The Experts below are selected from a list of 897 Experts worldwide ranked by ideXlab platform
Bruce Blumberg - One of the best experts on this subject based on the ideXlab platform.
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Obesity and endocrine-disrupting chemicals.
Endocrine connections, 2021Co-Authors: Angélica Amorim Amato, Hailey Britt Wheeler, Bruce BlumbergAbstract:Obesity is now a worldwide pandemic. The usual explanation given for the prevalence of obesity is that it results from consumption of a calorie dense diet coupled with physical inactivity. However, this model inadequately explains rising obesity in adults and in children over the past few decades, indicating that other factors must be important contributors. An Endocrine-Disrupting Chemical (EDC) is an exogenous chemical, or mixture that interferes with any aspect of hormone action. EDCs have become pervasive in our environment, allowing humans to be exposed daily through ingestion, inhalation, and direct dermal contact. Exposure to EDCs has been causally linked with obesity in model organisms and associated with obesity occurrence in humans. Obesogens are chemicals, including some EDCs that promote adipogenesis and obesity, in vivo, by a variety of mechanisms. The environmental Obesogen model holds that exposure to Obesogens elicits a predisposition to obesity and that such exposures may be an important yet overlooked factor in the obesity pandemic. Effects produced by EDCs and Obesogen exposure may be passed to subsequent, unexposed generations. This "generational toxicology" is not currently factored into risk assessment by regulators but may be another important factor in the obesity pandemic as well as in the worldwide increases in the incidence of noncommunicable diseases that plague populations everywhere. This review addresses the current evidence on how Obesogens affect body mass, discusses long-known chemicals that have been more recently identified as Obesogens, and how the accumulated knowledge can help identify EDCs hazards.
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Environmental Obesogens and Their Impact on Susceptibility to Obesity: New Mechanisms and Chemicals.
Endocrinology, 2020Co-Authors: Riann Jenay Egusquiza, Bruce BlumbergAbstract:The incidence of obesity has reached an all-time high, and this increase is observed worldwide. There is a growing need to understand all the factors that contribute to obesity to effectively treat and prevent it and associated comorbidities. The Obesogen hypothesis proposes that there are chemicals in our environment termed Obesogens that can affect individual susceptibility to obesity and thus help explain the recent large increases in obesity. This review discusses current advances in our understanding of how Obesogens act to affect health and obesity susceptibility. Newly discovered Obesogens and potential Obesogens are discussed, together with future directions for research that may help to reduce the impact of these pervasive chemicals.
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Transgenerational effects of Obesogens.
Basic & Clinical Pharmacology & Toxicology, 2019Co-Authors: Michelle Kira Lee, Bruce BlumbergAbstract:Obesity and associated disorders are now a global pandemic. The prevailing clinical model for obesity is overconsumption of calorie-dense food and diminished physical activity (the calories in-calories out model). However, this explanation does not account for numerous recent research findings demonstrating that a variety of environmental factors can be superimposed on diet and exercise to influence the development of obesity. The environmental Obesogen model proposes that exposure to chemical Obesogens during in utero and/or early life can strongly influence later predisposition to obesity. Obesogens are chemicals that inappropriately stimulate adipogenesis and fat storage, in vivo either directly or indirectly. Numerous Obesogens have been identified in recent years and some of these elicit transgenerational effects on obesity as well as a variety of health end-points after exposure of pregnant F0 females. Prenatal exposure to environmental Obesogens can produce lasting effects on the exposed animals and their offspring to at least the F4 generation. Recent results show that some of these transgenerational effects of Obesogen exposure can be carried across the generations via alterations in chromatin structure and accessibility. That some chemicals can have permanent effects on the offspring of exposed animals suggests increased caution in the debate about whether and to what extent exposure to endocrine-disrupting chemicals and Obesogens should be regulated.
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Current Research Approaches and Challenges in the Obesogen Field.
Frontiers in endocrinology, 2019Co-Authors: Raquel Chamorro-garcía, Bruce BlumbergAbstract:Obesity is a worldwide pandemic that also contributes to the increased incidence of other diseases such as type 2 diabetes. Increased obesity is generally ascribed to positive energy balance. However, recent findings suggest that exposure to endocrine-disrupting chemicals such as Obesogens during critical windows of development, may play an important role in the current obesity trends. Several experimental approaches, from in vitro cell cultures to transgenerational in vivo studies, are used to better understand the mechanisms of action of Obesogens, each of which contributes to answer different questions. In this review, we discuss current knowledge in the Obesogen field and the existing tools developed in research laboratories using tributyltin as a model Obesogen. By understanding the advantages and limitations of each of these tools, we will better focus and design experimental approaches that will help expanding the Obesogen field with the objective of finding potential therapeutic targets in human populations.
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Endocrine Disruptors and Obesity
Encyclopedia of Endocrine Diseases, 2019Co-Authors: Sigal A. Willner, Bruce BlumbergAbstract:Abstract Obesity is an epidemic in children and adults worldwide and is associated with comorbidities including diabetes, metabolic syndrome, heart disease and cancers. In the past, obesity has been considered the result of an imbalance between caloric intake and expenditure. However, more recent research has shown the roles of genetics, the endocrine system, and environmental toxins on obesity development. The DOHaD Hypothesis holds that prenatal and early life nutrition affect the development of obesity, and that there are critical periods of development during which environmental factors can cause phenotypical changes that result in increased susceptibility to diseases later in life. The Obesogen Hypothesis proposes that environmental chemicals, termed “Obesogens,” promote obesity by acting to increase adipocyte commitment, and differentiation or by altering the regulation of metabolism, appetite and satiety. These effects often begin during development, and lead to obesity later in life. Many Obesogens are endocrine disrupting chemicals that interfere with normal endocrine regulation of metabolism, adipose tissue development and maintenance, appetite, weight and energy balance. Endocrine disruptors are abundant in our environment, used in everyday products from food packaging to fungicides. This review explores the genetic, endocrine, and environmental factors that promote obesity in order to better understand their contribution to the obesity epidemic.
Ronny Blust - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of a Screening System for Obesogenic Compounds: Screening of Endocrine Disrupting Compounds and Evaluation of the PPAR Dependency of the Effect
2016Co-Authors: Anna Pereira-fern, Ronny Blust, Heidi Demaegdt, Tine L. M. Hectors, Caroline VanparysAbstract:Recently the environmental Obesogen hypothesis has been formulated, proposing a role for endocrine disrupting compounds (EDCs) in the development of obesity. To evaluate this hypothesis, a screening system for Obesogenic compounds is urgently needed. In this study, we suggest a standardised protocol for Obesogen screening based on the 3T3-L1 cell line, a well-characterised adipogenesis model, and direct fluorescent measurement using Nile red lipid staining technique. In a first phase, we characterised the assay using the acknowledged Obesogens rosiglitazone and tributyltin. Based on the obtained dose-response curves for these model compounds, a lipid accumulation threshold value was calculated to ensure the biological relevance and reliability of statistically significant effects. This threshold based method was combined with the well described strictly standardized mean difference (SSMD) method for classification of non-, weak- or strong Obesogenic compounds. In the next step, a range of EDCs, used in personal and household care products (parabens, musks, phthalates and alkylphenol compounds), were tested to further evaluate the Obesogenicity screening assay for its discriminative power and sensitivity. Additionally, the peroxisome proliferator activated receptor γ (PPARγ) dependency of the positive compounds was evaluated using PPARγ activation and antagonist experiments. Our results showed the adipogenic potential of all tested parabens, several musks and phthalate compounds and bisphenol A (BPA). PPARγ activatio
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Toxicogenomics in the 3T3-L1 Cell Line, a New Approach for Screening of Obesogenic Compounds
Toxicological sciences : an official journal of the Society of Toxicology, 2014Co-Authors: Anna Pereira-fernandes, Caroline Vanparys, Lucia Vergauwen, Dries Knapen, Philippe G. Jorens, Ronny BlustAbstract:The Obesogen hypothesis states that together with an energy imbalance between calories consumed and calories expended, exposure to environmental compounds early in life or throughout lifetime might have an influence on obesity development. In this work, we propose a new approach for Obesogen screening, i.e., the use of transcriptomics in the 3T3-L1 pre-adipocyte cell line. Based on the data from a previous study of our group using a lipid accumulation based adipocyte differentiation assay, several human-relevant Obesogenic compounds were selected: reference Obesogens (Rosiglitazone, Tributyltin), test Obesogens (Butylbenzyl phthalate, butylparaben, propylparaben, Bisphenol A), and non-Obesogens (Ethylene Brassylate, Bis (2-ethylhexyl)phthalate). The high stability and reproducibility of the 3T3-L1 gene transcription patterns over different experiments and cell batches is demonstrated by this study. Obesogens and non-Obesogen gene transcription profiles were clearly distinguished using hierarchical clustering. Furthermore, a gradual distinction corresponding to differences in induction of lipid accumulation could be made between test and reference Obesogens based on transcription patterns, indicating the potential use of this strategy for classification of Obesogens. Marker genes that are able to distinguish between non, test, and reference Obesogens were identified. Well-known genes involved in adipocyte differentiation as well as genes with unknown functions were selected, implying a potential adipocyte-related function of the latter. Cell-physiological lipid accumulation was well estimated based on transcription levels of the marker genes, indicating the biological relevance of omics data. In conclusion, this study shows the high relevance and reproducibility of this 3T3-L1 based in vitro toxicogenomics tool for classification of Obesogens and biomarker discovery. Although the results presented here are promising, further confirmation of the predictive value of the set of candidate biomarkers identified as well as the validation of their clinical role will be needed.
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Expression of Obesity Markers and Persistent Organic Pollutants Levels in Adipose Tissue of Obese Patients: Reinforcing the Obesogen Hypothesis?
PloS one, 2014Co-Authors: Anna Pereira-fernandes, Caroline Vanparys, Philippe G. Jorens, Eveline Dirinck, Alin C. Dirtu, Govindan Malarvannan, Adrian Covaci, Luc Van Gaal, Ronny BlustAbstract:Introduction Persistent Organic Pollutants (POPs) accumulate in adipose tissue and some are described to possess endocrine disrupting capacities. Therefore, it is important to evaluate their effects on key endocrine pathways in adipose tissue (AT), to further evaluate their potential role in metabolic pathologies such as obesity. Objectives The aim is twofold: (i) evaluate gene expression levels of obesity marker genes, i.e. the adipokines leptin (LEP), adiponectin (ADIPOQ) and Tumor Necrosis Factor α (TNFα) and the nuclear receptor, Peroxisome Proliferator Activated Receptor γ (PPARγ) in paired subcutaneous (SAT) and visceral (VAT) AT of obese subjects (n = 50) and to relate these values to serum concentrations of LEP and ADIPOQ (ii) evaluate the association of expression levels of marker genes in AT and serum with POP concentrations in AT. Results and Conclusions Leptin and adiponectin levels in serum were positively correlated to respectively expression levels of leptin in SAT and adiponectin in VAT. Our study shows more significant correlations between gene expression of obesity marker genes and POP concentrations in VAT compared to SAT. Since VAT is more important than SAT in pathologies associated with obesity, this suggests that POPs are able to influence the association between obesity and the development of associated pathologies. Moreover, this finding reveals the importance of VAT when investigating the Obesogen hypothesis. Concerning PPARγ expression in VAT, negative correlations with polychlorinated biphenyls (PCBs) concentrations were found in non T2D patients. LEP serum concentrations correlated with several PCBs in women whereas in men no correlations were found. This strengthens the potential importance of gender differences in obesity and within the Obesogen hypothesis.
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Evaluation of a screening system for Obesogenic compounds: screening of endocrine disrupting compounds and evaluation of the PPAR dependency of the effect.
PloS one, 2013Co-Authors: Anna Pereira-fernandes, Philippe G. Jorens, Ronny Blust, Heidi Demaegdt, Tine L. M. Hectors, Karine Vandermeiren, Caroline VanparysAbstract:Recently the environmental Obesogen hypothesis has been formulated, proposing a role for endocrine disrupting compounds (EDCs) in the development of obesity. To evaluate this hypothesis, a screening system for Obesogenic compounds is urgently needed. In this study, we suggest a standardised protocol for Obesogen screening based on the 3T3-L1 cell line, a well-characterised adipogenesis model, and direct fluorescent measurement using Nile red lipid staining technique. In a first phase, we characterised the assay using the acknowledged Obesogens rosiglitazone and tributyltin. Based on the obtained dose-response curves for these model compounds, a lipid accumulation threshold value was calculated to ensure the biological relevance and reliability of statistically significant effects. This threshold based method was combined with the well described strictly standardized mean difference (SSMD) method for classification of non-, weak- or strong Obesogenic compounds. In the next step, a range of EDCs, used in personal and household care products (parabens, musks, phthalates and alkylphenol compounds), were tested to further evaluate the Obesogenicity screening assay for its discriminative power and sensitivity. Additionally, the peroxisome proliferator activated receptor γ (PPARγ) dependency of the positive compounds was evaluated using PPARγ activation and antagonist experiments. Our results showed the adipogenic potential of all tested parabens, several musks and phthalate compounds and bisphenol A (BPA). PPARγ activation was associated with adipogenesis for parabens, phthalates and BPA, however not required for Obesogenic effects induced by Tonalide, indicating the role of other Obesogenic mechanisms for this compound.
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Unraveling the mode of action of an Obesogen: mechanistic analysis of the model Obesogen tributyltin in the 3T3-L1 cell line.
Molecular and cellular endocrinology, 2013Co-Authors: Anna Pereira-fernandes, Caroline Vanparys, Lucia Vergauwen, Dries Knapen, Philippe G. Jorens, Tine L. M. Hectors, Ronny BlustAbstract:Obesogenic compounds are chemicals that have an influence on obesity development. This study was designed to unravel the molecular mechanisms of the model Obesogen TBT, using microarray analysis in the 3T3-L1 in vitro system, and to evaluate the use of toxicogenomics for Obesogen screening. The microarray results revealed enrichment of Gene Ontology terms involved in energy and fat metabolism after 10 days of TBT exposure. Pathway analysis unveiled PPAR signalling pathway as the sole pathway significantly enriched after 1 day and the most significantly enriched pathway after 10 days of exposure. To our knowledge, this is the first study delivering an in depth mechanistic outline of the mode of action of TBT as an Obesogen, combining effects on both cell physiological and gene expression level. Furthermore, our results show that combining transcriptomics with 3T3-L1 cells is a promising tool for screening of potential Obesogenic compounds.
Marie-christine Chagnon - One of the best experts on this subject based on the ideXlab platform.
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multigenerational study of the Obesogen effects of bisphenol s after a perinatal exposure in c57bl6 j mice fed a high fat diet
Environmental Pollution, 2021Co-Authors: Axelle Brulport, Daniel Vaiman, Guillaume Maquart, Virginie Barbet, Aurélie Dastugue, Isabelle Séverin, Ludovic Le Corre, Marie-christine ChagnonAbstract:Abstract Background Bisphenol S is an endocrine disruptor exhibiting metabolic disturbances, especially following perinatal exposures. To date, no data are available on the Obesogen effects of BPS in a mutligenerational issue. Objectives We investigated Obesogen effects of BPS in a multigenerational study by focusing on body weight, adipose tissue and plasma parameters in male and female mice. Methods Pregnant C57BL6/J mice were exposed to BPS (1.5 μg/kg bw/day ie a human equivalent dose of 0.12 μg/kg bw/day) by drinking water from gestational day 0 to post natal day 21. All offsprings were fed with a high fat diet during 15 weeks. Body weight was monitored weekly and fat mass was measured before euthanasia. At euthanasia, blood glucose, insuline, triglyceride, cholesterol and no esterified fatty acid plasma levels were determined and gene expressions in visceral adipose tissue were assessed. F1 males and females were mated to obtain the F2 generation. Likewise, the F2 mice were cross-bred to obtain F3. The same analyses were performed. Results In F1 BPS induced an overweight in male mice associated to lipolysis gene expressions upregulation. In F1 females, dyslipidemia was observed. In F2, BPS exposure was associated to an increase in body weight, fat and VAT masses in males and females. Several plasma parameters were increased but with a sex related pattern (blood glucose, triglycerides and cholesterol in males and NEFA in females). We observed a down-regulation in mRNA expression of gene involved in lipogenesis and in lipolysis for females but only in the lipogenesis for males. In F3, a decrease in VAT mass and an upregulation of lipogenesis gene expression occurred only in females. Conclusions BPS perinatal exposure induced sex-dependent Obesogen multigenerational effects, the F2 generation being the most impacted. Transgenerational disturbances persisted only in females.
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Multigenerational study of the Obesogen effects of bisphenol S after a perinatal exposure in C57BL6/J mice fed a high fat diet
Environmental Pollution (Elsevier), 2021Co-Authors: Axelle Brulport, Ludovic Le Corre, Daniel Vaiman, Guillaume Maquart, Virginie Barbet, Aurélie Dastugue, Isabelle Séverin, Marie-christine ChagnonAbstract:Background : Bisphenol S is an endocrine disruptor exhibiting metabolic disturbances, especially following perinatal exposures. To date, no data are available on the Obesogen effects of BPS in a mutligenerational issue. Objectives : We investigated Obesogen effects of BPS in a multigenerational study by focusing on body weight, adipose tissue and plasma parameters in male and female mice. Methods : Pregnant C57BL6/J mice were exposed to BPS (1.5 μg/kg bw/day ie a human equivalent dose of 0.12 μg/kg bw/day) by drinking water from gestational day 0 to post natal day 21. All offsprings were fed with a high fat diet during 15 weeks. Body weight was monitored weekly and fat mass was measured before euthanasia. At euthanasia, blood glucose, insuline, triglyceride, cholesterol and no esterified fatty acid plasma levels were determined and gene expressions in visceral adipose tissue were assessed. F1 males and females were mated to obtain the F2 generation. Likewise, the F2 mice were cross-bred to obtain F3. The same analyses were performed. Results : In F1 BPS induced an overweight in male mice associated to lipolysis gene expressions upregulation. In F1 females, dyslipidemia was observed. In F2, BPS exposure was associated to an increase in body weight, fat and VAT masses in males and females. Several plasma parameters were increased but with a sex related pattern (blood glucose, triglycerides and cholesterol in males and NEFA in females). We observed a down-regulation in mRNA expression of gene involved in lipogenesis and in lipolysis for females but only in the lipogenesis for males. In F3, a decrease in VAT mass and an upregulation of lipogenesis gene expression occurred only in females. Conclusions : BPS perinatal exposure induced sex-dependent Obesogen multigenerational effects, the F2 generation being the most impacted. Transgenerational disturbances persisted only in females.
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Are epigenetic modifications linked to BPS Obesogen effect after perinatal exposure? Differential DNA methylation study in mouse livers
Toxicology Letters, 2018Co-Authors: Axelle Brulport, Ludovic Le Corre, Daniel Vaiman, Marie-christine ChagnonAbstract:In 2002, a correlation was established between the environmentalpollution increase and the exponential evolution of the obesity epi-demic. A few years later, the concept of Obesogen was developed.Most of the known Obesogens are endocrine disruptor compounds(EDCs)...
Anna Pereira-fernandes - One of the best experts on this subject based on the ideXlab platform.
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Toxicogenomics in the 3T3-L1 Cell Line, a New Approach for Screening of Obesogenic Compounds
Toxicological sciences : an official journal of the Society of Toxicology, 2014Co-Authors: Anna Pereira-fernandes, Caroline Vanparys, Lucia Vergauwen, Dries Knapen, Philippe G. Jorens, Ronny BlustAbstract:The Obesogen hypothesis states that together with an energy imbalance between calories consumed and calories expended, exposure to environmental compounds early in life or throughout lifetime might have an influence on obesity development. In this work, we propose a new approach for Obesogen screening, i.e., the use of transcriptomics in the 3T3-L1 pre-adipocyte cell line. Based on the data from a previous study of our group using a lipid accumulation based adipocyte differentiation assay, several human-relevant Obesogenic compounds were selected: reference Obesogens (Rosiglitazone, Tributyltin), test Obesogens (Butylbenzyl phthalate, butylparaben, propylparaben, Bisphenol A), and non-Obesogens (Ethylene Brassylate, Bis (2-ethylhexyl)phthalate). The high stability and reproducibility of the 3T3-L1 gene transcription patterns over different experiments and cell batches is demonstrated by this study. Obesogens and non-Obesogen gene transcription profiles were clearly distinguished using hierarchical clustering. Furthermore, a gradual distinction corresponding to differences in induction of lipid accumulation could be made between test and reference Obesogens based on transcription patterns, indicating the potential use of this strategy for classification of Obesogens. Marker genes that are able to distinguish between non, test, and reference Obesogens were identified. Well-known genes involved in adipocyte differentiation as well as genes with unknown functions were selected, implying a potential adipocyte-related function of the latter. Cell-physiological lipid accumulation was well estimated based on transcription levels of the marker genes, indicating the biological relevance of omics data. In conclusion, this study shows the high relevance and reproducibility of this 3T3-L1 based in vitro toxicogenomics tool for classification of Obesogens and biomarker discovery. Although the results presented here are promising, further confirmation of the predictive value of the set of candidate biomarkers identified as well as the validation of their clinical role will be needed.
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Expression of Obesity Markers and Persistent Organic Pollutants Levels in Adipose Tissue of Obese Patients: Reinforcing the Obesogen Hypothesis?
PloS one, 2014Co-Authors: Anna Pereira-fernandes, Caroline Vanparys, Philippe G. Jorens, Eveline Dirinck, Alin C. Dirtu, Govindan Malarvannan, Adrian Covaci, Luc Van Gaal, Ronny BlustAbstract:Introduction Persistent Organic Pollutants (POPs) accumulate in adipose tissue and some are described to possess endocrine disrupting capacities. Therefore, it is important to evaluate their effects on key endocrine pathways in adipose tissue (AT), to further evaluate their potential role in metabolic pathologies such as obesity. Objectives The aim is twofold: (i) evaluate gene expression levels of obesity marker genes, i.e. the adipokines leptin (LEP), adiponectin (ADIPOQ) and Tumor Necrosis Factor α (TNFα) and the nuclear receptor, Peroxisome Proliferator Activated Receptor γ (PPARγ) in paired subcutaneous (SAT) and visceral (VAT) AT of obese subjects (n = 50) and to relate these values to serum concentrations of LEP and ADIPOQ (ii) evaluate the association of expression levels of marker genes in AT and serum with POP concentrations in AT. Results and Conclusions Leptin and adiponectin levels in serum were positively correlated to respectively expression levels of leptin in SAT and adiponectin in VAT. Our study shows more significant correlations between gene expression of obesity marker genes and POP concentrations in VAT compared to SAT. Since VAT is more important than SAT in pathologies associated with obesity, this suggests that POPs are able to influence the association between obesity and the development of associated pathologies. Moreover, this finding reveals the importance of VAT when investigating the Obesogen hypothesis. Concerning PPARγ expression in VAT, negative correlations with polychlorinated biphenyls (PCBs) concentrations were found in non T2D patients. LEP serum concentrations correlated with several PCBs in women whereas in men no correlations were found. This strengthens the potential importance of gender differences in obesity and within the Obesogen hypothesis.
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Evaluation of a screening system for Obesogenic compounds: screening of endocrine disrupting compounds and evaluation of the PPAR dependency of the effect.
PloS one, 2013Co-Authors: Anna Pereira-fernandes, Philippe G. Jorens, Ronny Blust, Heidi Demaegdt, Tine L. M. Hectors, Karine Vandermeiren, Caroline VanparysAbstract:Recently the environmental Obesogen hypothesis has been formulated, proposing a role for endocrine disrupting compounds (EDCs) in the development of obesity. To evaluate this hypothesis, a screening system for Obesogenic compounds is urgently needed. In this study, we suggest a standardised protocol for Obesogen screening based on the 3T3-L1 cell line, a well-characterised adipogenesis model, and direct fluorescent measurement using Nile red lipid staining technique. In a first phase, we characterised the assay using the acknowledged Obesogens rosiglitazone and tributyltin. Based on the obtained dose-response curves for these model compounds, a lipid accumulation threshold value was calculated to ensure the biological relevance and reliability of statistically significant effects. This threshold based method was combined with the well described strictly standardized mean difference (SSMD) method for classification of non-, weak- or strong Obesogenic compounds. In the next step, a range of EDCs, used in personal and household care products (parabens, musks, phthalates and alkylphenol compounds), were tested to further evaluate the Obesogenicity screening assay for its discriminative power and sensitivity. Additionally, the peroxisome proliferator activated receptor γ (PPARγ) dependency of the positive compounds was evaluated using PPARγ activation and antagonist experiments. Our results showed the adipogenic potential of all tested parabens, several musks and phthalate compounds and bisphenol A (BPA). PPARγ activation was associated with adipogenesis for parabens, phthalates and BPA, however not required for Obesogenic effects induced by Tonalide, indicating the role of other Obesogenic mechanisms for this compound.
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Unraveling the mode of action of an Obesogen: mechanistic analysis of the model Obesogen tributyltin in the 3T3-L1 cell line.
Molecular and cellular endocrinology, 2013Co-Authors: Anna Pereira-fernandes, Caroline Vanparys, Lucia Vergauwen, Dries Knapen, Philippe G. Jorens, Tine L. M. Hectors, Ronny BlustAbstract:Obesogenic compounds are chemicals that have an influence on obesity development. This study was designed to unravel the molecular mechanisms of the model Obesogen TBT, using microarray analysis in the 3T3-L1 in vitro system, and to evaluate the use of toxicogenomics for Obesogen screening. The microarray results revealed enrichment of Gene Ontology terms involved in energy and fat metabolism after 10 days of TBT exposure. Pathway analysis unveiled PPAR signalling pathway as the sole pathway significantly enriched after 1 day and the most significantly enriched pathway after 10 days of exposure. To our knowledge, this is the first study delivering an in depth mechanistic outline of the mode of action of TBT as an Obesogen, combining effects on both cell physiological and gene expression level. Furthermore, our results show that combining transcriptomics with 3T3-L1 cells is a promising tool for screening of potential Obesogenic compounds.
Amanda Janesick - One of the best experts on this subject based on the ideXlab platform.
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Obesogens an emerging threat to public health
American Journal of Obstetrics and Gynecology, 2016Co-Authors: Amanda Janesick, Bruce BlumbergAbstract:Endocrine disrupting chemicals (EDCs) are defined as exogenous chemicals, or mixtures of chemicals, that can interfere with any aspect of hormone action. The field of endocrine disruption is historically rooted in wildlife biology and reproductive endocrinology where EDCs are demonstrated contributors to infertility, premature puberty, endometriosis, and other disorders. Recently, EDCs have been implicated in metabolic syndrome and obesity. Adipose tissue is a true endocrine organ and, therefore, an organ that is highly susceptible to disturbance by EDCs. A subset of EDCs, called "Obesogens," promote adiposity by altering programming of fat cell development, increasing energy storage in fat tissue, and interfering with neuroendocrine control of appetite and satiety. Obesity adds more than $200 billion to US healthcare costs and the number of obese individuals continues to increase. Hence, there is an urgent, unmet need to understand the mechanisms underlying how exposures to certain EDCs may predispose our population to be obese. In this review, we discuss the history of Obesogen discovery from its origins in reproductive biology to its latest role in the transgenerational inheritance of obesity in mice. We discuss the development of adipose tissue in an embryo, maintenance of adipocyte number in adults, how EDC disruption programs stem cells to preferentially make more adipocytes, the mechanisms by which chemicals can permanently alter the germline epigenome, and whether there are barriers to EDCs in the gametes.
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Obesogens, stem cells and the developmental programming of obesity
International journal of andrology, 2012Co-Authors: Amanda Janesick, Bruce BlumbergAbstract:development, endocrine disrupters, environmental factors, epigenetics, fish < animal models, hormone receptors, mouse < animal models, obesity, phthalates, sex hormones Summary Obesogens are chemicals that directly or indirectly lead to increased fat accu- mulation and obesity. Obesogens have the potential to disrupt multiple meta- bolic signalling pathways in the developing organism that can result in permanent changes in adult physiology. Prenatal or perinatal exposure to obes- ogenic endocrine disrupting chemicals has been shown to predispose an organ- ism to store more fat from the beginning of its life. For example, excess oestrogen or cortisol exposure in the womb or during early life resulted in an increased susceptibility to obesity and metabolic syndrome later in life. This review focuses on the effects of environmental chemicals, such as the model Obesogen, tributyltin (TBT), on the development of obesity. We discuss evi- dence linking the Obesogenic effects of TBT with its ability to activate the per- oxisome proliferator-activated receptor gamma and stimulate adipogenesis. We also discuss how TBT and other environmental Obesogens may lead to epigenetic changes that predispose exposed individuals to subsequent weight gain and obesity. This suggests that humans, who have been exposed to Obesogenic chemicals during sensitive windows of development, might be pre-programmed to store increased amounts of fat, resulting in a lifelong struggle to maintain a healthy weight and exacerbating the deleterious effects of poor diet and inadequate exercise.
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Endocrine disrupting chemicals and the developmental programming of adipogenesis and obesity.
Birth defects research. Part C Embryo today : reviews, 2011Co-Authors: Amanda Janesick, Bruce BlumbergAbstract:Obesity and related disorders are a burgeoning public health epidemic, particularly in the U.S. Currently 34% of the U.S. population is clinically obese (BMI > 30) and 68% are overweight (BMI > 25), more than double the worldwide average and 10-fold higher than Japan and South Korea. Obesity occurs when energy intake exceeds energy expenditure; however, individuals vary widely in their propensity to gain weight and accrue fat mass, even at identical levels of excess caloric input. Clinical, epidemiological, and biological studies show that obesity is largely programmed during early life, including the intrauterine period. The environmental Obesogen hypothesis holds that prenatal or early life exposure to certain endocrine disrupting chemicals can predispose exposed individuals to increased fat mass and obesity. Obesogen exposure can alter the epigenome of multipotent stromal stem cells, biasing them toward the adipocyte lineage at the expense of bone. Hence, humans exposed to Obesogens during early life might have an altered stem cell compartment, which is preprogrammed toward an adipogenic fate. This results in a higher steady state number of adipocytes and potentially a lifelong struggle to maintain a healthy weight, which can be exacerbated by societal influences that promote poor diet and inadequate exercise. This review focuses on the developmental origins of the adipocyte, the relationship between adipocyte number and obesity, and how Obesogenic chemicals may interfere with the highly efficient homeostatic mechanisms regulating adipocyte number and energy balance.
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Minireview: PPARγ as the target of Obesogens.
The Journal of Steroid Biochemistry and Molecular Biology, 2011Co-Authors: Amanda Janesick, Bruce BlumbergAbstract:The peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of adipogenesis and is medically important for its connections to obesity and the treatment of type II diabetes. Activation of this receptor by certain natural or xenobiotic compounds has been shown to stimulate adipogenesis in vitro and in vivo. Obesogens are chemicals that ultimately increase obesity through a variety of potential mechanisms, including activation of PPARγ. The first Obesogen for which a definitive mechanism of action has been elucidated is the PPARγ and RXR activator tributyltin; however, not all chemicals that activate PPARγ are adipogenic or correlated with obesity in humans. There are multiple mechanisms through which Obesogens can target PPARγ that may not involve direct activation of the receptor. Ligand-independent mechanisms could act through Obesogen-mediated post-translational modification of PPARγ which cause receptor de-repression or activation. PPARγ is active in multipotent stem cells committing to the adipocyte fate during fat cell development. By modifying chromatin structure early in development, Obesogens have the opportunity to influence the promoter activity of PPARγ, or the ability of PPARγ to bind to its target genes, ultimately biasing the progenitor pool towards the fat lineage. Obesogens that act by directly or indirectly activating PPARγ, by increasing the levels of PPARγ protein, or enhancing its recruitment to promoters of key genes in the adipogenic pathway may ultimately play an important role in adipogenesis and obesity.
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The Role of Environmental Obesogens in the Obesity Epidemic
Obesity Before Birth, 2010Co-Authors: Amanda Janesick, Bruce BlumbergAbstract:Prenatal exposure to certain environmental chemicals predisposes an organism to store more fat from the beginning of its life. These chemicals, termed Obesogens, have the potential to disrupt multiple metabolic signaling pathways in the developing fetus leading to permanent alterations in adult physiology. The most prominent studies on the prenatal programming of obesity have shown that maternal malnutrition or excess estrogen or cortisol exposure in the womb causes an increased susceptibility to obesity and metabolic syndrome later in life. This review focuses on the effects of environmental chemicals such as the model Obesogen, tributyltin (TBT). We provide evidence that TBT might also perturb estrogen and glucocorticoid signaling; however, the primary mechanism underlying the Obesogenic effects of TBT is its ability to activate the peroxisome proliferator-activated receptor gamma (PPARγ), thereby stimulating adipogenesis. Furthermore, we show that TBT alters the epigenome, particularly within the mesenchymal stromal cell compartment where the outcome is to bias cells to become adipocytes, at the expense of other lineages. This suggests that humans, who have been exposed to Obesogenic chemicals, might be pre-programmed to store increased amounts of fat, resulting in a lifelong struggle to maintain a healthy weight and exacerbating the deleterious effects of poor diet and inadequate exercise.
