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Although the anatomy of the nasal fossa is broadly similar among terrestrial mammals, differences are evident in the intricacies of nasal turbinal architecture, which varies from simple scroll-like to complex branching forms, and in the extent of nonsensory and olfactory epithelium covering the turbinals. In this study, detailed morphological and immunohistochemical examinations and quantitative measurements of the turbinals and epithelial lining of the nasal fossa were conducted in an array of species that include the gray squirrel, bobcat, coyote, and white-tailed deer. Results show that much more of the nose is lined with olfactory epithelium in the smallest species (gray squirrel) than in the larger species. In two species with similar body masses, bobcat and coyote, the foreshortened felid snout influences turbinal size and results in a decrease of olfactory epithelium on the ethmoturbinals relative to the longer canine snout. Ethmoturbinal surface area exceeds that of the maxilloturbinals in all four sampled animals, except the white-tailed deer, in which the two are similar in size. Combining our results with published data from a broader array of mammalian noses, it is apparent that olfactory epithelial surface area is influenced by body mass, but is also affected by aspects of life history, such as diet and habitat, as well as skull morphology, itself a product of multiple compromises between various functions, such as feeding, vision, and cognition. The results of this study warrant further examination of other mammalian noses to broaden our evolutionary understanding of nasal fossa anatomy. Anat Rec, 299:840-852, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The surface area of the maxilloturbinals and fronto-ethmoturbinals is commonly used as an osteological proxy for the respiratory and the olfactory epithelium, respectively. However, this assumption does not fully account for animals with short snouts in which these two turbinal structures significantly overlap, potentially placing fronto-ethmoturbinals in the path of respiratory airflow. In these species, it is possible that anterior fronto-ethmoturbinals are covered with non-sensory (respiratory) epithelium instead of olfactory epithelium. In this study, we analyzed the distribution of olfactory and non-sensory, respiratory epithelia on the turbinals of two domestic cats (Felis catus) and a bobcat (Lynx rufus). We also conducted a computational fluid dynamics simulation of nasal airflow in the bobcat to explore the relationship between epithelial distribution and airflow patterns. The results showed that a substantial amount of respiratory airflow passes over the anterior fronto-ethmoturbinals, and that contrary to what has been observed in caniform carnivorans, much of the anterior ethmoturbinals are covered by non-sensory epithelium. This confirms that in short-snouted felids, portions of the fronto-ethmoturbinals have been recruited for respiration, and that estimates of olfactory epithelial coverage based purely on fronto-ethmoturbinal surface area will be exaggerated. The correlation between the shape of the anterior fronto-ethmoturbinals and the direction of respiratory airflow suggests that in short-snouted species, CT data alone are useful in assessing airflow patterns and epithelium distribution on the turbinals., (© 2016. Published by The Company of Biologists Ltd.)

Previous findings from our laboratory highlighted marked ethnic differences in volatile organic compounds (VOCs) from cerumen among individuals of Caucasian, East Asian, and African-American descent, based, in part, on genetic differences in a gene that codes for a transport protein, which is a member of the ATP-binding cassette transporter, sub-family C, member 11 (ABCC11). In the current work, we hypothesized that axillary odorants produced by East Asians would differ markedly from those obtained from individuals of European or African descent based on the pattern of ethnic diversity that exists in ABCC11. Using gas chromatography/mass spectrometry (GC/MS) we examined differences in axillary odorant VOCs among 30 individuals of African-American, Caucasian, and East Asian descent with respect to their ABCC11 genotype. While no qualitative differences in the type of axillary odorants were observed across ethnic groups, we found that characteristic axillary odorants varied quantitatively with respect to ethnic origin. We propose that ABCC11 is not solely responsible for predicting the relative amounts of volatiles found in axillary secretions and that other biochemical pathways must be involved.

This report describes the volatile organic compounds (VOCs) associated with human cerumen (earwax) and the effects of ethnicity/race and variation on the ATP-binding cassette, sub-family C, member 11 gene (ABCC11). A single nucleotide polymorphism (SNP) in ABCC11 affects the cerumen VOC profiles of individuals from African, Caucasian, and Asian descent. Employing gas chromatography/mass spectrometry (GC/MS) we have identified the nature and relative abundance of cerumen VOCs from 32 male donors. Our results show that cerumen contains a complex mixture of VOCs and that the amounts of these compounds vary across individuals as well as across ethnic/racial groups. In six of the seven compounds whose detected concentrations were found to be statistically different across groups, individuals of African descent (AfD) > Caucasian descent (CaD) > Asians descent (AsD). Our findings also reveal that ABCC11 genotype alone does not predict the type and relative levels of volatiles found in human cerumen, and suggest that other biochemical pathways must be involved. Examination of the composition and diversity of external auditory canal microbiota in a small subset of our subject population revealed that the ear microbiota may not be directly correlated with either ethnic group membership or ABCC11 genotype.

We report here the initial examination of volatile organic compounds (VOCs) emanating from human earwax (cerumen). Recent studies link a single nucleotide polymorphism (SNP) in the adenosine triphosphate (ATP) binding cassette, sub-family C, member 11 gene (ABCC11) to the production of different types of axillary odorants and cerumen. ABCC11 encodes an ATP-driven efflux pump protein that plays an important function in ceruminous apocrine glands of the auditory canal and the secretion of axillary odor precursors. The type of cerumen and underarm odor produced by East Asians differ markedly from that produced by non-Asians. In this initial report we find that both groups emit many of the same VOCs but differ significantly in the amounts produced. The principal odorants are volatile organic C2-to-C6 acids. The physical appearance of cerumen from the two groups also matches previously reported ethnic differences, viz., cerumen from East Asians appears dry and white while that from non-Asians is typically wet and yellowish-brown., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Dogs can identify, by olfaction, melanoma on the skin of patients or melanoma samples hidden on healthy subjects, suggesting that volatile organic compounds (VOCs) from melanoma differ from those of normal skin. Studies employing gas chromatography-mass spectrometry (GC-MS) and gas sensors reported that melanoma-related VOCs differed from VOCs from normal skin sources. However, the identities of the VOCs that discriminate melanoma from normal skin were either unknown or likely derived from exogenous sources. We employed solid-phase micro-extraction, GC-MS and single-stranded DNA-coated nanotube (DNACNT) sensors to examine VOCs from melanoma and normal melanocytes. GC-MS revealed dozens of VOCs, but further analyses focused on compounds most likely of endogenous origin. Several compounds differed between cancer and normal cells, e.g., isoamyl alcohol was higher in melanoma cells than in normal melanocytes but isovaleric acid was lower in melanoma cells. These two compounds share the same precursor, viz., leucine. Melanoma cells produce dimethyldi- and trisulfide, compounds not detected in VOCs from normal melanocytes. Furthermore, analyses of the total volatile metabolome from both melanoma cells and normal melanocytes by DNACNT sensors, coupled with the GC-MS results, demonstrate clear differences between these cell systems. Consequently, monitoring of melanoma VOCs has potential as a useful screening methodology., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We explored genetic influences on the perception of taste and smell stimuli. Adult twins rated the chemosensory aspects of water, sucrose, sodium chloride, citric acid, ethanol, quinine hydrochloride, phenylthiocarbamide (PTC), potassium chloride, calcium chloride, cinnamon, androstenone, Galaxolide™, cilantro, and basil. For most traits, individual differences were stable over time and some traits were heritable (h(2) from 0.41 to 0.71). Subjects were genotyped for 44 single nucleotide polymorphisms within and near genes related to taste and smell. The results of these association analyses confirmed previous genotype-phenotype results for PTC, quinine, and androstenone. New associations were detected for ratings of basil and a bitter taste receptor gene, TAS2R60, and between cilantro and variants in three genes (TRPA1, GNAT3, and TAS2R50). The flavor of ethanol was related to variation within an olfactory receptor gene (OR7D4) and a gene encoding a subunit of the epithelial sodium channel (SCNN1D). Our study demonstrates that person-to-person differences in the taste and smell perception of simple foods and drinks are partially accounted for by genetic variation within chemosensory pathways.

Background: Information on nucleotide diversity along completely sequenced human genomes has increased tremendously over the last few years. This makes it possible to reassess the diversity status of distinct receptor proteins in different human individuals. To this end, we focused on the complete inventory of human olfactory receptor coding regions as a model for personal receptor repertoires., Results: By performing data-mining from public and private sources we scored genetic variations in 413 intact OR loci, for which one or more individuals had an intact open reading frame. Using 1000 Genomes Project haplotypes, we identified a total of 4069 full-length polypeptide variants encoded by these OR loci, average of ~10 per locus, constituting a lower limit for the effective human OR repertoire. Each individual is found to harbor as many as 600 OR allelic variants, ~50% higher than the locus count. Because OR neuronal expression is allelically excluded, this has direct effect on smell perception diversity of the species. We further identified 244 OR segregating pseudogenes (SPGs), loci showing both intact and pseudogene forms in the population, twenty-six of which are annotatively "resurrected" from a pseudogene status in the reference genome. Using a custom SNP microarray we validated 150 SPGs in a cohort of 468 individuals, with every individual genome averaging 36 disrupted sequence variations, 15 in homozygote form. Finally, we generated a multi-source compendium of 63 OR loci harboring deletion Copy Number Variations (CNVs). Our combined data suggest that 271 of the 413 intact OR loci (66%) are affected by nonfunctional SNPs/indels and/or CNVs., Conclusions: These results portray a case of unusually high genetic diversity, and suggest that individual humans have a highly personalized inventory of functional olfactory receptors, a conclusion that might apply to other receptor multigene families.

Twin pairs and their siblings rated the intensity of the odorants amyl acetate, androstenone, eugenol, Galaxolide, mercaptans, and rose (N = 1573). Heritability was established for ratings of androstenone (h (2) = 0.30) and Galaxolide (h(2) = 0.34) but not for the other odorants. Genome-wide association analysis using 2.3 million single nucleotide polymorphisms indicated that the most significant association was between androstenone and a region without known olfactory receptor genes (rs10966900, P = 1.2 × 10(-7)). A previously reported association between the olfactory receptor OR7D4 and the androstenone was not detected until we specifically typed this gene (P = 1.1 × 10(-4)). We also tested these 2 associations in a second independent sample of subjects and replicated the results either fully (OR7D4, P = 0.00002) or partially (rs10966900, P = 0.010; N = 266). These findings suggest that 1) the perceived intensity of some but not all odorants is a heritable trait, 2) use of a current genome-wide marker panel did not detect a known olfactory genotype-phenotype association, and 3) person-to-person differences in androstenone perception are influenced by OR7D4 genotype and perhaps by variants of other genes.

Both the olfactory and the trigeminal systems are able to respond to intranasal presentations of chemical vapor. Accordingly, when the nose detects a volatile chemical, it is often unclear whether we smell it, feel it, or both. The distinction may often be unimportant in our everyday perception of fragrances or aromas, but it can matter in experiments that purport to isolate olfactory processes or study the interaction between olfaction and chemesthesis. Researchers turn to a small pool of compounds that are believed to be "pure olfactory" stimuli with little or no trigeminal impact. The current report reexamines one such commonly used compound, namely eugenol, a flavor and fragrance ingredient that has anesthetic properties under some conditions. Using a standard method involving many trials during an experimental session (Experiment 1), subjects were unable to reliably lateralize eugenol, consistent with claims that this compound is detected primarily through olfaction. However, with more limited exposure (Experiments 2 and 3), subjects were able to lateralize eugenol. We speculate that anesthetic properties of eugenol could blunt its trigeminal impact in some paradigms. Regardless, the current experiments suggest that eugenol can in fact stimulate the trigeminal nerve but in a complex concentration-dependent manner. Implications and strategies for selection of model odorants are discussed.

Relatively, few studies have focused on how nasal irritation changes over time. To simulate the rhythm of natural respiration, subjects received 3-s pulses of volatile organic compounds interspersed with 3-s pulses of clean air. Each trial, subjects received 9 pulses of a chemical vapor over about 1 min. Subjects rated nasal irritation from each pulse using magnitude estimation. Within a trial, compound and concentration were fixed. Compound (ethanol, n-butanol, or n-hexanol) and concentration (4 levels for each compound) varied across trials. For all stimuli, rated irritation decreased over time (adaptation). Plots of log-rated intensity versus elapsed time were approximately linear (intensity decreased by a fixed ratio per unit time). Interestingly, the slopes of intensity versus time functions differed very little: Regardless of concentration and compound, rated irritation decreased by about 32% over the 9 pulses. The basic mechanism of short-term adaptation may be the same for the 3 alcohols studied. Regardless, these data suggest that very simple models might be able to describe some aspects of perceptual dynamics quite well.

For nasal irritation from volatile chemicals, a version of Haber's rule (k = C(n)T) can model the trade-off between concentration (C) and duration of exposure (T) to achieve a fixed sensory impact, e.g. threshold-level irritation or a fixed suprathreshold intensity. The term k is a constant. The exponent, n, represents how well the system integrates over time. An exponent of 1 indicates complete temporal integration: an x-fold increase in stimulus duration exactly compensates for cutting the concentration 1/x. An exponent greater than 1 indicates incomplete temporal integration: more than an x-fold increase in duration is needed. In a previous study of homologous alcohols, n varied systematically with number of methylene units: integration became more complete as the length of the carbon chain increased. To explore the generality of this finding, we tested homologous esters that differ in the number of methylene units: n-ethyl propionate, n-propyl propionate, and n-butyl propionate. Nasal lateralization was used to measure irritation thresholds. Human subjects received a fixed concentration of a single compound within each experimental session. Stimulus duration was varied to find the briefest stimulus that caused lateralizable irritation. Concentration and compound varied across sessions. Consistent with results with n-alcohols, integration became more complete as the number of methylene units increased. Lipid solubility varies with chain length; hence, solubility in the nasal mucosa may play a role in the dynamics of irritation. Further, preliminary analyses suggest that, for data pooled across both chemical series, n varies systematically with molecular parameters related to solubility and diffusion.

Dynamics, or how stimulation occurs over time, influences the somatosensory impact of volatile chemicals. Within an experimental session, sensation waxes with steady presentation over seconds to minutes, may reach a plateau, and then may fade. Long-term occupational exposure can desensitize the trigeminal system. Short- and long-term dynamics might be mediated by different mechanisms. For brief intranasal exposures (i.e., up to about 10 seconds), studies have systematically manipulated both time (duration of exposure) and concentration to maintain a fixed perceived intensity or a fixed level of detection. A simple mass integration model describes the trade-off between concentration and time quite well: a fixed-ratio increase in duration compensates for a fixed-ratio decrease in concentration. However, for most compounds, more than a two-fold increase in duration are required to compensate for cutting concentration in half. For example, for ethanol, an increase in duration of about six-fold are required. For such compounds that display highly imperfect integration, a fixed number of molecules might have a much greater sensory impact when presented over 0.2 seconds than over 0.5 seconds. Nasal chemesthesis may be temporally sluggish compared to olfaction, but fine-grained dynamics still matter. Time-intensity ratings of nasal irritation from dynamic stimuli also support this conclusion. Although integration is generally imperfect, compounds vary widely in how far they fall short of perfect time-concentration trading. Current studies use a structure-activity approach to determine how molecular parameters correlate with how well a compound integrates over time.

Background: Human skin emits a variety of volatile metabolites, many of them odorous. Much previous work has focused upon chemical structure and biogenesis of metabolites produced in the axillae (underarms), which are a primary source of human body odour. Nonaxillary skin also harbours volatile metabolites, possibly with different biological origins than axillary odorants., Objectives: To take inventory of the volatile organic compounds (VOCs) from the upper back and forearm skin, and assess their relative quantitative variation across 25 healthy subjects., Methods: Two complementary sampling techniques were used to obtain comprehensive VOC profiles, viz., solid-phase microextraction and solvent extraction. Analyses were performed using both gas chromatography/mass spectrometry and gas chromatography with flame photometric detection., Results: Nearly 100 compounds were identified, some of which varied with age. The VOC profiles of the upper back and forearm within a subject were, for the most part, similar, although there were notable differences., Conclusions: The natural variation in nonaxillary skin odorants described in this study provides a baseline of compounds we have identified from both endogenous and exogenous sources. Although complex, the profiles of volatile constituents suggest that the two body locations share a considerable number of compounds, but both quantitative and qualitative differences are present. In addition, quantitative changes due to ageing are also present. These data may provide future investigators of skin VOCs with a baseline against which any abnormalities can be viewed in searching for biomarkers of skin diseases.

Through temporal integration, sensory systems accumulate stimulus energy, e.g., photons, acoustic energy, or molecules, over time to detect weaker signals than they otherwise could. Past studies found imperfect temporal integration in detection of nasal irritation: To maintain a fixed level of detection, one must increase stimulus duration by more than twofold to compensate for cutting concentration in half. Despite this generality, integration varied widely among compounds, from nearly perfect, i.e., an increase in duration of slightly more than twofold could compensate for cutting concentration in half, to highly imperfect. How do such differences relate to molecular parameters? Perhaps molecules that more readily dissolve into the lipid-rich perireceptor environment will accumulate, and therefore integrate, better over time. To test this hypothesis, studies compared temporal integration for three compounds that differ systematically in lipid solubility: n-ethanol, n-butanol, and n-hexanol. Subjects were healthy, adult humans. Nasal lateralization was used to measure irritation threshold. Subjects received a fixed concentration of a single compound within each experimental session, and stimulus duration was varied to find the briefest stimulus subjects could reliably lateralize. Concentration and compound varied across sessions. Consistent with the hypothesis, integration did become closer to perfect as lipid solubility increased. That just one molecular parameter can help predict degree of integration suggests that a structure-activity approach to understanding temporal integration shows promise.

Two experiments examined the trade-off between concentration and stimulus duration in nasal lateralization of n-ethyl alcohol. In nasal lateralization, a common measure of irritation threshold, subjects receive chemical vapor in one nostril and clean air in the other. Subjects try to determine which nostril received the chemical. Within experimental runs, subjects received fixed concentrations (1650-5000 ppm) of ethanol, and duration was varied to find the shortest, lateralizable stimulus. In Experiment 1, a small group of subjects was tested intensively to obtain stable individual data. In Experiment 2, a larger group was studied using more rapid methods. In both cases, subjects could lateralize increasingly weaker concentrations with longer stimulus presentations. Hence integration occurred. However, more than a twofold increase in duration was required to compensate for a twofold decrease in concentration to maintain threshold lateralization. These results suggest that an imperfect, mass-integrator model can describe short-term integration of nasal lateralization of ethanol.

Two experiments examined integration of perceived irritation over short-term (approximately 100-4000 ms) delivery of ammonia into the nasal cavity of human subjects. Experiment 1 examined trade-offs between time and concentration at threshold level by means of nasal lateralization, a common measure of irritation threshold. Within experimental sessions, the duration of a fixed-concentration stimulus varied to determine the shortest, detectable pulse. Subjects could lateralize increasingly weaker concentrations with longer stimulus presentations. Experiment 2 examined an analogous trade-off for supra-threshold irritation. Subjects rated irritation from presentations of ammonia that varied both in concentration and in duration. Rated intensity for a given concentration increased with stimulus duration. Hence integration occurred at both threshold and supra-threshold levels. However, more than a twofold increase in duration was required to compensate for a twofold decrease in concentration to maintain threshold lateralization or a fixed level of perceived intensity. These results suggest that an imperfect mass-integrator model may be able to describe short-term integration of nasal irritation from ammonia at both the threshold and supra-threshold levels.

Human body odor may contribute to selection of partners. If so, sexual orientation may influence preference for and perhaps production of human body odors. In a test of these hypotheses, heterosexual and homosexual males and females made two-alternative forced-choice preference judgments for body odors obtained from other heterosexual and homosexual males and females. Subjects chose between odors from (a) heterosexual males and gay males, (b) heterosexual males and heterosexual females, (c) heterosexual females and lesbians, and (d) gay males and lesbians. Results indicate that differences in body odor are detected and responded to on the basis of, in part, an individual's gender and sexual orientation. Possible mechanisms underlying these findings are discussed.

In a very large study (N = 1,247,344), left-handedness showed no association with allergies overall (and an inconsistent association with individual allergies), but there was strong evidence that left-handers had lower rates of arthritis and ulcer--Arthritis: Odds-ratio (OR) = 0.942, 95% CI 0.922-0.962; Ulcer: OR = 0.920, 95% CI 0.896-0.944.

Among primates in general, pheromones are of variable importance to social communication. Data on humans have generated the greatest controversy regarding the existence of pheromonal communication. In this review, the likelihood of pheromonal communication in humans is assessed with a discussion of chemical compounds produced by the axilla that may function as pheromones; the likelihood that the vomeronasal organ (VNO), a putative pheromone receptor organ in many other mammals, is functional in humans; and the possible ways pheromones operate in humans. In the human axilla, the interactions between the cutaneous microflora and axillary secretions render this region analogous to scent glands found in other primates. Both the chemistry of axillary secretions and their effects on conspecifics in humans appear to be analogous to other mammalian pheromone systems. Whichever chemical compounds serve a pheromonal function in humans, another unknown is the receptor. Although the VNO has been implicated in the reception of pheromones in many vertebrates, it is not the only pathway through which such information has access to the central nervous system; there is ample evidence to support the view that the olfactory epithelium can respond to pheromones. Furthermore, if a chemical activates receptors within the VNO, this does not necessarily mean that the compound is a pheromone. An important caveat for humans is that critical components typically found within the functioning VNO of other, nonprimate, mammals are lacking, suggesting that the human VNO does not function in the way that has been described for other mammals. In a broader perspective, pheromones can be classified as primers, signalers, modulators, and releasers. There is good evidence to support the presence of the former three in humans. Examples include affects on the menstrual cycle (primer effects); olfactory recognition of newborn by its mother (signaler); individuals may exude different odors based on mood (suggestive of modulator effects). However, there is no good evidence for releaser effects in adult humans. It is emphasized that no bioassay-guided study has led to the isolation of true human pheromones, a step that will elucidate specific functions to human chemical signals., ((c) 2004 Wiley-Liss, Inc.)

Major histocompatibility complex (MHC) genes in mammals (H-2 in mice) play a major role in regulating immune function. They also bestow individuality in the form of a chemical signature or odortype. At present, the respective contributions of the olfactory epithelium and the vomeronasal organ (VNO) in the recognition of individual odortypes are not well defined. We examined a possible role for the VNO in the recognition of MHC odortypes in mice by first removing the organ (VNX) and then training the mice to distinguish the odors of two congenic strains of mice that differed only in their MHC type. C57BL/6J mice (bb at H-2) and C57BL/6J-H-2(k) (kk at H-2) provided urine for sensory testing. Eight VNX and six sham-operated mice were trained to make the discrimination. Neither the number of training trials-to-criterion nor the rate of learning differed significantly for VNX and sham-operated mice. We conclude that the VNO is not necessary for learning to discriminate between MHC odortypes.

Two experiments examined time/concentration trading for the detection of carbon dioxide, an irritant with little or no odor. Experiment 1 employed the nasal lateralization method: subjects attempted to determine which nostril received carbon dioxide and which received pure air when presented simultaneously. Experiment 2 employed a temporal, two-alternative, forced-choice, detection paradigm with monorhinal stimulation. In both experiments, stimulus duration was varied at a number of fixed concentrations to determine the shortest, detectable pulse. Under both conditions, threshold pulse duration decreased as stimulus concentration increased. Power functions with exponents of less than negative one described the data quite well: More than a twofold increase in duration was needed to compensate for a twofold decrease in concentration. Thus, for carbon dioxide, the nasal trigeminal system functions as an imperfect integrator at threshold-level.

In three experiments, subjects tracked intensity of nasal irritation during sustained presentation of carbon dioxide in the nose. Experiment 1 showed that: (i). functions of peak intensity vs. concentration and latency to first non-zero ratings agreed with published literature, thereby supporting the validity of the technique; (ii). on average, rated intensity peaked approximately 3-4 s after stimulus-onset and began to fall rapidly thereafter; (iii). large and stable individual differences in temporal dynamics occurred. Experiment 2 replicated experiment 1 with some methodological refinements. In experiment 3, application of the technique revealed that the nose regains sensitivity with very brief (300-500 ms) interruptions in presentation of carbon dioxide. In short: (i). the method developed here provides a temporally fine-grained tool to study the time-course of nasal irritation, and (ii). nasal irritation from carbon dioxide shows relatively rapid temporal dynamics.

Human underarm secretions, when applied to women recipients, alter the length and timing of the menstrual cycle. These effects are thought to arise from exposure to primer pheromones that are produced in the underarm. Pheromones can affect endocrine (primer) or behavioral (releaser) responses, provide information (signaler), or perhaps even modify emotion or mood (modulator). In this study, we extracted underarm secretions from pads worn by men and placed the extract under the nose of women volunteers while monitoring serum LH and emotion/mood. Pulses of LH are excellent indicators of the release of GnRH from the brain's hypothalamus. In women, the positive influence of GnRH on LH affects the length and timing of the menstrual cycle, which, in turn, affects fertility. Here we show that extracts of male axillary secretions have a direct effect upon LH-pulsing and mood of women. In our subjects, the putative male pheromone(s) advanced the onset of the next peak of LH after its application, reduced tension, and increased relaxation. These results demonstrate that male axillary secretions contain one or more constituents that act as primer and modulator pheromones.

Individuals can determine the side of the nose that receives an odorant during unilateral presentation (lateralize) if endings of the trigeminal nerve are stimulated. By using psychophysical methods, olfactory detection and trigeminal lateralization thresholds for 1-butanol were obtained from 142 individuals ranging in age from 20 to 89 year. Sensitivity in both chemosensory pathways declined with advancing age, especially in people older than 60 years.

The mammalian vomeronasal organ (VNO), a part of the olfactory system, detects pheromones--chemical signals that modulate social and reproductive behaviours. But the molecular receptors in the VNO that detect these chemosensory stimuli remain undefined. Candidate pheromone receptors are encoded by two distinct and complex superfamilies of genes, V1r and V2r (refs 3 and 4), which code for receptors with seven transmembrane domains. These genes are selectively expressed in sensory neurons of the VNO. However, there is at present no functional evidence for a role of these genes in pheromone responses. Here, using chromosome engineering technology, we delete in the germ line of mice an approximately 600-kilobase genomic region that contains a cluster of 16 intact V1r genes. These genes comprise two of the 12 described V1r gene families, and represent approximately 12% of the V1r repertoire. The mutant mice display deficits in a subset of VNO-dependent behaviours: the expression of male sexual behaviour and maternal aggression is substantially altered. Electrophysiologically, the epithelium of the VNO of such mice does not respond detectably to specific pheromonal ligands. The behavioural impairment and chemosensory deficit support a role of V1r receptors as pheromone receptors.

We previously found that exposure-induced increase in odor sensitivity involves, at least in part, the olfactory epithelium. We did this by exposing mice to 5 alpha-androst-16-en-3-one (androstenone) and measuring changes in the epithelium. Past research showed that sensitivity to androstenone also could be induced by exposing individuals to 4-(4',4'-dimethylcyclohexyl)-2-methylcyclohexanone (DMCMC), a structural and functional analog of androstenone. What remained unknown is whether structural and/or functional odorant analogs share peripheral components. In the current work, we used a well-established model to disconnect the olfactory epithelium from the olfactory bulbs (BNX) to disrupt mechanisms underlying olfactory coding (when the afferents reinnervate the bulb, they do not synapse in their original glomeruli), and to examine the effects of disruption and restoration on exposure-induced odor sensitivity. In this study, we determined whether analogs of androstenone, viz., 5 alpha-androstan-3-one (androstanone) and DMCMC, could induce sensitivity to androstenone after BNX. Results demonstrate that exposure to either androstanone or DMCMC can induce sensitivity to androstenone in control mice. Different results were observed in mice that had recovered from bilateral BNX. Exposure to androstanone for 10 days immediately after surgery increased sensitivity to androstenone; however, exposure to DMCMC did not. These results suggest that androstanone and DMCMC, although apparent perceptual analogs of androstenone, may be using different pathways of olfaction within the central nervous system (CNS).

Exposure-induced shifts in sensitivity to odors may involve peripheral and/or central components of the olfactory system. The ability to disconnect the olfactory epithelium from the bulbs provides a unique opportunity to examine how odorant exposure affects each component. In one experiment, odor thresholds were established for either amyl acetate or androstenone. The mice were then exposed for 10 days to the same test odorant for which a threshold was obtained. After exposure, sensitivity to the odorant increased relative to preexposure levels. The mice then underwent bilateral olfactory nerve transection (BNX). When both groups of mice were tested 45-50 days after recovery from surgery and return of olfactory function, increased sensitivity to the exposed odorant persisted; however, 121-203 days after surgery, sensitivity returned to preexposure levels. Another experiment was similar to the first except that mice were exposed to an odorant, either amyl acetate or androstenone, for 10 days beginning 1 day after BNX or sham surgery. When the mice were tested 45-50 days after surgery, sensitivity to the exposed odorant was increased relative to preexposure levels, whereas sensitivity to the nonexposed odorant remained at preexposure levels. Although further work is needed to determine the precise mechanism(s) underlying shifts in sensitivity to odors, these studies provide additional evidence for peripheral involvement in exposure-induced sensitization to odorants and demonstrate the remarkable capacity of the olfactory system to maintain or even regain sensitivity after injury.

Volatile sulfur compounds, as well as other volatiles found in the headspace above spent mushroom compost (SMC), were analyzed by gas chromatography and mass spectrometry. Data from these techniques as well as organoleptic evaluation of both the SMC and the chromatographic eluant indicated that the volatile sulfur compounds and cresol were important odorous components in SMC; cresol was reported as a musty, cattle-feces aroma. Samples consisted of headspaces from untreated SMC as well as SMC stirred with 1% (by weight) powered activated carbon (PAC). SMC stirred with and without PAC reduced headspace volatile concentrations, but the stirred with added PAC further decreased concentrations of important malodorants such as volatile sulfur compounds and cresol.

In olfaction, it is not possible to determine which nostril is being stimulated, i.e., lateralize, when a pure olfactory substance, e.g., phenylethyl alcohol or vanillin, is administered into one nostril, and, simultaneously, an odorless, solvent blank into the contralateral nostril. We subjected volunteers to extensive training, with feedback on each trial, in an attempt to determine whether it was possible, in these well-trained subjects, to overcome this apparent impossibility. We failed to obtain any evidence to support the notion that a pure olfactory stimulus could be lateralized when the odorant and blank were presented simultaneously. The task, however, became simple when the odorant and the blank entered each nostril sequentially. We investigated, using a two-channel olfactometer, temporal parameters that enabled such discrimination. We controlled the duration of odorant and blank air puffs, as well as their mutual timing, to determine the threshold stimulus onset-disparity, i.e., the interval between stimulus onset and blank onset, that resulted in an inability to lateralize. Latencies shorter than the threshold interval would be perceived as simultaneous stimulation. We determined that the onset interval was between 200 and 400 ms, depending on the duration of the stimuli (a shorter interval was noted for stimuli of 150-ms duration relative to 300- and 450-ms stimuli). This was also true when two odorants were applied, rather than an odorant and a blank, and the subject was instructed to focus on the sequence of odorant delivery and side of stimulation. The temporal onset threshold was the same for lateralization and for order of stimulation. Whether the olfactory system per se mediates this discrimination or whether inputs from olfaction and chemesthesis, via trigeminal free nerve endings stimulated by air-stream onset, combine to allow this discrimination has yet to be determined.

Sensitivity of olfaction (smell) and chemesthesis (irritation) was evaluated for 2-propanone (acetone) and 1-butanol in acetone-exposed workers (AEW; N = 32) during a workday and unexposed subjects (microES; N = 32). Irritation sensitivity was assessed using a method that relies on the ability of individuals to localize irritants on the body. When a volatile compound is inhaled into one nostril and air into the other, the stimulated side can be determined (lateralized) only after the concentration reaches a level that stimulates the trigeminal nerve (irritation); compounds stimulating olfaction alone cannot be lateralized. Intranasal lateralization thresholds offer an objective measure of sensory irritation elicited by volatile compounds. Test results indicated that neither olfactory nor lateralization thresholds for butanol differed between AEW and microES. Olfactory thresholds to acetone in AEW (855 ppm) were elevated relative to those of microES (41 ppm), as were lateralization thresholds (36,669 ppm and 15,758 ppm, respectively). Within AEW, level of occupational exposure was not correlated with thresholds. Other measures revealed that microES used more irritation descriptors than did AEW on trials where the acetone concentration was below the lateralization threshold. This is noteworthy because microES received lower concentrations of acetone to evaluate than did AEW. These results suggest that exposures to acetone induce changes in acetone sensitivity that are specific to acetone. The acetone concentrations eliciting sensory irritation using the lateralization technique were all well above current occupational exposure standards. The current study indicates that acetone is a weak sensory irritant and that sensory adaptation is an important factor affecting its overall irritancy.

Female prairie voles (Microtus ochrogaster) typically require an intact vomeronasal system and exposure to a chemical signal found in urine from male prairie voles to induce uterine growth necessary for reproduction. Urine from male mice (Mus musculus) does not contain an effective cue for activation of female vole reproduction: after 4 days of exposure to stimuli, voles exposed to urine from female or water had still uteri whereas voles exposed to urine from male voles had large uteri. The initial response to urine from male voles included neuronal activity in the vomeronasal system as indicated by FOS immunocytochemistry. Stimuli (urine from a male vole or a male mouse, or water) were painted on the nose of naive female voles 1 h before sacrifice. Female voles exposed to urine from male voles had more FOS-immunoreactive cells in the accessory olfactory bulb than voles exposed to mouse urine or to water. We conclude that exposure to urine from male voles stimulates the vomeronasal pathway (as measured by FOS immunoreactivity) and induces uterine growth in female voles, whereas exposure to urine from male mice (or water) does not. This suggests that some degree of functional specificity of the clinical cue is determined at or before the accessory olfactory bulb, perhaps in the expression of specific receptors within the vomeronasal organ, rather than entirely within the central nervous system.

The subjectivity of irritancy judgments can bias attempts to establish exposure guidelines that protect individuals from the sensory irritation produced by volatile chemicals. At low to moderate chemical concentrations, naive and occupationally exposed individuals often show considerable variation in the reported levels of perceived irritation. Such variation could result from differences in exposure history, differences in the perceived odor of a chemical, or differences in generalized response tendencies to report irritation, or response bias. Thus, experimental evaluation of sensory irritancy must dissociate sensory irritation from response bias. To this end, judgments of perceived irritation from 800 ppm acetone were obtained from acetone-exposed workers and age- and gender-matched naive controls. To assess the role of response bias during exposure to odorants, subjects were also exposed to phenylethyl alcohol (PEA), an odorant that does not produce sensory irritation. Following exposure, subjects completed a subjective symptom survey that included symptoms that have been associated with long-term solvent exposures and symptoms that have not. Acetone-exposed workers and naive controls reported large differences in the perceived intensity of odor and irritation from acetone, yet no differences in the perception of PEA. However, for both groups, the most significant factors mediating reported irritancy and health symptoms from acetone were the perceived intensity of its odor and an individual's bias to report irritation from PEA. The perception of odor intensity and degree of response bias will differ between and within groups of exposed and naive individuals; hence, an assessment of the influence of these factors in experimental and workplace studies of chemical irritancy is warranted.

Objective: Responses to volatile chemicals are often subjective and variable, both over time and across individuals. Although variability can derive from differences in individual olfactory sensitivity, the response to a chemical stimulus is also influenced by the complex environment surrounding the exposure, which can include the perceiver's cognitive state. To explore the role of cognitive bias in chemical exposures, we evaluated whether information about the consequences of exposure to acetone could influence ratings of odor and irritation during exposure and/or the frequency or intensity of reported health symptoms following exposure., Methods: Ninety adults (mean age 33.7, range 25-64) with no history of occupational exposure to solvents, were exposed to 800 ppm acetone in a chamber for 20 min. To control for non-specific responses to the odor of acetone, the subjects were also exposed for 20 min to 200 ppm phenylethyl alcohol (PEA), a non-irritant volatile chemical that produces a distinct odor but does not elicit irritation in the vapor phase. Subjects were assigned to one of three groups (n = 30/group); each group was given either a positive, negative or neutral bias towards the consequences of exposure to the chemicals in the study. During exposure, subjects rated the intensity of odor and irritation; following exposure, they completed symptom questionnaires., Results: During the 20-min exposure to acetone, the positive bias group exhibited the most adaptation to its odor and the lowest perceived irritation; following exposure they reported the fewest health symptoms. In contrast, the negative bias group rated higher levels of odor intensity and, on average, reported the most over-all irritation; following exposure they reported significantly more health symptoms than the other groups, None of the demographic variables studied (e.g., age, gender, race, smoking status) were predictive of the response to odor or irritation. The perceived irritancy of acetone was well predicted by a linear combination of the perceived odor of acetone and perceived irritation for PEA (the nonirritant), r2 = 0.73., Conclusions: The results provide strong evidence that both the perceived odor and cognitive expectations about a chemical can significantly affect how individuals respond to it. Moreover, because naive control subjects appear to exhibit extreme variation in their cognitive evaluations of chemical effects, there may be limited value in using non-exposed controls to assess the irritancy of chemicals for worker populations.

Any individual living or working in an odorous environment can experience changes in odor perception, some of which are long lasting. Often, these individuals report a significant reduction in the perception of an odor following long-term exposure to that odor (adaptation). Yet, most experimental analyses of olfactory adaptation use brief odorant exposures which may not typify real-world experiences. Using a procedure combining long-term odor exposure in a naturalistic setting with psychophysical tests in the laboratory, we present evidence to show that reduced odor intensity following long-term exposure is accompanied by odorant-specific shifts in threshold. Subjects were exposed continuously to one of two odorants while in their home for a period of 2 weeks. Exposure produced an odorant-specific reduction in sensitivity and perceived intensity compared with preexposure baselines: Detection thresholds for the adapting odorant were elevated following exposure and perceived intensity ratings for weak concentrations were reduced. For most individuals, reduced sensitivity to the test odorant was still evident up to 2 weeks following the last exposure. The persistence of the change, as evidenced by the duration of recovery from adaptation, distinguishes this phenomenon from the adaptation seen following shorter exposures and highlights the need for the study of exposure durations that are more similar to real-world exposures.

Cross-adaptation, the decrease in sensitivity to one odorant following exposure to a different odorant, is affected by odorant similarity, both perceptual and structural, but the precise relationship is obscure. The present series of studies was designed to explore various aspects of perceptual and structural similarity as they relate to cross-adaptation. In Experiment 1, cross-adaptation was assessed between androstenone and five odorants that share a common urinous note with androstenone, but retain unique perceptual characteristics; only the compound judged most perceptually similar to androstenone cross-adapted it. In Experiment 2, odorants both perceptually and structurally similar (androstenone and androstanone) displayed significant, mutual cross-adaptation. Furthermore, magnitude estimates for androstanone were significantly reduced following exposure to 3-methylidene-5 alpha-androstane (3M5A), a structurally similar, perceptually odorless compound. This finding appears to be the first demonstration that an odorless compound can affect, via cross-adaptation, the perception of an odorous compound. Finally, in Experiment 3, significant, asymmetric cross-adaptation was observed between compounds that are perceptually and structurally dissimilar (4-cyclohexylcyclohexanone [4-CHCH] and androstenone). These findings indicate that the role of similarity in cross-adaptation is difficult to quantify and emphasize the numerous odorant characteristics that can affect cross-adaptation.

Two experiments examined the chemosensory modalities by which males detect an ephemeral sex pheromone in the freshly voided urine of female mice. Experiment 1 examined the interaction of deafferenting the accessory olfactory system (vomeronasal organ removal) and subsequent sexual experience upon ultrasonic vocalizations by male mice to freshly voided female urine. In general, sexually experienced males vocalized substantially more than sexually naive males. In addition, males possessing a vomeronasal organ vocalized slightly more than those without. Nonetheless, a functioning vomeronasal organ clearly was not essential for vocalizing to fresh female urine. Experiment 2 examined the effects of deafferenting the main olfactory system (ZnSO4 nasal irrigation) and/or the accessory olfactory system (vomeronasal removal) in sexually experienced males. Males with both olfactory systems functioning vocalized at high levels to fresh urine, while males with only one functioning system vocalized at intermediate levels. Males with neither system functioning did not vocalize at all to fresh urine. In contrast, when female mice themselves served as stimuli, all groups of males vocalized at high levels. We conclude that adult male mice can detect the ephemeral pheromone via either the main olfactory system or the accessory olfactory system. However, vocalizations to the female herself can be mediated by other sensory systems as well.

Cross-adaptation has been interpreted as a measure of the degree to which odors share common sensory channels. How structural similarity, in the absence of perceptual similarity, influences cross-adaptation is unknown. The present study assessed cross-adaptation by structurally similar, but perceptually different, odorants. Magnitude estimates for a 10:1 mixture of (E)- and (Z)-3-methyl-2-hexenoic acid (3M2H), a principal component of human underarm odor, decreased following adaptation to a mixture of (E)- and (Z)-ethyl esters of 3M2H (EE3M2H), which possess a pleasant, fruity odor. Cross-adaptation was asymmetric; adaptation to 3M2H did not significantly affect the perceived intensity of EE3M2H. By contrast, there was no significant cross-adaptation between 3M2H and the fruity-smelling ethyl esters of its homologues, 3-methyl-2-octenoic acid (EE3M20) and 3-methyl-2-pentenoic acid (EE3M2P). Similarity ratings revealed no differences among the three ethyl esters in their perceptual similarity to 3M2H (i.e. all were rated equally dissimilar to 3M2H). Molecular modeling studies revealed no difference in the charge distribution of these molecules. Rather, differences in the shape and size of the hydrophobic part of the molecule may determine the extent of cross-adaptation. These results demonstrate that structurally-similar, yet perceptually-distinct, odorants may cross-adapt and suggest that the extent of cross-adaptation may be affected by the degree of structural, as well as perceptual, similarity.

Alterations of chemosensory function have been noted in human immunodeficiency virus (HIV)-infected patients, but their frequency, severity, and relationship to diet have not been adequately assessed. Odor and taste identification tests and a taste-intensity scaling task were administered to 25 men who were HIV-infected but otherwise healthy. Responses were compared to those of 49 comparably aged male control subjects. Dietary information was obtained by questionnaire. Although 72% of HIV-infected patients reported some chemosensory alteration, no significant differences in taste identification ability or intensity ratings were observed between patients and controls. Twelve percent of patients had poor odor identification scores, but the group mean was similar to that of controls. Neither measured nor self-reported sensory indices were significantly related to any variable of health (e.g., HIV helper cell (CD4) count, body weight, or body composition), treatment, or diet.

During individually administered 5-min tests conducted in a neutral cage, four age groups (n = 10 males and 10 females per group) of purebred beagles reacted to bedding from their home cage vs. bedding from another litter of the same age. The 20-24-day-old males and females preferred (p < 0.05) home cage bedding over strange cage bedding. Those aged 31-36 days or 66-72 days showed no reliable preference for either type of bedding. Among pups aged 52-56 days, the males preferred (p < 0.05) strange cage bedding, but the females showed no reliable preference. Chemosensory cues are sufficient as mediators of kin recognition in beagles, but their reactions to such cues vary with age-dependent factors, some stemming from changes in the strength of the mother-litter bond. The dogs providing the two types of bedding lived in the same room and on the same diet. Therefore, kin recognition could not have been mediated by different chemosensory cues produced by variations in these environmental factors.

Repeated exposure to olfactory ligands (odorants) increased peripheral olfactory sensitivity in mice. For two unrelated ligands, androstenone and isovaleric acid, induction of olfactory sensitivity was odorant-specific and occurred only in inbred strains that initially had low sensitivity to the exposure odorant. These data demonstrate stimulus-induced plasticity in a sensory receptor cell, suggesting a form of stimulus-controlled gene expression. Induction with two unrelated odorants implies that olfactory induction is a general phenomenon that may occur in a large fraction of the human population.

An odor description task was used to explore age-related change in odor perception based on 1.19 million U.S. and Canadian respondents (ages 10-90 years) to the National Geographic Smell Survey. Respondents sampled six microencapsulated odorants and selected 1 of 11 descriptors to characterize each smell. Four odors were characterized by strong consensus endorsement of a single descriptor. This consensus weakened with advancing age, and nonmodal descriptors were endorsed more frequently. Nonmodal responses were neither randomly selected, nor systematically biased across odors. Rather, they showed odor-specific patterns of change. Together, these results suggest a marked change in odor categorization across the life span. Odor descriptor profiles were used to generate age-specific multidimensional scaling maps. Stimulus configurations were stable from the third through fifth decades. Those from the sixth through ninth decades showed major displacements for two odors, and suggest that the sweet dimension of odor quality may be particularly variable with maturation.

Olfaction plays a significant role in the perception of foods. For the most part, taste is limited to sweet, sour, bitter, and salty. The sensory experiences during consumption of complex foods and drinks cannot be constructed from these units. Indeed, much of the taste of a meal derives from olfactory stimulation. Hence, factors that influence olfactory perception should affect treatment of food-related odors. This article initially reviews previously published observations on the effects of age on olfaction and food preferences and then presents the results of original analyses of data derived from a substantial database formed as a result of the National Geographic Smell Survey. Included in the Survey form were topics relevant to the present article. They include the following question: Would you eat something that smelled like this? Two of the odors in the Survey were food related and two were fragrance related. Hence, in addition, we assessed responses to the following question: Would you apply something that smelled like this to your body? Answers were affected in part by the age and gender of the respondent and by the perceived pleasantness and intensity of the odor.

A survey of 1,177,507 U.S. men and women between the ages of 10 and 86 included questions regarding hand preference for writing and throwing. Three effects were observed. Individuals with at least some left motoric bias comprised a smaller percent of the population with advancing age. This finding provides large-scale confirmation of a previously described phenomenon. Among sinistrals, concordance for writing and throwing was 2.2 times as prevalent as left-writing with right-throwing, and 4.1 times as prevalent as right-writing with left-throwing. These sinistral subpopulations displayed distinct and stable prevalence prior to age 50 and changing patterns of prevalence subsequent to age 50. The results confirm a decrease with age in the prevalence of sinistrality, but indicate that age-specific rates of mixed- and left-handedness are distinct. The implications for hypotheses regarding age-related change in the prevalence of sinistrality are discussed.

Results of the National Geographic Smell Survey were used to investigate the effects of pregnancy on olfactory perception and odor-related behavior. The responses to test odors and survey questions of 13,610 pregnant and 277,228 nonpregnant U.S. women between 20 and 40 years of age were analyzed. In comparison to nonpregnant women, pregnant women rated their own sense of smell lower, more often rated the test odors less pleasant smelling, more often classified the test odors as inedible, were less likely to report odor-evoked memories, and used perfume and cologne less frequently. Differences in odor detection and intensity rating did not favor either group.

Chemical cues from male voles activate reproduction in female prairie voles (Microtus ochrogaster). Twelve hours of contact with a male, followed by exposure to his soiled bedding for 2 days, is sufficient to initiate follicular maturation and induce uterine hypertrophy. Our recent work indicates that the chemosensory vomeronasal organ (VNO) can mediate this response. Here, we examined whether other sensory systems can acquire the ability to activate female reproduction as a result of learning or experience. To explore this issue, the VNO was removed (VNX) from nulliparous and primiparous females who were then exposed to cues from males. In Experiment 1, we found that nulliparous VNX females had lower uterine and ovarian weights than did sham-operated females. In Experiment 2, we determined that sexual experience did not ameliorate the reproductive deficits normally induced by VNX. The present results contrast with those of previous studies suggesting that males of some rodent species, when allowed reproductive experience prior to VNX, can utilize other sensory systems to mediate subsequent reproductive responses. We conclude that the role of the VNO in transducing chemosensory information is crucial for coordinating the reproductive efforts of male and female prairie voles.

In the last decade, research in our laboratories has focused on the effects of deafferentation of the mammalian chemosensory vomeronasal organ (VNX). Many different assays have been conducted and the results of some are briefly reviewed in this contribution, including the effects of VNX on neuroanatomical assessments using histochemistry (lectin binding) and immunohistochemistry (LHRH), male mouse and prairie vole ultrasonic vocalizations and hormone surges in response to cues from females, male mouse courtship and sexual behavior, territorial marking and inter-male aggression, the production of a puberty-altering substance found in mice, activation of reproduction in female voles (who generally do not exhibit estrous cycles) and maternal behaviors by female mice, including aggression directed toward intruder males. In some instances, the otherwise detrimental effects of VNX can be overcome by experience prior to deafferentation, especially in assays that are dependent upon expressions of behavior. In other situations, experience may have little impact on amelioration of the effects of VNX. The essential conclusions of this work focus our attention on reproductive physiology and behavior and a role for the vomeronasal organ in the perception of pheromones that modulate these functions.