Organotin compounds are a versatile group of organometallic chemicals that are used in a variety of industrial and agricultural applications. Tributyltin (TBT), a common organotin, brings about severe spermatotoxic and organotoxic effects. However, information about the adverse effects of TBT on liver, kidney and testis is scanty. Hence, the present study was undertaken to elucidate the TBT-mediated oxidative stress-induced impairments in these organs. Administration of TBT through oral route at increasing doses of 50, 100 and 150 ppm for 65 days to male Syrian hamsters resulted in drastically decreased activities of antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase and decreased mean levels of non-enzymatic antioxidants (reduced glutathione, vitamin C, and vitamin E) followed by a dramatic increase in the levels of lipid peroxidation in the liver, kidney and testis as compared to the control animals. Significantly high levels of serum urea, creatinine, uric acid and bilirubin were observed in TBT-treated hamsters. Also, TBT treatment induced drastic histopathological changes in the liver, kidney and testis combined with remarkable changes in serum levels of tissue injury marker enzymes Aspartate transaminases, Alkaline phosphatase and Alanine transaminase. These data affirm that exposure to TBT can lead to oxidative stress-induced damage to liver, kidney and testis.

The present study was carried out to elucidate the mechanisms underlying Verrucarin A (VA)-induced cytotoxicity in human breast cancer cell line MDA-MB-231. VA inhibited the growth of MDA-MB-231 cells by induction of reactive oxygen species (ROS)-dependent mitochondrial apoptosis. Elevation of ROS production, associated with changes in Bax/Bcl-2 ratio, led to loss of mitochondrial membrane potential (Δψm) and cytochrome c release in VA-treated cells. Release of cytochrome c from mitochondria to cytosol triggered activation of caspase-3, PARP cleavage, DNA fragmentation, and finally apoptotic cell death. Furthermore, VA-induced apoptosis was accompanied by the activation of p38MAPK and inhibition of phosphorylation of EGFR as well as of Akt and ERK1/2. However, pre-treatment with n-acetyl cysteine, an ROS scavenger, and SB202190, a p38MAPK inhibitor, significantly inhibited VA-induced ROS generation, EGFR inhibition, p38MAPK activation and apoptosis. Moreover, pharmacological inhibition of EGFR and ERK1/2 significantly accelerated the VA-induced apoptosis in MDA-MB-231 cells. Collectively, these results indicate that VA-induces ROS elevation in cancer cells, which results in the activation of p38MAPK and inhibition of EGFR/Akt/ERK signaling cascade and, ultimately, cancer cell death.

Tributyltin (TBT) is a common environmental contaminant used as the active ingredient in many products such as a biocides, wood preservatives, disinfecting agents, and antifouling paints. The TBT is a known endocrine disruptor. The aim of the current investigation was to determine the toxicity of TBT in the reproductive tract of adult male Syrian hamsters and to ascertain whether this compound results in untoward effects on apolipoprotein E (ApoE), a lipoprotein central to sex hormone synthesis. The TBT was administered orally to male Syrian hamsters at doses of 50, 100, and 150 ppm/kg for 65 days of treatment. We determined body weight, testis weight, sperm count, sperm morphology, testis histology, ApoE expression, serum lipid profile, testosterone level, follicle-stimulating hormone receptor (FSHR), and steroid hormone receptor expression compared to vehicle-treated controls. High doses of TBT significantly affected each of these parameters in Syrian hamsters. Weight and morphology of the testis were altered as well as sperm production. Real-time reverse-transcriptase polymerase chain reaction analysis revealed that expression of ApoE messenger RNA was upregulated in testes from TBT-treated groups compared with controls while the expression of androgen receptor, FSHR, estrogen receptor α (ESR1), and estrogen receptor β (ESR2) was decreased. We posit that exposure to TBT hinders intracellular cholesterol transport resulting in abnormal sex steroid biosynthesis and subsequent spermatogenic defects. Importantly, these effects may account for the decreased level of normal sperm observed in hamsters exposed to TBT.

Verrucarin A (VA), an active constituent of pathogenic fungus Myrothecium verrucaria, which has the ability to inhibit the growth of breast cancer cells. However, the mechanism by which VA exerts its inhibitory potential remains elusive. Here, we demonstrated that VA inhibited the growth of MCF-7 breast cancer cells, increased the levels of reactive oxygen species (ROS), and subsequently induced mitochondrial membrane potential (Δψm) loss, leading to the increase of Bax/Bcl-2 ratio, cytochrome c release, caspase activation, PARP degradation, and apoptosis. VA effectively increased the phosphorylation of p38MAPK and diminished the phosphorylation of ERK/Akt. In addition, VA caused cell cycle deregulation through the induction of p21 and p53. Furthermore, ROS scavenger (n-acetyl-L-cysteine) and p38MAPK inhibitor (SB202190) effectively abrogated the VA-induced cell cycle deregulation and apoptosis. Conversely, U0126, an ERK1/2 inhibitor, enhanced the VA-induced apoptotic signals. Taken together, our results suggest that VA-induces apoptosis and cell cycle deregulation in MCF-7 cells through ROS-dependent p38MAPK activation.

Tributyltins (TBT) are ubiquitous and persistent environmental contaminants that disturb normal endocrine function including gonadal function in humans and marine organisms. TBT was administered through oral route to male Syrian hamsters at daily doses of 50, 100, and 150 ppm/kg for 65 days. Changes in testis morphology, immunohistochemistry of iNOS, 3β-HSD, and 17β-HSD, cholesterol transport receptor, nuclear receptors, and transcription factors were analyzed. TBT treatment affected each of these parameters to significant levels in a dose-dependent manner compared to vehicle treated control. Real-time PCR and protein analyses revealed that expression levels of ApoE and LDL-R mRNA were up-regulated in the testis of TBT-treated animals while the expression levels of SR-B1, LXR, PPARs α, β, and γ, SCAP, SREBP 1 and 2, 3β-HSD, 17β-HSD, CYP17A1, and P450 were down-regulated. Leydig cells were isolated and separated adopting percoll gradient centrifugation under aseptic condition. The viability of Leydig cell was affected by TBT treatment in a dose- and time-dependent manner. Further, the mechanism of action of TBT was ascertained by siRNA transfection of ApoE, which was upregulated, and SREBP, which was down-regulated. These observations led us to infer that exposure to TBT hinders intracellular cholesterol transport resulting in abnormal sex steroid biosynthesis and alteration of steroidogenic enzyme activities. Finally, we could recognize ApoE and SREBP as the major factors regulating genes that control cholesterol biosynthesis and steroidogenesis that ultimately inhibit the synthesis of testosterone. Therefore, ApoE is one of the important molecular targets that can be intercepted in context of male infertility/male contraception.