When the Nose Must Remain Responsive: Glutathione Conjugation of the Mammary Pheromone in the Newborn Rabbit

Abstract

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.

Odorant-odorant metabolic interaction, a novel actor in olfactory perception and behavioral responsiveness

“…Aldehydes structurally related to 2MB2 and previously shown to be glutathione conjugated 23 were screened to identify challengers for glutathione conjugation metabolism toward 2MB2. With this aim, OE homogenate of newborn rabbits was incubated for 80 min at 37 °C with glutathione and a binary mixture composed of 2MB2 and a potential challenger or a non-challenger of 2MB2.…”

“…We previously developed a fast reliable and automated method to ex vivo measure endogenous global enzymatic odorant metabolism 23 , 24 . Briefly, in this validated method, a fresh total explant of newborn rabbit OE was put in a sealed 20 ml vial, in which a known concentration of gaseous odorant was injected.…”

“…We previously proposed that the high level of 2MB2 metabolism in the rabbit neonate OE optimizes its clearance, in order to maintain the reactivity of OSNs to subsequent 2MB2 stimulation 23 . Actually, rabbit pups do not rapidly habituate to 2MB2, since after 4 or 5 min of exposure (which is the normal duration of a nursing episode in that species 17 , 21 , 30 ) they often remain responsive to the pheromone (Coureaud, personal observation).…”

Understanding the Inguinal Sinus in Sheep (Ovis aries)—Morphology, Secretion, and Expression of Progesterone, Estrogens, and Prolactin Receptors

“…Lactating rabbits emit in their milk a volatile aldehyde, 2-methylbut-2-enal, that provokes searching and grasping behaviors in neonates [ 28 , 29 ]; newborn rabbits’ survival depends on the perception of this odor signal emitted from the mother’s ventrum area that allows them to locate the mother’s nipples and suckle. Emission of nipple pheromones in the rabbit is induced during pregnancy by the combined action of estrogen and progesterone [ 11 , 30 ].…”

Gene expression and immunochemical localization of major cytochrome P450 drug-metabolizing enzymes in bovine nasal olfactory and respiratory mucosa

“…The nasal olfactory and respiratory mucosae have been well documented to host a diverse array of phase I and II drug metabolizing enzymes (Gu et al, 2000; Heydel et al, 2013; Legendre et al, 2014; Thiebaud et al, 2013, 2010; Thornton-Manning, 1997; Watelet et al, 2009; Wong and Zuo, 2010; Zhang et al, 2005), some of which have been implicated in tissue-specific toxicological reactions. An increasing number of reports of the induction of nasal tumors or lesions in laboratory animals following inhalation of compounds undergoing metabolic activation to toxic compounds fueled interest in the area of enzymatic barrier properties of the nasal mucosa (Brittebo, 1997; Dahl and Hadley, 1991; Ding and Kaminsky, 2003; Reed, 1993; Thornton-Manning, 1997).…”