Organotin Antifouling Compounds and Sex-Steroid Nuclear Receptor Perturbation: Some Structural Insights

Abstract

Organotin compounds (OTCs) are a commercially important group of organometallic compounds of tin used globally as polyvinyl chloride stabilizers and marine antifouling biocides. Worldwide use of OTCs has resulted in their ubiquitous presence in ecosystems across all the continents. OTCs have metabolic and endocrine disrupting effects in marine and terrestrial organisms. Thus, harmful OTCs (tributyltin) have been banned by the International Convention on the Control of Harmful Antifouling Systems since 2008. However, continued manufacturing by non-member countries poses a substantial risk for animal and human health. In this study, structural binding of common commercial OTCs, tributyltin (TBT), dibutyltin (DBT), monobutyltin (MBT), triphenyltin (TPT), diphenyltin (DPT), monophenyltin (MPT), and azocyclotin (ACT) against sex-steroid nuclear receptors, androgen receptor (AR), and estrogen receptors (ERα, ERβ) was performed using molecular docking and MD simulation. TBT, DBT, DPT, and MPT bound deep within the binding sites of AR, ERα, and Erβ, showing good dock score, binding energy and dissociation constants that were comparable to bound native ligands, testosterone and estradiol. The stability of docking complex was shown by MD simulation of organotin/receptor complex with RMSD, RMSF, Rg, and SASA plots showing stable interaction, low deviation, and compactness of the complex. A high commonality (50–100%) of interacting residues of ERα and ERβ for the docked ligands and bound native ligand (estradiol) indicated that the organotin compounds bound in the same binding site of the receptor as the native ligand. The results suggested that organotins may interfere with the natural steroid/receptor binding and perturb steroid signaling.

Steroids Bearing Heteroatom as Potential Drugs for Medicine

“…They can serve as reagents in organic reactions, where the tin atom undergoes transformations while the organic groups remain intact. Organostannanes are particularly useful in cross-coupling reactions, where they can be coupled with other organic halides or pseudohalides to form new carbon-carbon or carbon-heteroatom bonds [343][344][345][346]. The synthesis of stannanes was initially achieved by Edward Frankland and later by Carl Jacob Löwig in the 1850s [347,348].…”

Environmental Health and Toxicology: Immunomodulation Promoted by Endocrine-Disrupting Chemical Tributyltin

“…In addition, doses of 100 µM of BPA, BPS, BPF and dimethyl terephthalate (DMTP) led to lower proliferation and viability of B lymphocytes isolated from the spleen of mice and stimulated with LPS, with BPA being the most toxic for B cells among these [ 118 ]. Interestingly, even though TBT is a PPARy agonist, it can induce a reduction in the mature population of B lymphocytes regardless of activation of the PPARy pathway by inducing changes in the bone marrow microenvironment that lead to adipogenesis in favor of lymphopoiesis [ 59 , 80 , 98 , 99 ]. It is important to mention that other endocrine disruptors that are agonists of the PPARy pathway (such as phthalate metabolites) are well known to affect the differentiation of B lymphocytes in the bone marrow by inducing the apoptosis of B lymphocyte precursors [ 119 , 120 , 121 ].…”

“…In parallel, CD8+ T lymphocytes express both ERα and ERβ in low amounts, but at equal rates [ 56 , 57 ]. Interestingly, TBT has also been described as an antagonist of human ERs by inhibiting the transcriptional activation of the ER-dependent reporter gene and the interaction between the ligand-binding domain of the β isoform (ERβ LBD) and the steroid receptor coactivator-1 (SRC1) [ 58 , 59 ]. Additionally, TBT acts as an inhibitor of aromatase, the enzyme accountable for the conversion of testosterone to estrogen, as well as the estrogen receptor in zebrafish, thereby reducing the effects of ethinylestradiol [ 60 ].…”

New Insights on Biological Activities, Chemical Compositions, and Classifications of Marine Actinomycetes Antifouling Agents

“…TBT and its derivatives have been used in antifouling coats for commercial ships and hulls for the past decades. It belongs to the class of organic compounds named the trisubstituted organotin compounds (OTCs) and has been used as an antifouling agent along with the other organotin derivatives (monobutyltin (MBT), monophenyltin (MPT), and azocyclotin (ACT) [46,47]. TBT and organotin derivatives are very toxic to several aquatic species [48].…”