Environmental Obesogen Tributyltin Chloride Leads to Abnormal Hypothalamic-Pituitary-Gonadal Axis Function By Disruption in Leptin/Kisspeptin Signalling in Female Rats

Presentation Number: OR15-3
Date of Presentation: April 1st, 2017

Gabriela Cavati Sena*1, Eduardo Merlo2, Priscila Lang Podratz2, Julia F P Araújo2, Leandro C Freitas-Lima2, Poliane A A Brandão2, Maria TWD Carneiro2, Marcelo M Morales3, Ana Paula S S Oliveira3, Leandro Miranda Alves3, Ian Victor Silva2 and Jones B Graceli4
1Federal University of Espirito Santo, Vitória, BRAZIL, 2Federal University of Espirito Santo, Vitoria, Brazil, 3Federal University of Rio de Janeiro, 4Federal University of Espirito Santo, Vitoria, BRAZIL

Abstract

Tributyltin chloride (TBT) is a xenobiotic used as a biocide in antifouling paints that has been demonstrated to induce endocrine-disrupting effects, such as obesity and reproductive abnormalities. An integrative metabolic control in the hypothalamus-pituitary-gonadal (HPG) axis was exerted by leptin. Obesity is associated with abnormal hypothalamic leptin action, affecting the reproductive function. Studies that have investigated the obesogenic TBT effects in the HPG axis are especially rare. We describe the reproductive and metabolic characterization as result of TBT exposure in female rats. To study whether obesity as result of TBT disrupted HPG function, we administered vehicle (CON, 0.4% ethanol) and TBT (TBT, 100 ng/kg/day) in the Wistar female rats for 15 days via gavage. TBT rats displayed a tin ovary accumulation (CON:3.97±0.58 vs TBT:48.70±9.72µg.kg−1; p≤0.05; n=5). TBT rats exhibited abnormal estrous cyclicity, showing fewer days in the proestrus phase (CON:0.95±0.04 vs TBT:0.50±0.05 d; p≤0.05, n=8-10) and predominately remained in a persistent metestrus-diestrus phase (CON:1.74±0.19 vs TBT:3.10±0.40 d; p≤0.05). TBT rats had lower surge serum LH levels (CON:19.84 ± 0.08 vs TBT:16.02 ± 0.09 mU/mL; p≤0.01; n=5-6). The GnRH mRNA was approximately 45% lower in the TBT hypothalamus (p≤0.01; n=4). Kisspeptin (Kiss) stimulation test was also performed. Interestingly, an approximately 25% decreased responsiveness to Kiss was identified in the TBT vs CON rats (CON: 2.39±0.06 vs CON-treated Kiss: 6.80 ± 0.11 mU/mL; TBT:1.51 ± 0.21 vs TBT-treated Kiss: 4.43±0.16 mU/mL; p≤0.001; n=5-6). Impaired fertility was noted with reduced number of pups/litter and corpora lutea in the female TBT rats (p≤0.05; n=6). TBT rats had higher testosterone (CON:0.20±0.01 vs TBT:0.35±0.03 ng/mL; p≤0.05; n=5-6) and lower estrogen levels (CON: 16.47±0.57 vs TBT:12.34±0.49 pg/mL; p≤0.01; n=5-6). Ovary and uterus atrophy, fibrosis and apoptosis was observed in TBT rats, as well the uterine inflammation (p≤0.05; n=4-8). The serum LH levels in the OVX control rats and OVX TBT rats were increased (p≤.001; n=5). There was an approximately 18% lower increase in the serum LH levels in the OVX TBT rats vs OVX CON rats (p≤0.05; n=5). Similarly, there was an approximately 50% lower increase in the GnRH mRNA levels in the OVX TBT rats (p≤0.01; n=4). An increased body weight gain was identified in the TBT rats (p≤0.01; n=10), as well as a hyperinsulinemia, hyperleptinemia and hypoadiponectinemia (p≥0.05; n=5). Increased values for the glucose tolerance test at 15 min (p ≤ 0.05; n=8) and the insulin sensitivity test at 30 min (p ≤ 0.05; n=8) were identified in the TBT rats. Thus, TBT disrupted proper functioning of the HPG axis as a result of obesity and abnormal leptin/kisspeptin signalling. This work supports the hypothesis that TBT impairs the normal metabolic control in the HPG axis.

 

Nothing to Disclose: GCS, EM, PLP, JFPA, LCF, PAAB, MTC, MMM, APSSO, LMA, IVS, JBG