Phermones and ectochromes

Charles J. Wysocki wysocki at
Mon Apr 17 09:03:43 EST 1995

: A friend has made a request of me that I am ill equipped to handle. If
: anyone can be of assistance, I would appreciate it. You can e-mail all
: information to me.

I have taken the liberty to post this response rather than a direct reply 
because there is considerable misunderstanding in the popular press about 
pheromones in general and especially about human chemical communication.

: explanation about pheromones and ectohormones.  Basically I need to know 
: what happens to humans when we smell these scents.  After we inhale, 
: does this stimulus travel to our brains and then to nerve endings?, etc.

In the original definition, a pheromone was a single chemical compound 
or limited set of compounds that, when released by the sender and 
detected by the recipient (of the same species), would elicit a 
stereotypical response each and every time.  Unfortunately, for most 
pheromonal responses, each of the components of the definition have 
fallen by the wayside.  Even for insects, wherein much more is known 
about pheromones than for mammals, the complexity is enormous.  For some 
responses the chemical stimulus is a bouquet, composed of a delicately 
balanced mixture of many compounds.  In other situations, the "pheromone" 
crosses species lines.  For example, the "pheromone" may be released by a 
predator who is sending out a mimic-message -- the sex-attractant of the 
female of the prey species.  The male responds to the amorous message 
only to find itself in the jaws of its prey.  In other situations, there 
may be considerable learning or context specificity, not at all what was 
in mind when the original definition was presented.  Furthermore, there 
is considerable diversity in the type of message/response that can occur. 

In general there are three types of pheromones:  primer, releaser and 

i) A primer pheromone may or may not be "smelled" per se, i.e., recognized
as an odor.  It induces long-term effects, typically as a result of a
neuroendocrine response.  For example, there are situations where expsoure
to the chemical signals of the opposite sex will stimulate the onset of
puberty -- the exposed animal reaches puberty before the unexposed animal. 
In other situations, exposure of a recently inseminated female to the
chemical signals of a strange male will induce pregnancy failure.  In one
species of voles, this can take place as late as a few day away from birth
resulting in a "miscarriage." 

ii) A releaser pheromone is what people generally think of when they hear
the term pheromone.  It is a chemical signal that elicits a recordable
response, e.g. sexual attraction.  There are many examples of releaser
pheromones in the literature; unfortunately, the chemical identity of 
most releaser pheromones in unknown.

iii) The third, and most problematic type of pheromone, is the signalling
pheromone -- chemicals that provide information but do not necessarily
elicit a behavioral response.  For example, among mammals, each individual
(including humans) has a unique odor-print that is, in part, genetically
determined by genes in the major histocompatibility complex (a set of
genes that regulates the immune response).  Odor-prints allow mothers to 
recognize their own baby on the day of birth and for new-borns to 
recognize their mother by scent alone.  Signalling pheromones also 
provide information about social status, e.g., level of dominance in a 
group, diet, gender, age, etc.  Signalling pheromones are informational.

Among humans, NO releaser pheromones have been identified, although there 
have been comercial products that claim the contrary.  There are 
fragrances that possess pheromones of other mammals, e.g., a pig releaser 
pheromone, androstenone or androstenol, that induces sows to assume the 
mating posture if they are in heat.  There are some suggestions that 
humans may have primer pheromones.  Females that live together tend to 
syncronize their menstrual cycles.  Some studies have generated evidence 
that this syncrony may be based in part in chemical communication between 
the females.  There is yet another small group of studies to suggest that 
the chemical cues from males tend to regularize the cycles of females.

: I'm considering writing an article about men's and women's fragrances, and
: how we, as humans, are attracted to these scents.

In the world of pheromones, many primer pheromones are detected via a 
specialized structure in the nose, the vomeronasal organ.  There has been 
a recent resurgence of interest in this structure because of possibility 
that humans may possess this chemosensory organ.  Like olfaction, 
sensory receptors in the nose have specialized receptor proteins on their 
external membrane (in the mucus overlying the sensory sheet).  These 
receptor proteins are most likely analogous to neurotransmitter or 
hormone receptors.  When activated by a ligand, these receptors transduce 
the chemical information into an electrical response that is conveyed 
along the axon of the cell to the respective structure in the brain -- 
the olfactory bulb for olfaction and the accessory olfactory bulb for 
vomeronasal receptors.  

I am going to take this discussion one step further by including 
information that I have posed in this group in the past.  I do this 
because of its relevance to this thread.

--------------------old thread starts here------------

     The terms vomeronasal organ and Jacobson's organ have been used
interchangeably; however, the homology has yet to be demonstrated. 
Throughout many decades of comparative research, it became clear that some
amphibians, most reptiles, and most mammals have a vomeronasal organ
(birds lack this structure -- it is present during embryogenesis but
disappears).  The problems begin to arise when descriptions of primates
became available.  There is no question that New World primates have a
fully developed vomeronasal organ.  Where it has been investigated,
prosimians also have a vomeronasal organ.  Whether Old World primates
possess a vomeronasal organ (and hence an accessory olfactory system in
general) remains wide open for discussion.  One can find as many
references to support the argument that, as adults, Old World primates
lack a vomeronasal organ as references to support the claim that they have
a vomeronasal organ (see Wysocki, C.J. 1979 Neurobehavioral evidence for
the involvement of the vomeronasal system in mammalian reproduction. 
Neuroscience and Biobehavioral Reviews, 3, 301-341).  If Old World
primates have a vomeronasal organ, then it is possible that humans also
have a vomeronasal organ.  If Old World primates lack a vomeronasal organ
and a vomeronasal system one would be hard pressed to generate an argument
that this structure reemerged with the advent of homo sapiens.  If the
former, then Jacobson's Organ may be homologous with the vomeronasal
organ, but there is much comparative work to be done to demonstrate this. 

     It is true that the bipolar receptor cells of animals that have a
well-defined vomeronasal organ project to the accessory olfactory bulb. 
This has NOT been demonstrated for humans or for any other Old World
primate.  As a side issue, the term accessory olfactory is a misnomer.  In
many instances, the accessory olfactory system, with its receptors in the
vomeronasal organ, is primary, i.e., it is the system that is critical in
response to some chemical signals, especially those that affect
reproductive physiology or behavior. 

     Electrical responses, equivalent to generator potentials, have been
recorded from the human Jacobson's organ; however, one should be cautious in
interpreting the origin of these responses.  Furthermore, it is possible
to generate autonomic responses from activation of free nerve endings of
the trigeminal nerve endings of the trigeminal nerve, which innervates the
vomeronasal organ.  As for the reported sexual dimorphism in the
electrical response -- there could be numerous reasons, including
differences in the mucus layer. 

     Another big question that remains unanswered is whether Jacobson's
Organ has a neural connection with the brain that is like that seen in
other species that possess a functional vomeronasal organ.  In the latter,
there exist bipolar receptor cells whose dendrites possess putative
pheromone receptors.  To my knowledge none of these have yet been cloned,
although there are numerous reports of cloned putative olfactory
receptors, e.g.,

Benarie, N.  Lancet, D., Taylor, C., Khen, M., Walker, N., Ledbetter,
D.H., Carrozzo, R., Patel, K., Sheer, D., Lehrach, H. and North, M.A. 
Olfactory receptor gene cluster on human chromosome 17 - possible
duplication of an ancestral receptor repertoire.  Hum. Mol. Genet.
3:22-235, 1994. 

Buck, L. Identification and Analysis of a Multigene Family Encoding
Odorant Receptors - Implications for Mechanisms Underlying Olfactory
Information Processing.  Chem. Senses.  18:203-208, 1993. 

Buck, L. and Axel, R.  A Novel Multigene Family May Encode Odorant
Receptors.  A Molecular Basis for Odor Recognition.  Cell 65:175-187,

Buck, L.B.  Receptor diversity and spatial patterning in the mammalian
olfactory system.  Molecular Basis of Smell and Taste Transduction.  179,

Chess, A., Buck, L., Dowling, M.M., Axel, R. and Ngai, J. Molecular
biology of smell - expression of the multigene family encoding putative
odorant receptors.  Cold Spring Harb. Symp. Quant. Biol. 57505-516: 1992. 

Lancet, D., Benarie, N., Cohen, S., Gat, U., Grossisscroff, R. Hornsaban,
S., Khen, M., Lehrach, H., Natochin, M., North, M., Seidemann, E. and
Walker, N.  Olfactory receptors - transduction, diversity, human
psychophysics and genome analysis.  Molecular Basis of Smell and Taste
Transduction.  179, 1993. 

Lancet, D. Grossisseroff, R., Margalit, T., Seidemann, E. and Benarie, N. 
Olfaction - From Signal Transduction and Termination to Human Genome
Mapping.  Chem. Sense 18:217-225, 1993. 

Margalit, T. and Lancet, D.  Expression of Olfactory Receptor and
Transduction Genes During Rat Development.  Brain Res. Dev. Brain Res.
73:7-16, 1993. 

Ngai, J., Dowling, M.M., Buck, L., Axel, R. and Chess, A.  The Family of
Genes Encoding Odorant Receptors in the Channel Catfish.  Cell. 
73:657-666, 1993. 

Ressler, K.J., Sullivan, S.L. and Buck, L.B.  A zonal organization of
odorant receptor gene expression in the olfactory epithelium.  Cell.  73:
597-609, 1993. 

Parmentier, M., Libert, F., Schurmans, S., Schiffmann, S., Lefort, A.,
Eggericks, D., Ledent, Cl, Mollereau, C., Gerard,C., Perret, J.,
Grootegoed, A. and Vassart, G.  Expression of Members of the Putative
Olfactory Receptor Gene Family in Mammalian Germ Cells.  Nature. 
355:453-455, 1992. 

Schurmans, S., Muscatelli, F., Miot, F., Mattei, M.G., Vassart, G. and
Parmentier, M. The OLFR1 gene encoding the HGMP07c putative olfactory
receptor maps to the 17p13->p12 region of the human genome and reveals an
mspi restriction fragment length polymorphism.  Cytogenet.Cell.Genet. 
63:200-204, 1993. 

Vanderhaeghen, P., Schurmans, S., Vassart, G. and Parmeentier, M. 
Olfactory receptors are displayed on dog mature sperm cells.  J.Cell.Biol. 
123:1441-1452, 1993. 

     Back to the bipolar receptor cell in the vomeronasal organ -- the
cell bodies of the bipolar cells are located along the medial wall of a
lumen within the vomeronasal organ (bilaterally).  The axons of these
cells exit the vomeronasal organ and traverse the nasal septum, cross the
cribriform plate, bypass the main olfactory bulbs and synapse in the
accessory olfactory bulbs.  It is these bipolar cells that many claim are
lacking in the human.  There are two recent papers that address this
issue.  The first,

Takami, S., Getchell, M.L., Chen, Y., Montibloch, LO., Berliner, D.L.,
Stensaas, L.J. and Getchell, T.V.  Vomeronasal epithelial cells of the
adult human express neuron-specific molecules.  Neuroreport.  4:375-378,

purports to have found a few cells that have a bipolar appearance.  The
cells did stain for some epitopes that are associated with neurons, viz.,
neuron-specific enolase and PGP 9.5, but these epitopes also are found on
neuroendocrine cells.  Importantly, the cells did not stain for olfactory
marker protein, which does react with bipolar cells in other species that
have been investigated.  The second

Boehm, N. and Gasser, B.  Sensory receptor-like cells in the human foetal
vomeronasal organ.  Neuroreport.  4:867-870, 1993. 

(since this posting, another paper has appeared -- 
Boehm, B., Roos, J. and Gasser, B.  Luteinizing hormone-releasing hormone 
(LHRH)-expressing cells in the nasal septum of human fetuses.  
Developmental Brain REsearch, 82:175-180, 1994.)

reports the presence of bipolar cells in the early stages of fetal
development; however, staining is not found in the oldest sample,
suggesting that a vomeronasal epithelium is present during embryonic
development but regresses. 

     There is considerable evidence to suggest that humans might respond
to chemical cues that are not detected as a smell or that the responses
are involuntary.  Some of the most recent are those that address some of
the points raised by other contributors to this thread.  They include: 

Schank, J.C. and McClintock, M.K.  A Coupled-Oscillator Model of
Ovarian-Cycle Syncrony Among Female Rats. J. Theor. Biol. 157:317-362,

Weller, A. and Weller, L. Menstrual Synchrony Between Mothers and
Daughters and Between Roommates.  Physiol. Behav. 53:943-949, 1993. 

Weller, A. and Weller, L.  The impact of social interaction factors on
menstrual synchrony in the workplace.  Psychoneuroendocrinology. 
20:21-31, 1995. 

Weller, J. and Weller, A. Human menstrual synchrony - a critical
assessment.  Neurosci. Biobehav. Rev. 17:427-439, 1993. 

and earlier work referenced therein.

Charles J. Wysocki, Ph.D.       wysocki at
Monell Chemical Senses Center   FAX:    215-898-2084
3500 Market Street              Phone:  215-898-4265
Philadelphia, PA  19104-3308    telex:  7106700328

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