Environmental obesogen tributyltin chloride leads to abnormal hypothalamic-pituitary-gonadal axis function by disruption in kisspeptin/leptin signaling in female rats.
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.
Department of Morphology, Federal University of Espírito Santo, Brazil.
Gabriela C
GC
Sena
Department of Morphology, Federal University of Espírito Santo, Brazil.
Leandro C
LC
Freitas-Lima
Department of Morphology, Federal University of Espírito Santo, Brazil.
Eduardo
E
Merlo
Department of Morphology, Federal University of Espírito Santo, Brazil.
Priscila L
PL
Podratz
Department of Morphology, Federal University of Espírito Santo, Brazil.
Julia F P
JF
de Araújo
Department of Chemistry, Federal University of Espírito Santo, Brazil.
Poliane A A
PA
Brandão
Department of Chemistry, Federal University of Espírito Santo, Brazil.
Maria T W D
MT
Carneiro
Department of Food Science, Faculty of Pharmacy, Federal University of Minas Gerais, Brazil.
Marina C
MC
Zicker
Department of Basic Nursing, Nursing School, Federal University of Minas Gerais, Brazil.
Adaliene V M
AV
Ferreira
Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Brazil.
Christina M
CM
Takiya
Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Brazil.
Carolina M
CM
de Lemos Barbosa
Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Brazil.
Marcelo M
MM
Morales
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.
Ana Paula
AP
Santos-Silva
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.
Leandro
L
Miranda-Alves
Department of Morphology, Federal University of Espírito Santo, Brazil.
Ian V
IV
Silva
Department of Morphology, Federal University of Espírito Santo, Brazil. Electronic address: jbgraceli@gmail.com.
Jones B
JB
Graceli
D000818:Animals; D052244:Endocrine Disruptors / Q000633:toxicity; D004781:Environmental Exposure / Q000009:adverse effects; D030762:Estrous Cycle / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007028:Hypothalamic Hormones / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism*; D059648:Kisspeptins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020738:Leptin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012098:Reproduction / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014220:Trialkyltin Compounds / Q000633:toxicity*
D052244:Endocrine Disruptors; D007028:Hypothalamic Hormones; D059648:Kisspeptins; D020738:Leptin; D014220:Trialkyltin Compounds; C011559:tributyltin
Endocrine-disrupting chemicals; HPG axis; Kisspeptin; Leptin; Obesity; Tributyltin chloride