Short-term exposure to gossypol causes reversible reproductive toxicity and nephrotoxicity in mice / 南方医科大学学报

OBJECTIVE@#To study the toxic effects of short-term exposure to gossypol on the testis and kidney in mice and whether these effects are reversible.@*METHODS@#Twenty 7 to 8-week-old male mice were randomized into blank control group, solvent control group, gossypol treatment group and drug withdrawal group. In the former 3 groups, the mice were subjected to daily intragastric administration of 0.3 mL of purified water, 1% sodium carboxymethylcellulose solution, and 30 mg/mL gossypol solution for 14 days, respectively; In the drug withdrawal group, the mice were treated with gossypol solution in the same manner for 14 days followed by treatment with purified water for another 14 days. After the last administration, the mice were euthanized and tissue samples were collected. The testicular tissue was weighed and observed microscopically with HE and PAS staining; the kidney tissue was stained with HE and examined for mitochondrial ATPase activity.@*RESULTS@#Compared with those in the control group, the mice with gossypol exposure showed reduced testicular seminiferous epithelial cells with rounded seminiferous tubules, enlarged space between the seminiferous tubules, interstitium atrophy of the testis, and incomplete differentiation of the spermatogonia. The gossypol-treated mice also presented with complete, non-elongated spermatids, a large number of cells in the state of round spermatids, and negativity for acrosome PAS reaction; diffuse renal mesangial cell hyperplasia, increased mesangial matrix, and adhesion of the mesangium to the wall of the renal capsule were observed, with significantly shrinkage or even absence of the lumens of the renal capsules and reduced kidney mitochondrial ATPase activity. Compared with the gossypol-treated mice, the mice in the drug withdrawal group showed obvious recovery of morphologies of the testis and the kidney, acrosome PAS reaction and mitochondrial ATPase activity.@*CONCLUSIONS@#Shortterm treatment with gossypol can cause reproductive toxicity and nephrotoxicity in mice, but these toxic effects can be reversed after drug withdrawal.

Mecanismos da intoxicação do fígado de rato causada pelo gossipol / Mechanisms of the intoxication of rat liver caused by gossypol

O fígado desempenha uma função central no metabolismo devido à sua interposição entre o trato digestivo e a circulação geral do organismo. Ele é também o principal órgão envolvido na biotransformação de substâncias exógenas (xenobióticos), com capacidade de converter compostos hidrofóbicos em hidrossolúveis, mais facilmente eliminados pelo organismo. O gossipol é uma substância fenólica tóxica presente na semente de algodão (Gossypium sp). Com o objetivo de estudar os mecanismos envolvidos na hepatotoxicidade do gossipol avaliou-se os seus efeitos no sistema antioxidante do fígado de ratos no que diz respeito ao estresse oxidativo e aspectos histopatológicos. Foram utilizados ratos machos da linhagem Wistar, separados em dois grupos, sendo que um recebeu óleo de canola (veículo, grupo Controle) e o outro recebeu gossipol na dosagem de 40 mg/kg de peso vivo do animal por 15 dias (grupo Tratado). O tratamento com gossipol promoveu alterações na atividade sérica das enzimas marcadoras de dano hepático e um significativo estresse oxidativo caracterizado pela diminuição nos níveis da glutationa reduzida (GSH) e consequente aumento da glutationa oxidada (GSSG), incluindo, ainda, danos à membrana plasmática e de organelas demonstrados pela peroxidação lipídica. O resultado da avaliação histopatológica demonstrou degeneração dos hepatócitos.

The liver plays a central role in metabolism due to its interposition between the digestive tract and the general circulation of the organism. It is also the main organ involved in biotransformation of exogenous substances (xenobiotics), with ability to convert hydrophobic compounds in water-soluble, more easily eliminated by the body. Gossypol is a toxic phenolic substance present in cotton seed (Gossypium sp.). Aiming to study the mechanisms involved in the hepatotoxicity of gossypol we evaluate its effects on the antioxidant system of rat liver performing an experiment that investigated the oxidative stress and the histopathological alterations. In this study, we used Wistar rats, divided into two groups, one that received canola oil (vehicle, Control group) and another that received gossypol at a dose of 40mg/kg body weight of the animal for 15 days (Treated group). The treatment with gossypol caused alterations in the activity of seric enzymes that indicate hepatic injury and a significant oxidative stress characterized by a decrease of reduced glutathione (GSH) levels and a consequent increase in oxidized glutathione (GSSG), including further damage to the plasma membrane and organelles showed by lipid peroxidation. The result of histopathological evaluation showed degeneration of the hepatocytes.

Morphological changes induced by cottonseed flour in rat testes

Gossypol, a component of the cottonseed, has anti-fertility effects. The present study was planned to determine whether diets containing whole cottonseed flour could produce morphological changes in the rat testes similar to pure gossypol. Sixteen animals were randomly divided into two groups, Control [C] and Test [T] groups. Each group comprised of 08 animals. Control group received standard diet, while test group received 70% standard diet and 30% cottonseed flour. A significant decrease in body weight, testicular weight and diet consumption was seen in the test group. Histological sections were stained in serial order by three different stains, H and E, PAS and Masson's Trichrome. Microscopic examination revealed significant increase in luminal diameter [P<0.0001] and decrease in wall thickness of seminiferous tubules [P<0.0007] of test group. Cell count per tubule was significantly decreased in test group [P<0.002]. Degenerative changes in the epithelium were seen in 78.8% and degenerative cells in the lumen of the seminiferous tubules in 41.23% of tubules were observed in test group. Sertoli and leydig cell counts were not different from those of control. No disruption of basement membrane was observed. Pigment laden cells in the interstitial tissue were observed in the test group. The observed morphological changes induced by cottonseed flour suggest that cottonseed flour, by virtue of its contents of the compound gossypol is equally toxic to rat testes like pure extract of gossypol