The Renin-Angiotensin System Signalling Plays an Important Role in Metabolic Disruption As Result of Environmental Obesogen Tributyltin Exposure in Female Rats

Presentation Number: SAT 254
Date of Presentation: April 1st, 2017

Jones B Graceli*1, Leandro C Freitas-Lima2, Eduardo Merlo2, Priscila Lang Podratz2, Julia C F.P. de Araújo2, Marina C. Zicker3, Adaliene V. M.Ferreira4, Leandro Miranda-Alves5, Sérgio HS Santos6, Miriane de Oliveira7, Celia R Nogueira8 and Ian V Silva2
1Federal University of Espirito Santo, Vitoria, BRAZIL, 2Federal University of Espirito Santo, Vitoria, Brazil, 3Faculty of Pharmacy, Federal University of Minas Gerais, Brazil, Belo Horizonte, 4Nursing School, Federal University of Minas Gerais, Brazil, Belo Horizonte, 5Federal University of Rio de Janeiro, Rio de Janeiro, BRAZIL, 6Universidade de Montes Claros, 7Botucatu School of Medicine, University of São Paulo State, Brazil, Distrito de Rubiao, 8Botucatu School of Medicine, University of São Paulo State, Brazil., Botucatu


Tributyltin chloride (TBT) is an obesogen xenobiotic that has been reported to induce endocrine-disrupting effects, such as obesity. It is characterized by systemic inflammation, which in part emanates from white adipose tissue (WAT). WAT with inflammation secrete pro-inflammatory substances , as angiotensin (Ang) II. However, studies that have investigated the obesogenic TBT effects associated with the Renin Angiotensin System (RAS) are especially rare. Here, we describe the metabolic characterization as result of TBT+RAS inhibition treatment in female rats. To study whether RAS inhibition improve the obesity and metabolic disruption as result of TBT exposure, we administered vehicle (CON, 0.4% ethanol), TBT (TBT, 100 ng/kg/day), TBT+Captopril (CAP, 30mg/kg/day) and TBT+Losartan (LOS, 50mg/kg/day) in the Wistar female rats for 15 days via gavage. TBT rats displayed a higher body weight (CON:222.5±2.8 vs TBT:238.2±2.5 vs CAP:224.0±3.2 vs LOS:226.5±3.8 g; p≤0.01; n=6-10) and adiposity (CON:0.030±0.001 vs TBT:0.040±0.001 vs CAP:0.032±0.001 vs LOS:0.032±0.001 g/g; p≤0.01; n=6-10) that were similar to CON rats with CAP and LOS treatments. An increased in adiposity was associated with higher retroperitoneal and parametrial WAT weight in TBT rats that were normalized with CAP and LOS treatments (p≤0.01; n=6-10). TBT rats had higher AT1 expression and no significant change in the AT2 expression in the parametrial WAT using immunoblotting assay (p≤0.01; n=9-10). Interestingly, we also observed a reduction in the Ang (1-7) expression in the TBT parametrial WAT using immunohistochemical assay (p≤0.05; n=4). Further, fasted glucose level showed no significant change between all groups analyzed (p≥0.05; n=6-10). However, a hyperleptinemia was observed in TBT rats that were normalized with LOS treatment (CON:1769.7±101.2 vs TBT: 2411.4±160.9 vs CAP:2414.8±85.9 vs LOS:1781.0±226.0 ng/mL; p≤0.01; n=4-6). Also, hypoadiponectinemia (CON:2.7±0.1 vs TBT: 2.2±0.1 vs CAP: 2.6±0.3 vs LOS: 2.4±0.1 g/g; p≤0.05; n=6-10) was observed in TBT rats that were normalized after CAP and LOS treatments. Increased values for the glucose tolerance test at 30 min were identified in the TBT rats that were similar CON rats with CAP and LOS treatments (p0.05; n=8). TBT (10 nM for 24h) increased lipids droplets accumulation in the murine 3T3-L1 cell model using the Oil Red O stain. However, both CAP (30µM for 24h) and LOS (10 µM for 24h) treatments were able to reduce total lipids accumulation in 3T3-L1 cells compared with TBT treatment (CON:6.0±0.3 vs TBT:11.8±0.5 vs CAP:9.4±0.2 vs LOS:10.1±0.4 x105%; p≤0.001; n=5). Thus, TBT disrupted proper functioning of the metabolic and WAT function as a result of obesity and abnormal RAS signalling. This work supports the hypothesis that metabolic disease as result of TBT exposure could be mediated by dysfunctional RAS effects.


Nothing to Disclose: JBG, LCF, EM, PLP, JCF, MC, AV, LM, SHS, MD, CRN, IVS