Globally persistent man-made chemicals display ever-growing ecosystemic consequences, a hallmark of the Anthropocene epoch. In this context, the assessment of how lineage-specific gene repertoires influence organism sensitivity toward endocrine disruptors is a central question in toxicology. A striking example highlights the role of a group of compounds known as obesogens. In mammals, most examples involve the modulation of the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). To address the structural and biological determinants of PPARγ exploitation by a model obesogen, tributyltin (TBT), in chordates, we employed comparative genomics, transactivation and ligand binding assays, homology modeling, and site-directed-mutagenesis. We show that the emergence of multiple PPARs (α, β and γ) in vertebrate ancestry coincides with the acquisition of TBT agonist affinity, as can be deduced from the conserved transactivation and binding affinity of the chondrichthyan and mammalian PPARγ. The amphioxus single-copy PPAR is irresponsive to TBT; as well as the investigated teleosts, this is a probable consequence of a specific mutational remodeling of the ligand binding pocket. Our findings endorse the modulatory ability of man-made chemicals and suggest an evolutionarily diverse setting, with impacts for environmental risk assessment.

Complement component 8 γ ( C8γ) is a subunit of complement protein 8 (C8), which itself is a subunit of the complement cytolytic membrane attack complex. However, C8γ is also suggested to be a carrier protein for the general clearance of endogenous and exogenous compounds because it belongs to the lipocalin family of small secreted proteins that have the common ability to bind small hydrophobic ligands. Although retinoic acid, a metabolite of vitamin A, has been suggested as a potential ligand of C8γ, it remains unclear which other substances are able to bind to C8γ as ligands. Here, we evaluated the binding affinity of several organotin compounds that are ligands of a receptor of retinoic acid, retinoid X receptor, by using radioligand binding assays. The amount of [ 14 C]triphenyltin (TPT), a tri-substituted organotin, that bound to purified recombinant C8γ was increased with increasing protein concentration, whereas that of [ 3 H]all-trans retinoic acid and [ 3 H]9-cis retinoic acid was unchanged. Scatchard analysis revealed that [ 14 C]TPT bound to C8γ with an equilibrium dissociation constant (K d ) of 56.2 ± 16.2 nM. Non-radiolabeled tributyltin (TBT), another tri-substituted organotin, blocked the binding of [ 14 C]TPT to C8γ in a competitive manner, but non-radiolabeled mono-or di-substituted organotin compounds did not. Together, our present observations indicate that TBT and TPT, but not retinoic acid or mono-or di-substituted organotin compounds, are potent ligands of C8γ, suggesting that C8γ may be involved in the toxicities of these organotin compounds.