PMID- 28161095
OWN - NLM
STAT- MEDLINE
DCOM- 20170531
LR  - 20220317
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Linking)
VI  - 319
DP  - 2017 Mar 15
TI  - Environmental obesogen tributyltin chloride leads to abnormal 
      hypothalamic-pituitary-gonadal axis function by disruption in kisspeptin/leptin 
      signaling in female rats.
PG  - 22-38
LID - S0041-008X(17)30049-2 [pii]
LID - 10.1016/j.taap.2017.01.021 [doi]
AB  - 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. However, studies 
      that have investigated the obesogenic TBT effects on the HPG axis are especially 
      rare. We investigated whether metabolic disorders as a result of TBT are 
      correlated with abnormal hypothalamus-pituitary-gonadal (HPG) axis function, as 
      well as kisspeptin (Kiss) action. Female Wistar rats were administered vehicle 
      and TBT (100ng/kg/day) for 15days via gavage. We analyzed their effects on the 
      tin serum and ovary accumulation (as biomarker of TBT exposure), estrous 
      cyclicity, surge LH levels, GnRH expression, Kiss action, fertility, testosterone 
      levels, ovarian apoptosis, uterine inflammation, fibrosis, estrogen negative 
      feedback, body weight gain, insulin, leptin, adiponectin levels, as well as the 
      glucose tolerance (GTT) and insulin sensitivity tests (IST). TBT led to increased 
      serum and ovary tin levels, irregular estrous cyclicity, and decreased surge LH 
      levels, GnRH expression and Kiss responsiveness. A strong negative correlation 
      between the serum and ovary tin levels with lower Kiss responsiveness and GnRH 
      mRNA expression was observed in TBT rats. An increase in the testosterone levels, 
      ovarian and uterine fibrosis, ovarian apoptosis, and uterine inflammation and a 
      decrease in fertility and estrogen negative feedback were demonstrated in the TBT 
      rats. We also identified an increase in the body weight gain and abnormal GTT and 
      IST tests, which were associated with hyperinsulinemia, hyperleptinemia and 
      hypoadiponectinemia, in the TBT rats. TBT disrupted proper functioning of the HPG 
      axis as a result of abnormal Kiss action. The metabolic dysfunctions co-occur 
      with the HPG axis abnormalities. Hyperleptinemia as a result of obesity induced 
      by TBT may be associated with abnormal HPG function. A strong negative 
      correlation between the hyperleptinemia and lower Kiss responsiveness was 
      observed in the TBT rats. These findings provide evidence that TBT leads to toxic 
      effects direct on the HPG axis and/or indirectly by abnormal metabolic regulation 
      of the HPG axis.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Sena, Gabriela C
AU  - Sena GC
AD  - Department of Morphology, Federal University of Espirito Santo, Brazil.
FAU - Freitas-Lima, Leandro C
AU  - Freitas-Lima LC
AD  - Department of Morphology, Federal University of Espirito Santo, Brazil.
FAU - Merlo, Eduardo
AU  - Merlo E
AD  - Department of Morphology, Federal University of Espirito Santo, Brazil.
FAU - Podratz, Priscila L
AU  - Podratz PL
AD  - Department of Morphology, Federal University of Espirito Santo, Brazil.
FAU - de Araujo, Julia F P
AU  - de Araujo JF
AD  - Department of Morphology, Federal University of Espirito Santo, Brazil.
FAU - Brandao, Poliane A A
AU  - Brandao PA
AD  - Department of Chemistry, Federal University of Espirito Santo, Brazil.
FAU - Carneiro, Maria T W D
AU  - Carneiro MT
AD  - Department of Chemistry, Federal University of Espirito Santo, Brazil.
FAU - Zicker, Marina C
AU  - Zicker MC
AD  - Department of Food Science, Faculty of Pharmacy, Federal University of Minas 
      Gerais, Brazil.
FAU - Ferreira, Adaliene V M
AU  - Ferreira AV
AD  - Department of Basic Nursing, Nursing School, Federal University of Minas Gerais, 
      Brazil.
FAU - Takiya, Christina M
AU  - Takiya CM
AD  - Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de 
      Janeiro, Brazil.
FAU - de Lemos Barbosa, Carolina M
AU  - de Lemos Barbosa CM
AD  - Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de 
      Janeiro, Brazil.
FAU - Morales, Marcelo M
AU  - Morales MM
AD  - Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de 
      Janeiro, Brazil.
FAU - Santos-Silva, Ana Paula
AU  - Santos-Silva AP
AD  - Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de 
      Janeiro, Brazil; Experimental Endocrinology Research, Development and Innovation 
      Group, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, 
      Brazil; Postgraduate Program in Endocrinology, School of Medicine, Federal 
      University of Rio de Janeiro, Brazil.
FAU - Miranda-Alves, Leandro
AU  - Miranda-Alves L
AD  - Experimental Endocrinology Research, Development and Innovation Group, Institute 
      of Biomedical Sciences, Federal University of Rio de Janeiro, Brazil; 
      Postgraduate Program in Endocrinology, School of Medicine, Federal University of 
      Rio de Janeiro, Brazil.
FAU - Silva, Ian V
AU  - Silva IV
AD  - Department of Morphology, Federal University of Espirito Santo, Brazil.
FAU - Graceli, Jones B
AU  - Graceli JB
AD  - Department of Morphology, Federal University of Espirito Santo, Brazil. 
      Electronic address: jbgraceli@gmail.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170202
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Endocrine Disruptors)
RN  - 0 (Hypothalamic Hormones)
RN  - 0 (Kisspeptins)
RN  - 0 (Leptin)
RN  - 0 (Trialkyltin Compounds)
RN  - 4XDX163P3D (tributyltin)
SB  - IM
MH  - Animals
MH  - Endocrine Disruptors/toxicity
MH  - Environmental Exposure/adverse effects
MH  - Estrous Cycle/drug effects/metabolism
MH  - Female
MH  - Hypothalamic Hormones/antagonists & inhibitors/*metabolism
MH  - Hypothalamo-Hypophyseal System/drug effects/*metabolism
MH  - Kisspeptins/antagonists & inhibitors/*metabolism
MH  - Leptin/antagonists & inhibitors/*metabolism
MH  - Obesity/chemically induced/metabolism
MH  - Pituitary-Adrenal System/drug effects/*metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Reproduction/drug effects/physiology
MH  - Signal Transduction/drug effects/physiology
MH  - Trialkyltin Compounds/*toxicity
OTO - NOTNLM
OT  - Endocrine-disrupting chemicals
OT  - HPG axis
OT  - Kisspeptin
OT  - Leptin
OT  - Obesity
OT  - Tributyltin chloride
EDAT- 2017/02/06 06:00
MHDA- 2017/06/01 06:00
CRDT- 2017/02/06 06:00
PHST- 2016/09/13 00:00 [received]
PHST- 2017/01/27 00:00 [revised]
PHST- 2017/01/30 00:00 [accepted]
PHST- 2017/02/06 06:00 [pubmed]
PHST- 2017/06/01 06:00 [medline]
PHST- 2017/02/06 06:00 [entrez]
AID - S0041-008X(17)30049-2 [pii]
AID - 10.1016/j.taap.2017.01.021 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2017 Mar 15;319:22-38. doi: 10.1016/j.taap.2017.01.021. 
      Epub 2017 Feb 2.