- Department of Pharmacology and Pharmaceutical Sciences
School of Pharmacy
1985 Zonal Avenue - 3234421369
- Dr. Papadopoulos is the Dean of the School of Pharmacy at the University of Southern California. Dr. Papadopoulos ho... moreDr. Papadopoulos is the Dean of the School of Pharmacy at the University of Southern California. Dr. Papadopoulos holds the John Stauffer Dean’s Chair in Pharmaceutical Sciences and is Professor of Pharmacology and Pharmaceutical Sciences at the University of Southern California. He is a graduate of the School of Pharmacy of the University of Athens. Dr. Papadopouloa completed his PhD in Health and Life Science at Université Pierre et Marie Curie, Paris and post-doctoral studies in France and Australia. In 1988, he joined the faculty of Georgetown University School of Medicine, where he rose through the ranks to become Professor and Chair of the Department of Biochemistry and Molecular Biology, Associate Vice President for Research and then Director of the Biomedical Graduate Research Organization at Georgetown University Medical Centre. In 2007, he moved to Montreal as the Executive Director and Chief Scientific Officer of the Research Institute of the McGill University Health Centre, and Professor of Medicine at McGill University where he held the Canada Research Chair in Biochemical Pharmacology and the Phil Gold Chair in Medicine. Dr. Papadopoulos’ research focus is on the pharmacology of steroid hormone biosynthesis in relation to endocrine pathologies, male reproductive disorders, neuropathologies and cancer. He has published over 350 papers, holds numerous patents and served on advisory committees of various U.S., Canadian, European and other government agencies, foundations and corporations. Dr. Papadopoulos is an elected member of the French National Academies of Pharmacy and Medicine, a fellow of the U.S. American Association for the Advancement of Science, a fellow of the Canadian Academy of Health Sciences and has served as President of the American Society of Andrology.edit
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Research Interests: Chemical Engineering, Biological Sciences, Humans, DSS, Mice, and 18 moreGABA receptors, Cholesterol, Structured data, Animals, Physical sciences, Ligand Binding, Cattle, Protein Sequence Analysis, Secondary Structure, Protein Secondary Structure Prediction, Structural Properties, HSQC, Membrane Protein, Protein Quaternary Structure, Recombinant Protein, Structure activity Relationship, Noesy, and Biochemistry and cell biology
Sterol carrier protein-2 (SCP2), also called nonspecific lipid-transfer protein, is thought to play a major role in intracellular lipid transport and metabolism, and it has been associated with diseases involving abnormalities in lipid... more
Sterol carrier protein-2 (SCP2), also called nonspecific lipid-transfer protein, is thought to play a major role in intracellular lipid transport and metabolism, and it has been associated with diseases involving abnormalities in lipid trafficking, such as Zellweger syndrome. The Scp2 gene encodes the 58 kDa sterol carrier protein-x (SCPX) and 15 kDa pro-SCP2 proteins, both of which contain a 13 kDa SCP2 domain in their C-termini. We found that 22-NBD-cholesterol, a fluorescent analog of cholesterol and a preferred SCP2 ligands, was not localized in the peroxisomes. This raises questions about previous reports on the localization of the SCPX and SCP2 proteins and their relationship to peroxisomes and mitochondria in intracellular cholesterol transport. Immunofluorescent staining of cryosections of mouse testis and of MA-10 mouse tumor Leydig cells showed that SCPX and SCP2 are present in both mouse testicular interstitial tissue and in MA-10 cells. Fluorescent fusion proteins of SCP...
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Chronic inflammation of the gastrointestinal tract increasing the risk of cancer has been described to be linked to the high expression of the mitochondrial translocator protein (18 kDa; TSPO). Accordingly, TSPO drug ligands have been... more
Chronic inflammation of the gastrointestinal tract increasing the risk of cancer has been described to be linked to the high expression of the mitochondrial translocator protein (18 kDa; TSPO). Accordingly, TSPO drug ligands have been shown to regulate cytokine production and to improve tissue reconstruction. We used HT-29 human colon carcinoma cells to evaluate the role of TSPO and its drug ligands in tumor necrosis factor (TNF)-induced inflammation. TNF-induced interleukin (IL)-8 expression, coupled to reactive oxygen species (ROS) production, was followed by TSPO overexpression. TNF also destabilized mitochondrial ultrastructure, inducing cell death by apoptosis. Treatment with the TSPO drug ligand PK 11195 maintained the mitochondrial ultrastructure, reducing IL-8 and ROS production and cell death. TSPO silencing and overexpression studies demonstrated that the presence of TSPO is essential to control IL-8 and ROS production, so as to maintain mitochondrial ultrastructure and to...
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Fatty acid metabolism and steroid biosynthesis are two major pathways shared by peroxisomes and mitochondria. Both organelles are in close apposition to the endoplasmic reticulum, with which they communicate via inter-organelle membrane... more
Fatty acid metabolism and steroid biosynthesis are two major pathways shared by peroxisomes and mitochondria. Both organelles are in close apposition to the endoplasmic reticulum, with which they communicate via inter-organelle membrane contact sites to promote cellular signaling and the exchange of ions and lipids. To date, no convincing evidence of the direct contact between peroxisomes and mitochondria was reported in mammalian cells. Hormone-induced, tightly controlled steroid hormone biosynthesis requires inter-organelle interactions. Using immunofluorescent staining and live-cell imaging, we found that dibutyryl-cyclic adenosine monophosphate treatment of MA-10 mouse tumor Leydig cells rapidly induces peroxisomes to approach mitochondria and form peroxisome-mitochondrial contact sites/fusion, revealed by the subcellular distribution of the endogenous ACBD2/ECI2 isoform A generated by alternative splicing, and further validated using a proximity ligation assay. This event occur...
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Previous work in our laboratory demonstrated that in-utero exposure to a mixture of the phytoestrogen Genistein (GEN), and plasticizer DEHP, induces short- and long-term alterations in testicular gene and protein expression different from... more
Previous work in our laboratory demonstrated that in-utero exposure to a mixture of the phytoestrogen Genistein (GEN), and plasticizer DEHP, induces short- and long-term alterations in testicular gene and protein expression different from individual exposures. These studies identified fetal and adult Leydig cells as sensitive targets for low dose endocrine disruptor (ED) mixtures. To further investigate the direct effects and mechanisms of toxicity of GEN and DEHP, MA-10 mouse tumor Leydig cells were exposed in-vitro to varying concentrations of GEN and MEHP, the principal bioactive metabolite of DEHP. Combined 10μM GEN+10μM MEHP had a stimulatory effect on basal progesterone production. Consistent with increased androgenicity, the mRNA of steroidogenic and cholesterol mediators Star, Cyp11a, Srb1 and Hsl, as well as upstream orphan nuclear receptors Nr2f2 and Sf1 were all significantly increased uniquely in the mixture treatment group. Insl3, a sensitive marker of Leydig endocrine ...
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Although exposures to environmental toxicants occur throughout life, little attention has been paid to the possible effects of exposures early in life on later exposure effects. We asked whether DEHP administered in utero... more
Although exposures to environmental toxicants occur throughout life, little attention has been paid to the possible effects of exposures early in life on later exposure effects. We asked whether DEHP administered in utero (GD14-parturition) affects how male rats respond to later exposures. Neither in utero nor juvenile (PND21-35) exposures to 100mg/kg/day DEHP affected testis weight or histology as assessed on PND35. However, after in utero DEHP, subsequent juvenile exposure resulted in significantly reduced testis weight and altered testicular histology. Both in utero and juvenile exposures resulted in significant reductions in serum testosterone, but there was no effect of earlier on later exposure. Whether or not there had been in utero DEHP exposure, juvenile DEHP exposure had no effect on body, kidney or liver weights. These observations indicate that in utero exposure can, but will not necessarily, alter later exposure effects, with outcomes dependent upon endpoints measured a...
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Translocator protein TSPO is an 18 kDa protein implicated in numerous cell functions and is highly expressed in secretory and glandular tissues, especially in steroidogenic cells. TSPO expression is altered in pathological conditions such... more
Translocator protein TSPO is an 18 kDa protein implicated in numerous cell functions and is highly expressed in secretory and glandular tissues, especially in steroidogenic cells. TSPO expression is altered in pathological conditions such as certain cancers and neurological ...
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Intratumoral androgen formation may be a factor in the development of prostate cancer (PCa), particularly castration-resistant prostate cancer (CRPC). To evaluate the ability of the human prostate to synthesize de novo steroids, we... more
Intratumoral androgen formation may be a factor in the development of prostate cancer (PCa), particularly castration-resistant prostate cancer (CRPC). To evaluate the ability of the human prostate to synthesize de novo steroids, we examined the expression of key enzymes and proteins involved in steroid biosynthesis and metabolism. Using TissueScan™ Cancer qPCR Arrays and quantitative RT-PCR, we performed comparative gene expression analyses between various prostate cell lines and biopsies, including normal, hyperplastic, cancerous, and androgen-deprived prostate cells lines, as well as normal, benign prostate hyperplasia (BPH), PCa, and CRPC human specimens. These studies were complemented with steroid biosynthesis studies in normal and BPH cells. Normal human prostate WPMY-1 and WPE1-NA22, benign prostate hyperplasia BPH-1, and cancer PC-3, LNCaP, and VCaP cell lines, as well as normal, BPH, PCa, and CRPC specimens, were used. Although all cell lines express mRNA encoding for hydro...
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The translocator protein (TSPO; 18k Da) is an evolutionarily conserved outer mitochondrial membrane (OMM) protein highly expressed in steroid-synthesizing cells and found to possess a number of physiological and drug-binding partners.... more
The translocator protein (TSPO; 18k Da) is an evolutionarily conserved outer mitochondrial membrane (OMM) protein highly expressed in steroid-synthesizing cells and found to possess a number of physiological and drug-binding partners. Extensive pharmacological, biochemical and cell biological research over the years has led to a model of TSPO involvement in mitochondrial cholesterol transport and promotion of steroid synthesis, a model guiding the design of drugs useful in stimulating neurosteroid synthesis and alleviating psychopathological symptoms. The involvement of TSPO in these processes has been called into question; however, with the publication of TSPO-deletion mouse models which saw no changes in steroid production. Here, we review work characterizing TSPO in steroidogenesis and offer perspective to research into TSPO pharmacology and its involvement in steroid biosynthesis.
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Research Interests: Pathology, Statistics, Free Radicals, Neuroanatomy, Documentation, and 55 moreStem Cells, Data Analysis, Neuropharmacology, Informed Consent, Treatment, Hypoxia, Risk assessment, Density, Cryopreservation, Probability, Structural, Anatomy, Side Effects, Transport, Chemicals, Pluripotency, Hemodynamics, Spermatogenesis, Pesticides, Pharmaceutical, Measurement, Relaxation, STEM, Duration, Obstetrics and gynecology, Progenitor Cells, Regression to the Mean, Frequency, Function, Etiology, Embryonic Stem Cells, Pediatric, Differentiation, CYP, Mathematical, Collection, Exposure, Gaussian distribution, Xenobiotics, Size, Stimulation, Risk Assessment, Rho-kinase, P Value, G Proteins, Environmental, Area Under the Curve, Subclinical, Potency, Therapeutic, Central Limit Theorem, Diagnostic Tests, Sry gene, DNA fragmentation, and TUNEL-assay
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The capacity of Brown Norway rat Leydig cells to produce testosterone (T) decreases with aging. In a previous study, we reported that a new generation of Leydig cells can be restored in both young and old rat testes after a single... more
The capacity of Brown Norway rat Leydig cells to produce testosterone (T) decreases with aging. In a previous study, we reported that a new generation of Leydig cells can be restored in both young and old rat testes after a single injection of ethane dimethanesulfonate (EDS), and that the abilities of the new Leydig cells in young and old rats to produce T were equivalent. Our objective herein was to compare the steroidogenic fate of the new Leydig cells over time. Young (3month-old) and old (18month-old) rats were injected with EDS to eliminate the existing Leydig cells. Ten weeks after EDS, Leydig cells had been restored and T production by the new Leydig cells isolated from young and old rat testes was equivalent. Thirty weeks after EDS treatment of young rats, the ability of the new Leydig cells to produce T had not diminished from 10weeks post-EDS. In contrast, at 30weeks post-EDS, T production by new cells in old rat testes was reduced significantly from the 10-week level. Ser...
For decades, only few tissues and cell types were defined as steroidogenic, capable of de novo steroid synthesis from cholesterol. However, with the refinement of detection methods, several tissues have now been added to the list of... more
For decades, only few tissues and cell types were defined as steroidogenic, capable of de novo steroid synthesis from cholesterol. However, with the refinement of detection methods, several tissues have now been added to the list of steroidogenic tissues. Besides their critical role as long-range acting hormones, steroids are also playing more discreet roles as local mediators and signaling molecules within the tissues they are produced. In testis, steroidogenesis is carried out by the Leydig cells through a broad network of proteins, mediating cholesterol delivery to CYP11A1, the first cytochrome of the steroidogenic cascade, and the sequential action of enzymes insuring the production of active steroids, the main one being testosterone. The knowledge that male germ cells can be directly regulated by steroids and that they express several steroidogenesis-related proteins led us to hypothesize that germ cells could produce steroids, acting as autocrine, intracrine and juxtacrine mod...
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The action of prostaglandin F2 alpha (PG F2 alpha) on incubated small bovine luteal cells in the presence or in the absence of bovine luteinizing hormone (LH) or dibutyryl cyclic adenosine monophosphate (db cAMP) was investigated. In the... more
The action of prostaglandin F2 alpha (PG F2 alpha) on incubated small bovine luteal cells in the presence or in the absence of bovine luteinizing hormone (LH) or dibutyryl cyclic adenosine monophosphate (db cAMP) was investigated. In the absence of LH and db cAMP, PG F2 alpha stimulated progesterone synthesis at concentrations of 10 ng/ml and 100 ng/ml but had no effects at concentrations below 1 ng/ml. PG F2 alpha partially inhibited the LH or db cAMP stimulated progesterone synthesis. This inhibition was maximal for PG F2 alpha concentrations around 100 pg/ml whereas distinctly higher or lower concentrations were without effect. At the concentration of 100 pg/ml, PG F2 alpha partially inhibited the LH induced cAMP accumulation. These results demonstrate an "in vitro" action of PG F2 alpha on bovine luteal cells. They indicate that the luteolytic action of PG F2 alpha in the bovine species could involve, as already suggested for the rat, both an inhibition of the LH induc...
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As a major regulator in obesity and its associated metabolic complications, the proper functioning of adipocytes is crucial for health maintenance, thus serving as an important target for the development of anti-obese and anti-diabetic... more
As a major regulator in obesity and its associated metabolic complications, the proper functioning of adipocytes is crucial for health maintenance, thus serving as an important target for the development of anti-obese and anti-diabetic therapies. There is increasing evidence that mitochondrial malfunction is a pivotal event in disturbing adipocyte cell homeostasis. Among major mitochondrial structure components, the high-affinity drug- and cholesterol-binding outer mitochondrial membrane translocator protein (18kDa; TSPO) has shown importance across a broad spectrum of mitochondrial functions. Recent studies demonstrated the presence of TSPO in white adipocyte mitochondria of mice, and administration of TSPO drug ligands to obese mice reduced weight gain and lowered glucose level. Therefore, it is of great interest to assess whether TSPO in adipocytes could serve as a drug target to regulate adipocyte activities with potential influence on weight control and glucose metabolism. Two structurally distinct TSPO drug ligands, PK 11195 and FGIN-1-27, improved the intracellular dynamics of 3T3-L1 adipocytes, such as the production and release of adipokines, glucose uptake, and adipogenesis. TSPO knockdown in either differentiated adipocytes or preadipocytes impaired these functions. Findings from 3T3-L1 cells were related to human primary cells, where TSPO expression was tightly associated with the metabolic state of primary adipocytes and the differentiation of primary preadipocytes. These results suggest that TSPO expression is essential to safeguard healthy adipocyte functions, and that TSPO activation in adipocytes improves their metabolic status in regulating glucose homeostasis. Adipocyte TSPO may serve as a pharmacologic target for the treatment of obesity and diabetes.
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ABSTRACT •The action of prostaglandin F2σ (PG F2σ) on incubated small bovine luteal cells in the presence or in the absence of bovine luteinizing hormone (LH) or dibutyryl cyclic adenosine monophosphate (db cAMP) was investigated.•In the... more
ABSTRACT •The action of prostaglandin F2σ (PG F2σ) on incubated small bovine luteal cells in the presence or in the absence of bovine luteinizing hormone (LH) or dibutyryl cyclic adenosine monophosphate (db cAMP) was investigated.•In the absence of LH and db cAMP, PG F2σ stimulated progesterone synthesis at concentrations of 10 ng/ml and 100 ng/ml but had no effects at concentrations below 1 ng/ml. PG F2σ partially inhibited the LH or db cAMP stimulated progesterone synthesis. This inhibition was maximal for PG F2σ concentrations around 100 pg/ml whereas distinctly higher or lower concentrations were without effect. At the concentration of 100 pg/ml, PG F2σ partially inhibited the LH induced cAMP accumulation.•These results demonstrate an “in vitro” action of PG F2σ on bovine luteal cells. They indicate that the luteolytic action of PG F2σ in the bovine species could involve, as already suggested for the rat, both an inhibition of the LH induced synthesis of cAMP and on inhibition of the action of cAMP.
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Plastics are generally mixed with additives like plasticizers to enhance their flexibility, pliability, and elasticity proprieties. Plasticizers are easily released into the environment and are absorbed mainly through ingestion, dermal... more
Plastics are generally mixed with additives like plasticizers to enhance their flexibility, pliability, and elasticity proprieties. Plasticizers are easily released into the environment and are absorbed mainly through ingestion, dermal contact, and inhalation. One of the main classes of plasticizers, phthalates, has been associated with endocrine and reproductive diseases. In 2002, 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) was introduced in the market for use in plastic materials and articles intended to come into contact with food, and it received final approval from the European Food Safety Authority in 2006. At present, there is limited knowledge about the safety and potential metabolic and endocrine-disrupting properties of DINCH and its metabolites. The purpose of this study was to evaluate the biological effects of DINCH and its active metabolites, cyclohexane-1,2-dicarboxylic acid (CHDA) and cyclohexane-1,2-dicarboxylic acid mono isononyl ester (MINCH), on rat primary stromal vascular fraction (SVF) of adipose tissue. DINCH and its metabolite, CHDA, were not able to directly affect SVF differentiation. However, exposure of SVF to 50μM and 100μM concentrations of MINCH affected the expression of Cebpa and Fabp4, thus inducing SVF preadipocytes to accumulate lipids and fully differentiate into mature adipocytes. The effect of MINCH was blocked by the specific peroxisome proliferator-activated receptor (PPAR)-α antagonist, GW6471. Taken together, these results suggest that MINCH is a potent PPAR-α agonist and a metabolic disruptor, capable of inducing SVF preadipocyte differentiation, that may interfere with the endocrine system in mammals.
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Tissue-specific expression of steroidogenic enzymes allows the modulation of active steroid levels in a local manner. Thus, the measurement of local steroid concentrations, rather than the circulating levels, has been recognized as a more... more
Tissue-specific expression of steroidogenic enzymes allows the modulation of active steroid levels in a local manner. Thus, the measurement of local steroid concentrations, rather than the circulating levels, has been recognized as a more accurate indicator of the steroid action within a specific tissue. Adipose tissue, one of the largest endocrine tissues in the human body, has been established as an important site for steroid storage and metabolism. Locally produced steroids, through the enzymatic conversion from steroid precursors delivered to adipose tissue, have been proven to either functionally regulate adipose tissue metabolism, or quantitatively contribute to the whole body's steroid levels. Most recently, it has been suggested that adipose tissue may contain the steroidogenic machinery necessary for the initiation of steroid biosynthesis de novo from cholesterol. This review summarizes the evidence indicating the presence of the entire steroidogenic apparatus in adipose tissue and discusses the potential roles of local steroid products in modulating adipose tissue activity and other metabolic parameters.
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The 14-3-3 protein family comprises adaptors and scaffolds that regulate intracellular signaling pathways. The 14-3-3γ isoform is a negative regulator of steroidogenesis that is hormonally induced and transiently functions at the... more
The 14-3-3 protein family comprises adaptors and scaffolds that regulate intracellular signaling pathways. The 14-3-3γ isoform is a negative regulator of steroidogenesis that is hormonally induced and transiently functions at the initiation of steroidogenesis by delaying maximal steroidogenesis in MA-10 mouse tumor Leydig cells. Treatment of MA-10 cells with the cAMP analog 8-bromo-cAMP (8-Br-cAMP), which stimulates steroidogenesis, triggers the interaction of 14-3-3γ with the steroidogenic acute regulatory protein (STAR) in the cytosol, limiting STAR activity to basal levels. Over time, this interaction ceases, allowing for a 2-fold induction in STAR activity and maximal increase in the rate of steroid formation. The 14-3-3γ/STAR pattern of interaction was found to be opposite that of the 14-3-3γ homodimerization pattern. Phosphorylation and acetylation of 14-3-3γ showed similar patterns to homodimerization and STAR binding, respectively. 14-3-3γ Ser(58) phosphorylation and 14-3-3γ...
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Alzheimer's disease (AD) is the most common form of dementia occurring in the elderly. Several hypotheses have been proposed to explain the pathophysiology of AD, including amyloidogenesis, disruption of calcium homeostasis, energetic... more
Alzheimer's disease (AD) is the most common form of dementia occurring in the elderly. Several hypotheses have been proposed to explain the pathophysiology of AD, including amyloidogenesis, disruption of calcium homeostasis, energetic failure, induction of oxidative stress, and hyperphosphorylation of tau protein. This review examines associations between cellular and subcellular injuries, neurodegeneration, and cell death in experimental models, clinical symptoms, and autopsy reports of AD to identify the subcellular events leading to disease onset and progression. The order in which these events occur is discussed. The first injuries reported in AD are subcellular and occur at the Golgi apparatus before any β-amyloid proteins deposit in the Golgi and endosomes. This is followed by lysosomal alterations and the inability of cells to clear β-amyloid. The next stage reveals functional changes and modifications in hippocampal synaptic transmission before structural changes are obs...
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Exposure to environmental toxicants during fetal development alters gene expression and promotes disease later in life. Di-(2-ethylhexyl) phthalate (DEHP) is a plasticizer widely used for the manufacturing of consumer products. Exposure... more
Exposure to environmental toxicants during fetal development alters gene expression and promotes disease later in life. Di-(2-ethylhexyl) phthalate (DEHP) is a plasticizer widely used for the manufacturing of consumer products. Exposure to DEHP has been associated with obesity, asthma, and low T levels. In utero exposure of pregnant dams to DEHP from gestational day 14 until birth resulted in reduced levels of serum T and aldosterone in the adult male offspring. Because DEHP is rapidly cleared from the body, the effects observed in the adult are likely epigenetic in origin. Under the same experimental conditions, we used reduced-representation bisulfite sequencing to assess changes in DNA methylation. We identified hot spots of DNA methylation changes primarily within CpG islands followed by shelf regions of the genome known to control regional gene expression. We also identified epigenomic areas responsive to exposure to environmental levels of DEHP and found the chromosomal region...
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The environmental obesogen hypothesis proposes that exposure to endocrine disruptors during developmental 'window' contributes to adipogenesis and the development of obesity. MEHP [mono-(2-ethylhexyl)... more
The environmental obesogen hypothesis proposes that exposure to endocrine disruptors during developmental 'window' contributes to adipogenesis and the development of obesity. MEHP [mono-(2-ethylhexyl) phthalate], a metabolite of the widespread plasticizer DEHP [di-(2-ethylhexyl) phthalate], has been found in exposed organisms and identified as a selective PPARγ (peroxisome-proliferator-activated receptor γ) modulator. However, implication of MEHP on adipose tissue development has been poorly investigated. In the present study, we show the dose-dependent effects of MEHP on adipocyte differentiation and GPDH (glycerol-3-phosphate dehydrogenase) activity in the murine 3T3-L1 cell model. MEHP induced the expression of PPARγ as well as its target genes required for adipogenesis in vitro. Moreover, MEHP perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to a low dose of MEHP significantly increased b.w. (body weight) and fat pad weight in male offspring at PND (postnatal day) 60. In addition, serum cholesterol, TAG (triacylglycerol) and glucose levels were also significantly elevated. These results suggest that perinatal exposure to MEHP may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders.