h exposure. Protein samples from Leydig cells exposed to a non-cytotoxic concentration of 3-MeSO2-DDE (10 mu M) were subjected to nano-LC-MS/MS and analyzed on a Q Exactive mass spectrometer and quantified using label-free quantitative algorithm. Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA) were carried out for functional annotation and identification of protein interaction networks. 3-MeSO2-DDE regulated Leydig cell steroidogenesis differentially depending on cell culture condition. Whereas its effect on testosterone secretion at basal condition was stimulatory, the effect on LH-stimulated cells was inhibitory. From triplicate experiments, a total of 6804 proteins were identified in which the abundance of 86 proteins in unstimulated Leydig cells and 145 proteins in LH-stimulated Leydig cells was found to be significantly regulated in response to 3-MeSO2-DDE exposure. These proteins not only are the first reported in relation to 3-MeSO2-DDE exposure, but also display small number of proteins shared between culture conditions, suggesting the action of 3-MeSO2-DDE on several targeted pathways, including mitochondrial dysfunction, oxidative phosphorylation, EIF2-signaling, and glutathione-mediated detoxification. Further identification and characterization of these proteins and pathways may build our understanding to the molecular basis of 3-MeSO2-DDE induced endocrine disruption in Leydig cells.
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| 7. |
- Keune, Hans, et al.
(författare)
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We’re only in it for the knowledge? : a problem solving turn in environment and health expert elicitation
- 2012
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Ingår i: Environmental Health. - 1476-069X. ; 11:Supplement 1, s. S3-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The FP6 EU HENVINET project aimed at synthesizing the scientific information available on a number of topics of high relevance to policy makers in environment and health. The goal of the current paper is to reflect on the methodology that was used in the project, in view of exploring the usefulness of this and similar methodologies to the policy process. The topics investigated included health impacts of the brominated flame retardants decabrominated diphenylether (decaBDE) and hexabromocyclododecane (HBCD), phthalates highlighting di(2-ethylhexyl)phthalate (DEHP), the pesticide chlorpyrifos (CPF), nanoparticles, the impacts of climate change on asthma and other respiratory disorders, and the influence of environment health stressors on cancer induction. Methods: Initially the focus was on identifying knowledge gaps in the state of the art in scientific knowledge. Literature reviews covered all elements that compose the causal chain of the different environmental health issues from emissions to exposures, to effects and to health impacts. Through expert elicitation, knowledge gaps were highlighted by assessing expert confidence using calibrated confidence scales. During this work a complementary focus to that on knowledge gaps was developed through interdisciplinary reflections. By extending the scope of the endeavour from only a scientific perspective, to also include the more problem solving oriented policy perspective, the question of which kind of policy action experts consider justifiable was addressed. This was addressed by means of a questionnaire. In an expert workshop the results of both questionnaires were discussed as a basis for policy briefs. Results: The expert elicitation, the application of the calibrated confidence levels and the problem solving approach were all experienced as being quite challenging for the experts involved, as these approaches did not easily relate to mainstream environment and health scientific practices. Even so, most experts were quite positive about it. In particular, the opportunity to widen one's own horizon and to interactively exchange knowledge and debate with a diversity of experts seemed to be well appreciated in this approach. Different parts of the approach also helped in focussing on specific relevant aspects of scientific knowledge, and as such can be considered of reflective value. Conclusions: The approach developed by HENVINET was part of a practice of learning by doing and of interdisciplinary cooperation and negotiation. Ambitions were challenged by unforeseen complexities and difference of opinion and as no Holy Grail approach was at hand to copy or follow, it was quite an interesting but also complicated endeavour. Perfection, if this could be defined, seemed out of reach all the time. Nevertheless, many involved were quite positive about it. It seems that many felt that it fitted some important needs in current science when addressing the needs of policy making on such important issues, without anyone really having a clue on how to actually do this. Challenging questions remain on the quality of such approach and its product. Practice tells us that there probably is no best method and that the best we can do is dependent on contextual negotiation and learning from experiences that we think are relevant.
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| 8. |
- Lundberg, Rebecca, et al.
(författare)
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Perinatal exposure to PCB 153, but not PCB 126, alters bone tissue composition in female goat offspring
- 2006
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Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 228:1, s. 33-40
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate if environmentally relevant doses of the putative estrogenic non dioxin-like PCB 153 and the dioxin-like PCB 126 caused changes in bone tissue in female goat offspring following perinatal exposure. Goat dams were orally dosed with PCB 153 in corn oil (98 microg/kg body wt/day) or PCB 126 (49 ng/kg body wt/day) from day 60 of gestation until delivery. The offspring were exposed to PCB in utero and through mother's milk. The suckling period lasted for 6 weeks. Offspring metacarpal bones were analysed using peripheral quantitative computed tomography (pQCT) after euthanisation at 9 months of age. The diaphyseal bone was analysed at a distance of 18% and 50% of the total bone length, and the metaphyseal bone at a distance of 9%. Also, biomechanical three-point bending of the bones was conducted, with the load being applied to the mid-diaphyseal pQCT measure point (50%). PCB 153 exposure significantly decreased the total cross-sectional area (125 mm(2)+/-4) versus non-exposed (142 mm(2)+/-5), decreased the marrow cavity (38 mm(2)+/-4) versus non-exposed (50 mm(2)+/-3) and decreased the moment of resistance (318 mm(3)+/-10) versus non-exposed (371 mm(3)+/-20) at the diaphyseal 18% measure point. At the metaphyseal measure point, the trabecular bone mineral density (121 mg/cm(3)+/-5) was increased versus non-exposed (111 mg/cm(3)+/-3). PCB 126 exposure did not produce any observable changes in bone tissue. The biomechanical testing of the bones did not show any significant changes in bone strength after PCB 153 or PCB 126 exposure. In conclusion, perinatal exposure to PCB 153, but not PCB 126, resulted in altered bone composition in female goat offspring.
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| 9. |
- Lyche, Jan L., et al.
(författare)
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Reproductive and developmental toxicity of phthalates
- 2009
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Ingår i: Journal of toxicology and environmental health. Part B, Critical reviews. - : Informa UK Limited. - 1093-7404 .- 1521-6950. ; 12:4, s. 225-249
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Tidskriftsartikel (refereegranskat)abstract
- The purposes of this review are to (1) evaluate human and experimental evidence for adverse effects on reproduction and development in humans, produced by exposure to phthalates, and (2) identify knowledge gaps as for future studies. The widespread use of phthalates in consumer products leads to ubiquitous and constant exposure of humans to these chemicals. Phthalates were postulated to produce endocrine-disrupting effects in rodents, where fetal exposure to these compounds was found to induce developmental and reproductive toxicity. The adverse effects observed in rodent models raised concerns as to whether exposure to phthalates represents a potential health risk to humans. At present, di(2-ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DBP), and butyl benzyl phthalate (BBP) have been demonstrated to produce reproductive and developmental toxicity; thus, this review focuses on these chemicals. For the general population, DEHP exposure is predominantly via food. The average concentrations of phthalates are highest in children and decrease with age. At present, DEHP exposures in the general population appear to be close to the tolerable daily intake (TDI), suggesting that at least some individuals exceed the TDI. In addition, specific high-risk groups exist with internal levels that are several orders of magnitude above average. Urinary metabolites used as biomarkers for the internal levels provide additional means to determine more specifically phthalate exposure levels in both general and high-risk populations. However, exposure data are not consistent and there are indications that secondary metabolites may be more accurate indicators of the internal exposure compared to primary metabolites. The present human toxicity data are not sufficient for evaluating the occurrence of reproductive effects following phthalate exposure in humans, based on existing relevant animal data. This is especially the case for data on female reproductive toxicity, which are scarce. Therefore, future research needs to focus on developmental and reproductive endpoints in humans. It should be noted that phthalates occur in mixtures but most toxicological information is based on single compounds. Thus, it is concluded that it is important to improve the knowledge of toxic interactions among the different chemicals and to develop measures for combined exposure to various groups of phthalates.
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| 10. |
- Nuruddin, Syed, et al.
(författare)
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Elevated mRNA-Levels of Gonadotropin-Releasing Hormone and Its Receptor in Plaque-Bearing Alzheimer's Disease Transgenic Mice
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8, s. e103607-
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Tidskriftsartikel (refereegranskat)abstract
- Research on Alzheimer's disease (AD) has indicated an association between hormones of the hypothalamic-pituitary-gonadal (HPG) axis and cognitive senescence, indicating that post meno-/andropausal changes in HPG axis hormones are implicated in the neuropathology of AD. Studies of transgenic mice with AD pathologies have led to improved understanding of the pathophysiological processes underlying AD. The aims of this study were to explore whether mRNA-levels of gonadotropin-releasing hormone (Gnrh) and its receptor (Gnrhr) were changed in plaque-bearing Alzheimer's disease transgenic mice and to investigate whether these levels and amyloid plaque deposition were downregulated by treatment with a gonadotropin-releasing hormone analog (Gnrh-a; Leuprorelin acetate). The study was performed on mice carrying the Arctic and Swedish amyloid-b precursor protein (AbPP) mutations (tgArcSwe). At 12 months of age, female tgArcSwe mice showed a twofold higher level of Gnrh mRNA and more than 1.5 higher level of Gnrhr mRNA than age matched controls. Male tgArcSwe mice showed the same pattern of changes, albeit more pronounced. In both sexes, Gnrha treatment caused significant down-regulation of Gnrh and Gnrhr mRNA expression. Immunohistochemistry combined with quantitative image analysis revealed no significant changes in the plaque load after Gnrh-a treatment in hippocampus and thalamus. However, plaque load in the cerebral cortex of treated females tended to be lower than in female vehicle-treated mice. The present study points to the involvement of hormonal changes in AD mice models and demonstrates that these changes can be effectively counteracted by pharmacological treatment. Although known to increase in normal aging, our study shows that Gnrh/Gnrhr mRNA expression increases much more dramatically in tgArcSwe mice. Treatment with Leuprorelin acetate successfully abolished the transgene specific effects on Gnrh/Gnrhr mRNA expression. The present experimental approach should serve as a platform for further studies on the usefulness of Gnrh-a treatment in suppressing plaque development in AD.
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