In vitro immunotoxicity of bis(tri- n -butyltin)oxide (TBTO) studied by toxicogenomics

• Published in: Toxicology (Amsterdam) 2007-07, Vol.237 (1), p.35-48
• Main Authors: Baken, Kirsten A, Arkusz, Joanna, Pennings, Jeroen L.A, Vandebriel, Rob J, van Loveren, Henk
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - immunology; Biological and medical sciences; Bis(tri-n-butyltin)oxide (TBTO); Cell Survival - drug effects; Cell Survival - immunology; Cells, Cultured; Chemical and industrial products toxicology. Toxic occupational diseases; Dose-Response Relationship, Drug; Emergency; Gene Expression - drug effects; Gene Expression - immunology; Gene Expression Profiling; Immunotoxicity; Immunotoxicogenomics; Male; Medical sciences; Metals and various inorganic compounds; Microarray analysis; Multigene Family; Oligonucleotide Array Sequence Analysis; Rats; Rats, Wistar; Receptors, Glucocorticoid - genetics; Signal Transduction - drug effects; Signal Transduction - immunology; Thymus Gland - cytology; Thymus Gland - drug effects; Thymus Gland - immunology; Toxicogenetics; Toxicogenomics in vitro; Toxicology; Trialkyltin Compounds - toxicity
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2007.04.018

Abstract The biocide and environmental pollutant bis(tri- n -butyltin)oxide (TBTO) causes thymus atrophy in rodents. Whether the depletion of thymic lymphocytes by tributyltin compounds may be the result of inhibition of cell proliferation or induction of apoptosis is subject of debate. We examined gene expression profiles in primary rat thymocytes exposed to TBTO in vitro at dose levels of 0, 0.1, 0.3, 0.5, and 1.0 μM. By measuring cell viability and apoptosis, exposure conditions were selected that would provide information on changes in gene expression preceding or accompanying functional effects of TBTO. Several processes related to TBTO-induced toxicity were detected at the transcriptome level. Effects on lipid metabolisms appeared to be the first indication of disruption of cellular function. Many transcriptional effects of TBTO at higher dose levels were related to apoptotic processes, which corresponded to present or subsequent thymocyte apoptosis observed phenotypically. The gene expression profile was, however, not unambiguous since expression of apoptosis-related genes was both increased and decreased. Stimulation of glucocorticoid receptor signaling appeared to be a relevant underlying mechanism of action. These findings suggest that TBTO exerts its toxic effects on the thymus primarily by affecting apoptotic processes, but the possibility is discussed that this may in fact represent an early effect that precedes inhibition of cell proliferation. At the highest dose level tested, TBTO additionally repressed mitochondrial function and immune cell activation. Our in vitro toxicogenomics approach thus identified several cellular and molecular targets of TBTO that may mediate the toxicity towards thymocytes and thereby its immunosuppressive effects.