The role of retinoic acid receptors and their cognate ligands in reproduction in a context of triorganotin based endocrine disrupting chemicals

Abstract

Retinoic acid (RA), an active form of vitamin A, regulates the embryonic development, male and female reproduction and induces important effects on the cell development, proliferation, and differentiation. These effects are mediated by the retinoid (RAR) and rexinoid nuclear receptors (RXR), which are considered to be a ligand-activated, DNA-binding, trans-acting, and transcription-modulating proteins, involved in a general molecular mechanism responsible for the transcriptional responses in target genes. Organotin compounds are typical environmental contaminants and suspected endocrine disrupting substances. They may affect processes of reproductive system in mammals, predominantly via nuclear receptor signaling pathways. Triorganotins, such as tributyltin chloride (TBTCl) and triphenyltin chloride (TPTCl), are capable to bind to RXR molecules, and thus represent potent agonists of RXR subtypes of nuclear receptors not sharing any structural characteristics with endogenous ligands of nuclear receptors. Th is article summarizes selected effects of biologically active retinoids and rexinoids on both male and female reproduction and also deals with the effects of organotin compounds evoking endocrine disrupting actions in reproduction.

Triorganotin Derivatives Induce Cell Death Effects on L1210 Leukemia Cells at Submicromolar Concentrations Independently of P-glycoprotein Expression

“…Due to the induction of progesterone biosynthesis, effects on aromatase activity, and the capability of inducing the transcriptional activity of thyroid hormone receptor, these compounds are endocrine-disrupting agents [ 10 , 11 , 12 ]. Moreover, as retinoid X receptor ligands, these compounds may induce multimodal alterations of the cell phenotype [ 13 ].…”

Organotin Compounds Toxicity: Focus on Kidney

“…Organotin compounds have many biological impacts and are associated with endocrine and physiologic disruptor effects, acting as EDCs ( 50 ). It was recently demonstrated that they are able to bind nuclear receptor, such as glucocorticoid receptors and retinoid X receptor subtypes, forming a complex OTs-nuclear receptors with coactivators and inducing transcription of target genes ( 51 , 52 ). This process promotes changes in the expression of proteins in addition to mitochondrial and cell dysfunctions ( 51 , 52 ).…”

Multispecies study: low-dose tributyltin impairs ovarian theca cell cholesterol homeostasis through the RXR pathway in five mammalian species including humans

“…Binding to these nuclear receptors results in energy metabolism disruption supportive of its obesogenic ability (reviewed in (Veiga-Lopez et al 2018)). TBT can also interfere with reproductive function (reviewed in (Delgado et al 2011;Macejova et al 2016)) and result in early embryonic loss (Harazono and Ema 2000). In aquatic organisms, TBT can act as an estradiol sulfation inhibitor and reduce steroid synthesis and specific metabolism pathways in fish (Thibaut and Porte 2004).…”