When the nose must remain responsive: glutathione conjugation of the mammary pheromone in the newborn rabbit

In insects, xenobiotic-metabolizing enzymes were demonstrated to regulate pheromones inactivation, clearing them from the olfactory periphery and keeping receptors ready for stimulation renewal. Here, we investigate whether similar processes could occur in mammals, focusing on the pheromonal communication between female rabbits and their newborns. Lactating rabbits emit in their milk a volatile aldehyde, 2-methylbut-2-enal, that elicits searching-grasping in neonates; called the mammary pheromone (MP), it is critical for pups which are constrained to find nipples within the 5 min of daily nursing. For newborns, it is thus essential to remain sensitive to this odorant during the whole nursing period to display several actions of sucking. Here, we show that the MP is enzymatically conjugated to glutathione in newborn olfactory epithelium (OE), in accordance with the high mRNA expression of glutathione transferases evidenced by quantitative reverse transcription-PCR. This activity in the nose is higher than in the liver and in OE of newborns compared with weanlings (no more responsive to the pheromone). Therefore, the results pinpoint the existence of a high level of MP-glutathione conjugation activity in the OE of young rabbits, especially in the developmental window where the perceptual sensitivity toward the MP is crucial for survival

Glutathione conjugation of the rabbit mammary pheromone 2-methylbut-2-enal

International audienceIn the process of smell, the olfactory signal is initiated by the binding of odorous molecules to olfactory receptors. In the receptor environment,associated events are supposed to modulate this signal.Thus, the xenobiotic metabolizing enzymes, potentially involved in the clearance of the odorous molecules, could modulate the availability of these molecules for the olfactory receptors, and consequently could participate indirectly in the olfactory signal termination. A mammary pheromone, which is an odorous aldehyde (2-methylbut-2-enal or 2MB2) has been recently characterized in the rabbit by our group. The aim of this work was to elucidate the metabolism of 2MB2 in the rabbit olfactory mucosa (OM). Results of in vitro studies demonstrate that 2MB2 is conjugated to glutathione in OM, and that this metabolism is much stronger than in the liver. Besides, 2MB2 is less conjugated to glutathione in newborn rabbit OM than in weanling or adult animal mucosa. This last result is correlated with age-related variations in the expression of different olfactory glutathione transferase isoforms. In addition to in vitro studies, we developed an ex-vivo method in order to evaluate the metabolism of 2MB2 in a whole-tissue sample. This approach allows the nasal cavity to keep its complex structure, which is necessary for the olfactory physiological process. The disappearance of the volatile aldehyde is measured in the headspace around the isolated nasal cavity put in a closed vial, enabling a global measurement of the pheromone metabolism. These results demonstrate that 2MB2 is metabolized by the rabbit olfactory mucosa especially as glutathione conjugates, and suggest the use of this pheromone as an interesting tool for further investigations on the possible involvement of the xenobiotic metabolizing enzymes in the process of smell

(n-3) long-chain PUFA differentially affect resistance to Pseudomonas aeruginosa infection of male and female cftr-/- mice.

International audienceThe aim of this study was to determine whether oral supplementation with EPA/DHA (10.5 and 5.1% of fat, respectively) could improve the outcome of pulmonary P. aeruginosa infection in cftr(-/-) mice compared with wild-type (Wt) mice similarly treated. Because gender could influence the susceptibility of cftr-deficient mice, results were analyzed by gender. Wt and (-/-) mice were randomized for 6 wk to consume a control or EPA/DHA diet, infected with endotracheal injection of 5 × 10(7) CFU/mouse of P. aeruginosa, and killed 24 h later. Cftr(-/-) mice were more susceptible to infection than were Wt mice; (-/-) males had more neutrophils (P < 0.01) and a higher keratinocyte-derived chemokine (KC) level (P < 0.05), and (-/-) females had greater lung injury and mortality (P < 0.05). Female (-/-) mice were more susceptible than (-/-) males with a higher mortality and lung injury (P < 0.05). The EPA/DHA diet reduced neutrophil numbers and KC and IL-6 levels (P < 0.05) in (-/-) males and reduced mortality rate (P < 0.001), lung permeability, and IL-6 level (P < 0.05) in (-/-) females compared with (-/-) mice fed the control diet. These results were associated with a reduction in the pulmonary bacterial load (P < 0.05), an increase in the EPA/DHA concentration in cell membranes of (-/-) males and females (P < 0.01), and an increased weight gain only in males compared with (-/-) mice fed the control diet (P < 0.01). In conclusion, EPA/DHA improves the host resistance of (-/-) mice, although the beneficial effect differed in males and females