RESUMEN
BACKGROUND: Early-life phthalate exposures may disrupt metabolic processes; however few prospective studies have assessed whether these associations extend to cardiometabolic outcomes during adolescence. METHODS: Among 183 mother-adolescent pairs in a prospective cohort study that enrolled pregnant women in Cincinnati, OH (2003-2006), we quantified nine phthalate metabolites in spot urine samples collected twice from mothers during pregnancy and up to seven times from children. At age 12 years, we assessed triglycerides, high-density (HDL) and low-density (LDL) lipoprotein cholesterol, insulin, and glucose from fasting serum samples and calculated homeostatic model assessment of insulin resistance (HOMA-IR). Using multiple informant models, we estimated covariate-adjusted associations between urinary phthalate concentrations at each time period and cardiometabolic biomarkers at age 12 years, including modification by child sex. RESULTS: Although most associations were weak or null, monoethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), and monobenzyl phthalate (MBzP) concentrations were generally associated with lower LDL at age 12 years. A 10-fold increase in 4- and 12-year MEP was associated with -15.3 mg/dL (95% CI: 27.5, -3.13 mg/dL) and -11.8 mg/dL (-22.0, -1.51 mg/dL) lower LDL, respectively. Discrepant associations were observed in females versus males: a 10-fold increase in 3-year MEP concentrations was associated with 12.0 mg/dL (95% CI: 7.11, 31.1 mg/dL) higher LDL levels in males and -30.4 mg/dL (95% CI: 50.9, -9.8 mg/dL) lower LDL levels in females. Some urinary phthalate concentrations were cross-sectionally associated with HOMA-IR. CONCLUSIONS: Early-life phthalate biomarker concentrations may be inversely associated with LDL during early adolescence in an exposure-period and sex-dependent manner.
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Enfermedades Cardiovasculares , Contaminantes Ambientales , Resistencia a la Insulina , Ácidos Ftálicos , Masculino , Niño , Humanos , Femenino , Embarazo , Adolescente , Estudios Prospectivos , Contaminantes Ambientales/orina , Ácidos Ftálicos/orina , Biomarcadores , Lípidos , Exposición a Riesgos Ambientales/análisisRESUMEN
Polybrominated diphenyl ethers (PBDEs) are persistent organic chemicals implied as flame retardants. Humans are mainly exposed to BDE-47, -99, and -209 congeners by diet. PBDEs are metabolic disruptors with the liver as the main target organ. To investigate their mode of action at a human-relevant concentration, we exposed HepG2 cells to these congeners and their mixture at 1 nM, analyzing their transcriptomic and proteomic profiles. KEGG pathways and GSEA Hallmarks enrichment analyses evidenced that BDE-47 disrupted the glucose metabolism and hypoxia pathway; all the congeners and the MIX affected lipid metabolism and signaling Hallmarks regulating metabolism as mTORC1 and PI3K/AKT/MTOR. These results were confirmed by glucose secretion depletion and increased lipid accumulation, especially in BDE-47 and -209 treated cells. These congeners also affected the EGFR/MAPK signaling; further, BDE-47 enriched the estrogen pathway. Interestingly, BDE-209 and the MIX increased ERα gene expression, whereas all the congeners and the MIX induced ERß and PPARα. We also found that PBDEs modulated several lncRNAs and that HNRNAP1 represented a central hub in all the four interaction networks. Overall, the PBDEs investigated affected glucose and lipid metabolism with different underlying modes of action, as highlighted by the integrated omics analysis, at a dietary relevant concentration. These results may support the mechanism-based risk assessment of these compounds in relation to liver metabolism disruption.
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Éteres Difenilos Halogenados , Metabolismo de los Lípidos , Humanos , Éteres Difenilos Halogenados/toxicidad , Células Hep G2 , Glucosa , Transcriptoma , Proteómica , Fosfatidilinositol 3-Quinasas/metabolismo , DietaRESUMEN
Obesogens, as environmental endocrine-disrupting chemicals, are supposed to have had an impact on the prevalence of rising obesity around the world over the last forty years. These chemicals are probably able to contribute not only to the development of obesity and metabolic disturbances in individuals, but also in their progeny, having the capability to epigenetically reprogram genetically inherited set-up points for body weight and body composition control during critical periods of development, such as fetal, early life, and puberty. In individuals, they may act on myriads of neuro-endocrine-immune metabolic regulatory pathways, leading to pathophysiological consequences in adipogenesis, lipogenesis, lipolysis, immunity, the influencing of central appetite and energy expenditure regulations, changes in gut microbiota-intestine functioning, and many other processes. Evidence-based medical data have recently brought much more convincing data about associations of particular chemicals and the probability of the raised risk of developing obesity. Foods are the main source of obesogens. Some obesogens occur naturally in food, but most are environmental chemicals, entering food as a foreign substance, whether in the form of contaminants or additives, and they are used in a large amount in highly processed food. This review article contributes to a better overview of obesogens, their occurrence in foods, and their impact on the human organism.
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Disruptores Endocrinos , Exposición a Riesgos Ambientales , Adipogénesis , Disruptores Endocrinos/toxicidad , Alimentos , Humanos , Obesidad/epidemiología , Obesidad/etiologíaRESUMEN
Bisphenols and phthalates, chemicals frequently used in plastic products, promote obesity in cell and animal models. However, these well-known metabolism-disrupting chemicals (MDCs) represent only a minute fraction of all compounds found in plastics. To gain a comprehensive understanding of plastics as a source of exposure to MDCs, we characterized the chemicals present in 34 everyday products using nontarget high-resolution mass spectrometry and analyzed their joint adipogenic activities by high-content imaging. We detected 55,300 chemical features and tentatively identified 629 unique compounds, including 11 known MDCs. Importantly, the chemicals extracted from one-third of the products caused murine 3T3-L1 preadipocytes to proliferate, and differentiate into adipocytes, which were larger and contained more triglycerides than those treated with the reference compound rosiglitazone. Because the majority of plastic extracts did not activate the peroxisome proliferator-activated receptor γ and the glucocorticoid receptor, the adipogenic effects are mediated via other mechanisms and, thus, likely to be caused by unknown MDCs. Our study demonstrates that daily-use plastics contain potent mixtures of MDCs and can, therefore, be a relevant yet underestimated environmental factor contributing to obesity.
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Adipogénesis , Plásticos , Células 3T3-L1 , Adipocitos , Animales , Ratones , Obesidad , PPAR gamma , Plásticos/farmacologíaRESUMEN
Even though microplastic (MP) pollution in aquatic environment is nowadays widely studied, a huge gap of knowledge exists on their actual biological effects. In this study we first reported environmental baseline data on the occurrence and characterization of ï¬oating MPs in Italian coastal waters of the Central Adriatic Sea by using a standardized monitoring protocol. Further, we analyzed the concentrations of MP-associated chemicals and evaluated their potential adipogenic effects using 3T3-L1 preadipocytes. MPs were found in each sampling stations showing the highest abundance (1.88 ± 1.78 items/m3) in the sites more distant from the coast with fragments as the most common shape category. All targeted organic pollutants (i.e. polychlorinated biphenyls - PCBs, polycyclic aromatic hydrocarbons -PAHs, organophosphorus - OP, and organochlorine - OC pesticides) have been detected on the surface of the collected MPs. The highest concentrations of PAHs were found on MPs from inshore (i.e. <1.5 NM) surface waters with low-ring PAHs as dominant components. Similarly, MPs from inshore waters had higher ΣPCB concentrations (64.72 ng/g plastic) than those found in offshore (i.e. >6 NM) waters (10.37 ng/g plastic). Among pesticides, all measured OPs were detected in each sample analyzed with pirimiphos-methyl as the most representative compound. For OCs, the sum of all concentrations of congeners was higher in coastal with respect to offshore waters. Moreover, in vitro 3T3-L1 screening of MP extracts indicated potential metabolic effects resulting in both adipogenesis and lipid uptake/storage.
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Monitoreo del Ambiente , Microplásticos/análisis , Contaminantes Químicos del Agua/análisis , Adipogénesis , Hidrocarburos Clorados/análisis , Italia , Microplásticos/toxicidad , Plaguicidas/análisis , Plásticos , Bifenilos Policlorados/análisis , Hidrocarburos Policíclicos Aromáticos/análisis , Contaminantes Químicos del Agua/toxicidadRESUMEN
During the last two decades, the constitutive androstane receptor (CAR; NR1I3) has emerged as a master activator of drug- and xenobiotic-metabolizing enzymes and transporters that govern the clearance of both exogenous and endogenous small molecules. Recent studies indicate that CAR participates, together with other nuclear receptors (NRs) and transcription factors, in regulation of hepatic glucose and lipid metabolism, hepatocyte communication, proliferation and toxicity, and liver tumor development in rodents. Endocrine-disrupting chemicals (EDCs) constitute a wide range of persistent organic compounds that have been associated with aberrations of hormone-dependent physiological processes. Their adverse health effects include metabolic alterations such as diabetes, obesity, and fatty liver disease in animal models and humans exposed to EDCs. As numerous xenobiotics can activate CAR, its role in EDC-elicited adverse metabolic effects has gained much interest. Here, we review the key features and mechanisms of CAR as a xenobiotic-sensing receptor, species differences and selectivity of CAR ligands, contribution of CAR to regulation hepatic metabolism, and evidence for CAR-dependent EDC action therein.
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Disruptores Endocrinos/farmacología , Receptores Citoplasmáticos y Nucleares/fisiología , Factores de Transcripción/fisiología , Animales , Receptor de Androstano Constitutivo , Humanos , Inactivación Metabólica , Hígado/metabolismo , Redes y Vías Metabólicas/efectos de los fármacos , Ratones , Ratas , Xenobióticos/metabolismoRESUMEN
CONTEXT: Per- and polyfluoroalkyl substances (PFAS) exposure may alter glucose homeostasis. Research on PFAS exposure and glucose tolerance during pregnancy is limited. OBJECTIVE: The objective of this work is to estimate associations between first-trimester plasma PFAS concentrations and glucose tolerance assessed in late second pregnancy trimester. DESIGN, SETTING, PARTICIPANTS, AND MAIN OUTCOME MEASURES: Pregnant women (nâ =â 1540) enrolled in Project Viva in 1999 to 2002 provided first-trimester plasma samples analyzed for 8 PFAS. At approximately 28 weeks' gestation, women completed 1-hour nonfasting, 50-g oral glucose challenge tests (GCTs); if abnormal, women completed subsequent 3-hour oral glucose tolerance tests (OGTTs) to screen for gestational diabetes mellitus (GDM). We assessed both continuous GCT glucose levels and 4 categories of glucose tolerance (normal glycemia [reference], isolated hyperglycemia, impaired glucose tolerance, GDM). We used multinomial logistic regression to estimate associations of PFAS with glucose tolerance categories. We used multivariable linear regression and Bayesian kernel machine regression (BKMR) to assess individual and joint effects of PFAS on continuous GCT glucose levels, respectively. We evaluated effect modification by maternal age and race/ethnicity. RESULTS: PFAS were not associated with glucose tolerance categories. In BKMR analyses, we observed a positive association between ln-perfluorooctane sulfonate (PFOS) and glucose levels (Δ25th to 75th percentile: 6.2 mg/dL, 95% CI, 1.1-11.3) and an inverse-U shaped association between 2-(N-perfluorooctane sulfonamide) acetate and glucose levels. Individual linear regression results were similar. We found suggestive evidence that associations varied by age and racial/ethnic group. CONCLUSION: Certain PFAS may alter glucose homeostasis during pregnancy, but may not be associated with overt GDM.
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Diabetes Gestacional/inducido químicamente , Diabetes Gestacional/epidemiología , Contaminantes Ambientales/sangre , Fluorocarburos/sangre , Intolerancia a la Glucosa/epidemiología , Adulto , Glucemia/análisis , Diabetes Gestacional/sangre , Diabetes Gestacional/diagnóstico , Contaminantes Ambientales/efectos adversos , Femenino , Fluorocarburos/efectos adversos , Intolerancia a la Glucosa/sangre , Intolerancia a la Glucosa/inducido químicamente , Intolerancia a la Glucosa/diagnóstico , Prueba de Tolerancia a la Glucosa , Humanos , Estudios Longitudinales , Embarazo , Primer Trimestre del Embarazo/sangre , Segundo Trimestre del Embarazo/sangreRESUMEN
Previous studies conducted in our laboratory have found altered adult health outcomes in animals with prenatal exposure to environmentally relevant levels of unconventional oil and gas (UOG) chemicals with endocrine-disrupting activity. This study aimed to examine potential metabolic health outcomes following a preconception, prenatal and postnatal exposure to a mixture of 23 UOG chemicals. Prior to mating and from gestation day 1 to postnatal day 21, C57BL/6J mice were developmentally exposed to a laboratory-created mixture of 23 UOG chemicals in maternal drinking water. Body composition, spontaneous activity, energy expenditure, and glucose tolerance were evaluated in 7-month-old female offspring. Neither body weight nor body composition differed in 7-month female mice. However, females exposed to 1.5 and 150 µg/kg/day UOG mix had lower total and resting energy expenditure within the dark cycle. In the light cycle, the 1,500 µg//kg/day group had lower total energy expenditure and the 1.5 µg/kg/day group had lower resting energy expenditure. Females exposed to the 150 µg/kg/day group had lower spontaneous activity in the dark cycle, and females exposed to the 1,500 µg/kg/day group had lower activity in the light cycle. This study reports for the first time that developmental exposure to a mixture of 23 UOG chemicals alters energy expenditure and spontaneous activity in adult female mice.
RESUMEN
In vertebrate systems, many endocrine disruptors (EDs) can also interfere with energy and lipid metabolism, thus acting as metabolic disruptors. At the cellular level, these effects are mainly mediated by interactions with nuclear receptors/transcription factors, leading to the modulation of genes involved in lipid homeostasis, as well as by rapid, receptor-independent pathways. Several potential metabolic disruptors are found in aquatic environments. In fish, different EDs have been shown to affect hepatic lipid homeostasis both in vivo and in vitro. However, little information is available in aquatic invertebrates due to our poor knowledge of the regulatory pathways of lipid metabolism. In this work, primary cell cultures from the digestive gland of the bivalve Mytilus galloprovincialis were utilized to investigate the effects of model EDs (bisphenol A (BPA) and perfluorooctane sulphonate (PFOS)) on lipid homeostasis. Both compounds (at 24 and 3h of exposure) increased intracellular lipid and tryglyceride-TAG content, with strongest effects of PFOS at 10-7M. Acyl-CoA oxidase activity was unaffected, whereas some changes in the activity of glycolytic, antioxidant/biotransformation enzymes were observed; however, no clear relationship was found with lipid accumulation. Evaluation of mitochondrial membrane potential Δψm and determination of extracellular TAG content indicate that PFOS interferes with mitochondrial function and lipid secretion, whereas BPA mainly affects lipid secretion. Experiments with specific inhibitors showed that activation of PI-3 kinase and extracellularly regulated mitogen-activated protein kinase (ERK MAPK) plays a key role in mediating lipid accumulation. Mussel digestive gland cells represent a simple in vitro model for screening the metabolic effects of EDs in marine invertebrates.
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Ácidos Alcanesulfónicos/toxicidad , Compuestos de Bencidrilo/toxicidad , Sistema Digestivo/efectos de los fármacos , Disruptores Endocrinos/toxicidad , Metabolismo Energético/efectos de los fármacos , Monitoreo del Ambiente/métodos , Fluorocarburos/toxicidad , Metabolismo de los Lípidos/efectos de los fármacos , Mytilus/efectos de los fármacos , Fenoles/toxicidad , Contaminantes Químicos del Agua/toxicidad , Animales , Células Cultivadas , Sistema Digestivo/metabolismo , Relación Dosis-Respuesta a Droga , Proteínas de Peces/antagonistas & inhibidores , Proteínas de Peces/metabolismo , Potencial de la Membrana Mitocondrial , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mytilus/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Cultivo Primario de Células , Inhibidores de Proteínas Quinasas/farmacología , Triglicéridos/metabolismoRESUMEN
Concerns about children's weight have steadily risen alongside the manufacture and use of myriad chemicals in the US. One class of chemicals, known as metabolic disruptors, interfere with human endocrine and metabolic functioning and are of specific concern to children's health and development. This article examines the effect of residential concentrations of metabolic disrupting chemicals on children's school performance for the first time. Census tract-level ambient concentrations for known metabolic disruptors come from the US Environmental Protection Agency's National Air Toxics Assessment. Other measures were drawn from a survey of primary caretakers of 4th and 5th grade children in El Paso Independent School District (El Paso, TX, USA). A mediation model is employed to examine two hypothetical pathways through which the ambient level of metabolic disruptors at a child's home might affect grade point average. Results indicate that concentrations of metabolic disruptors are statistically significantly associated with lower grade point averages directly and indirectly through body mass index. Findings from this study have practical implications for environmental justice research and chemical policy reform in the US.
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Contaminantes Atmosféricos/efectos adversos , Escolaridad , Disruptores Endocrinos/efectos adversos , Exposición por Inhalación/efectos adversos , Contaminantes Atmosféricos/análisis , Índice de Masa Corporal , Niño , Disruptores Endocrinos/administración & dosificación , Femenino , Humanos , Exposición por Inhalación/análisis , Aprendizaje/efectos de los fármacos , Masculino , Modelos Teóricos , Instituciones Académicas , Texas/epidemiología , Estados Unidos , United States Environmental Protection AgencyRESUMEN
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.