Are MUPs a Toxic Waste Disposal System?

Abstract

Male house mice produce large quantities of major urinary proteins (MUPs), which function to bind and transport volatile pheromones, though they may also function as scavengers that bind and excrete toxic compounds (‘toxic waste hypothesis’). In this study, we demonstrate the presence of an industrial chemical, 2,4-di-tert-butylphenol (DTBP), in the urine of wild-derived house mice (Mus musculus musculus). Addition of guanidine hydrochloride to male and female urine resulted in an increased release of DTBP. This increase was only observed in the high molecular weight fractions (HMWF; > 3 kDa) separated from male or female urine, suggesting that the increased release of DTBP was likely due to the denaturation of MUPs and the subsequent release of MUP-bound DTBP. Furthermore, when DTBP was added to a HMWF isolated from male urine, an increase in 2-sec-butyl-4,5-dihydrothiazole (SBT), the major ligand of MUPs and a male-specific pheromone, was observed, indicating that DTBP was bound to MUPs and displaced SBT. These results suggest that DTBP is a MUP ligand. Moreover, we found evidence for competitive ligand binding between DTBP and SBT, suggesting that males potentially face a tradeoff between eliminating toxic wastes versus transporting pheromones. Our findings support the hypothesis that MUPs bind and eliminate toxic wastes, which may provide the most important fitness benefits of excreting large quantities of these proteins.

On the saliva proteome of the Eastern European house mouse (Mus musculus musculus) focusing on sexual signalling and immunity

“…This hypothesis or as we call it the ‘toxic waste hypothesis’27 has later been suggested by another laboratory72 with the first experimental evidence provided in a recent paper42. They demonstrated that mice loaded with an industrial chemical, 2,4-di-tert-butylphenol (DTBP) use MUPs for a consequent detoxification42. Here we suggest that the nasal and olfactory lipocalins (including MUPs) transport potential toxic waste and various degradation products from chemical signals to the oral cavity, and further to the digestive tract where they are decomposed.…”

“…We have already suggested that evolution of chemical communication and of the system of detoxification might have been driven by similar selective forces because both systems use the same pool of lipocalin transporters2731. This hypothesis or as we call it the ‘toxic waste hypothesis’27 has later been suggested by another laboratory72 with the first experimental evidence provided in a recent paper42. They demonstrated that mice loaded with an industrial chemical, 2,4-di-tert-butylphenol (DTBP) use MUPs for a consequent detoxification42.…”

Mouse Lipocalins (MUP, OBP, LCN) Are Co-expressed in Tissues Involved in Chemical Communication

“…Furthermore, many species do not have multiple copies of Mup genes and thus MUP products-a major component of chemical signaling and olfaction in mice and rats-but express functional OBPs. This has been shown in many mammals (Singer and Macrides, 1990;Stopkova et al, 2010;Hagemeyer et al, 2011;Nagnan-Le Meillour et al, 2014) and it is our hope that potentially diverse functionsi.e., including the detoxification roles (Stopková et al, 2009;Kwak et al, 2011Kwak et al, , 2016)-of these proteins will be further resolved.…”

“…The "toxic waste hypothesis" states that various lipocalins are involved in removing toxic waste from the body (Stopková et al, 2009;Kwak et al, 2011) and that some of the compounds might have been constituting a signal under selection (Stopková et al, 2009). The toxic waste disposal role has been experimentally demonstrated in a recent paper (Kwak et al, 2016) where mice loaded with an industrial chemical, 2,4-di-tertbutylphenol (DTBP) used MUPs for a consequent detoxification (Kwak et al, 2016). To conclude, lipocalins are ubiquitous proteins with diverse functions and multiple sites of their expression.…”

Diversity of major urinary proteins (MUPs) in wild house mice

“…The low individual variation of Mup genes and linked microsatellites suggest that these genes are evolving under purifying selection26, perhaps through a selective sweep in this large region40, and the high homology of different Mup loci may be generated by concerted evolution (gene conversion)4142. It is unclear why selection favours low individual variation and high homology of MUP loci, and studies are needed to investigate possible effects on individual survival43, as well as reproductive success (through chemical communication).…”