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70 THE ANATOMICAL RECORD (NEW ANAT.)
FEATURE ARTICLE
Biology of Taste Buds and the Clinical Problem
of Taste Loss
GINA M. NELSON
Taste buds are the anatomical structures that mediate the sense of taste. They comprise taste cells and nerve fibers
within specialized epithelial structures. Taste cells are traditionally described by histologic methods as basal, dark,
intermediate, and light cells, with the nerve fibers surrounding and infiltrating the taste buds. By means of
immunohistochemical methods, taste cells and gustatory nerve fibers can be classified in functional groups based on
the expression of various cell adhesion molecules and other proteins. When taste buds become damaged, the loss of
the ability to taste results. This loss is not uncommon and can impact health and quality of life. Patients who receive
radiation therapy for head and neck cancer often experience taste loss, which leads to compromised nutritional intake
and a worse outcome than patients who do not experience taste loss. The mode of radiation damage to taste cells and
nerve fibers has been investigated using cell adhesion molecules, synaptic vesicle proteins, and other cell markers.
The light and intermediate cells are preferentially affected by ionizing radiation, whereas the nerve fibers remain
structurally intact. Experimental studies of radiation-induced taste loss are performed via a unique animal/human
model. Anat. Rec. (New Anat.) 253:70–78, 1998. r 1998 Wiley-Liss, Inc.
KEY WORDS: taste buds; taste loss; head/neck cancer; radiation therapy; radiation model; cancer therapy
WHAT MAKES UP THE SENSE
OF TASTE?
Of the five senses, taste is the sense
which is least thought about by most
people. Unlike the senses of vision and
hearing, taste does not have much
impact on our day-to-day life—or does
it? Taste buds play a greater role in our
lives than we might imagine. In combination with our sense of smell, we are
able to enjoy the aroma and taste of
our food and drink. More importantly,
we recognize spoiled food, if not by
the smell then by the terrible taste. For
our ancestors more than for modern
humans, taste warned of poisonous
Dr. Nelson has long had an interest in
chemoreceptive sciences, beginning
with invertebrate chemoreception. She
has an MD and PhD from the University
of Colorado Health Sciences Center,
where she developed an animal model
of radiation-induced taste loss. Dr. Nelson is currently a resident in anatomic
pathology at the University of Iowa Hospitals and Clinics and plans to continue
work on the animal model and human
studies in taste loss through the Department of Anatomy and Cell Biology after
residency.
r 1998 Wiley-Liss, Inc.
plants, as they have a very bitter taste
due to the presence of various alkaloid
compounds.
What happens when our sense of
taste goes awry? The understanding of
the mechanisms of vision and hearing
is far ahead of the understanding of
the mechanisms of taste. Glasses and
artificial lenses are available to correct
vision deficits, and hearing aids are
available for those with diminished
hearing, but what corrective aids are
available for the loss of taste? Have
you ever known a person, a relative or
a friend perhaps, who cannot taste?
What is the world of taste like for that
person? What causes taste loss? Is the
ability to taste affected by illness or by
therapies designed to treat these illnesses?
WHERE ARE MY TASTE BUDS?
Taste buds are the anatomical structures which contain the receptor cells
that mediate the sense of taste. Taste
buds are found in the oral cavity, primarily on the tongue but also on the
palate, back of the mouth, pharynx,
epiglottis, and larynx. The tongue (Fig.
1) is covered with numerous papillae
which come in four varieties. Filliform
papillae are the most numerous and
appear as short, rough structures covered with thick keratinized epithelium
(they feel particularly rough on a cat’s
tongue). They do not contain taste
buds. The fungiform papillae are dispersed across the surface of the tongue.
They are more box-like, with a connective tissue core and a thin covering of
epithelium. Most of the fungiform papillae contain a single taste bud on the
tip. The larger circumvallate papillae
are located on the posterior aspect of
the dorsal surface, appearing as pincushions with a surrounding trough,
called a crypt. The crypt is lined by an
epithelium, called the gustatory epithelium, which contains several taste buds.
The pores of the taste buds open into
the crypt. In humans there are 12–15
circumvallate papillae, but in rodents
(as in mice or rats) there is only one.
Foliate papillae lie on the lateral sides
of the tongue and appear like slits.
These are less developed in rats and
humans than they are in other species.
Each taste bud is oval (Fig. 2) and
opens to the epithelial surface via a
small opening called a taste pore. From
REVIEW
THE ANATOMICAL RECORD (NEW ANAT.) 71
Fig. 1. Dorsal surface of tongue. Pictured is the upper surface of the tongue showing the
location of the pincushion–shaped circumvallate papillae on the very back of the tongue and
the fungiform papillae over the surface between the circumvallate papillae and the tip of the
tongue.
this pore protrudes the microvilli arising from the tips of the individual
taste cells. Each taste bud contains
50–100 taste receptor cells and support cells. Taste cells are described as
basal, dark, intermediate, and light,
based on electron microscopic characteristics1 (Fig. 2). The basal cells are at
the base of the taste bud and constitute a proliferative population of cells.
They divide to produce postmitotic
light, intermediate, and dark taste cells
with a life span of 10–11 days. Dark
cells are defined by a dark cytoplasm
(electron-dense), dense-core granules
(small vesicles with a dark center) at
the tip of the cell, indentations in the
nuclear membrane, and collections of
heterochromatin (the DNA) along the
inner edge of the nucleus. Light cells
are characterized by a light cytoplasm
(electron-lucent), clear vesicles and mitochondria in the tip of the cell, and a
round to oval nucleus with less heterochromatin (DNA) along the inner edge.
Intermediate cells have characteristics
that are intermediate between the light
*Authors vary in their use of the different systems of nomenclature. While
some correlations have been made
between the two systems, they are not
totally equivalent. The information
here is given in relation to the article
in which it was originally presented,
maintaining the system by which it
was described.
and dark cells. Which taste cell type is
actually the receptor has not been
proven, although every type has been
proposed. Taste cells have also been
designated as Type I, II, III, and IV,
with Type I being similar to dark cells,
Type II similar to light cells, and Type
IV being the basal cells. In this schema,
the Type III cells are like intermediate
cells and are thought to be the gustatory receptor cells,2 primarily due to
the presence of what are believed to be
afferent synaptic contacts* (afferent 5
nerve fibers carrying information to
the brain). The dense-core vesicles are
located in dark cells and to a lesser
extent in intermediate cells1 in association with both the tip of the cells and
the presynaptic regions. These vesicles
are thought to contain serotonin.3
Fungiform taste buds are innervated by the chorda tympani branch of
cranial nerve VII, while the circumvallate taste buds are innervated by cranial nerve IX. Taste buds in the pharynx are innervated by cranial nerve X.
In the region of the taste buds, nerve
fibers are described by anatomical location (refer to Fig. 2). The subepithelial plexus are the nerve fibers in the
connective tissue beneath the gustatory epithelium (the epithelium containing the taste buds). The basal
plexus nerve fibers are in the basal
portion of each bud, forming a kind of
a nest around the basal cells. Intragemmal fibers are those within the taste
bud, and perigemmal fibers are those
around the taste bud. The intragemmal nerve fibers are the nerve fibers
which receive synaptic contacts from
all three types of taste cells.4 While the
perigemmal fibers are generally
thought to be outside of the taste bud,
some perigemmal nerve fibers enter
the taste bud from the side. Some
perigemmal nerve fibers reach the surface of the epithelium; others reach
around the taste pore. In addition,
both Type II and III cells form two
types of synaptic contacts with the
intragemmal nerve fibers, thought to
represent efferent (efferent 5 nerve
fibers carrying information from the
brain) and afferent synaptic contacts.5
It has been proposed that the substance P–containing fibers within the
taste bud may mediate oral pain.6
A nutritional, or trophic, interaction
(i.e., one cell emits a substance that a
second cell needs to grow) between
the nerve fiber and taste buds exists.
Interruption of the nerve fiber by either cut or crush injury results in the
Taste buds play a greater
role in our lives than we
might imagine.
disappearance of the taste buds (Fig.
3). If the nerve fiber is allowed to grow
back, the taste buds will reappear. This
indicates that there is an unknown
molecule originating from the nerve
fiber that is required for the taste buds
to retain their form. The mechanisms
of sensory transduction of various taste
stimuli across the taste cell membrane
is a topic worthy of its own review, and
the reader is referred to excellent papers on this topic.7
ANATOMICAL CONCEPTS BASED
ON CELL MARKERS
Until recently, the elements of the taste
system have been described anatomically and histologically. An alternative
method is to describe the components
of the taste system based on their
function, which makes sense biologically. By comparison, vision receptors
are the rods and cones, and the vestibular and cochlear nerves transmit specific sensory information in the ear.
72 THE ANATOMICAL RECORD (NEW ANAT.)
REVIEW
Fig. 2. Schematic of a normal taste bud. All of the elements of a taste bud are illustrated. The taste bud contains basal cells (B) in the lower
portion of the bud and all three types of taste cells extending upward to the opening at the top, the taste pore. The light cells (L), intermediate
cells (I), and dark cells (D) are pictured with some of the features that characterize each cell type. In addition, the intragemmal and perigemmal
nerve fibers are seen. The nerve fibers are present in the subepithelial connective tissue and enter each bud from the base. The red fibers
represent the nerve fibers which contain synaptic vesicle proteins, and the black fibers represent nerve fibers which contain peptides. S,
synapse.
Fig. 3. Damage to the taste bud following nerve injury. After crushing or cutting the nerve (e.g., glossopharyngeal) that innervates the taste
buds, the taste buds degenerate. Small, atrophic buds remain, as seen in the illustration. If the nerve fiber regenerates, the taste buds will grow
back.
REVIEW
THE ANATOMICAL RECORD (NEW ANAT.) 73
Fig. 4. The technique of immunohistochemistry. The protein of interest (pentagon in the
illustration), termed the antigen, is isolated and purified and then injected into the host mouse.
The mouse’s immune system sees the antigen as a foreign molecule and makes antibodies
against it. The antibodies are then taken from the mouse’s serum. A thin piece of tissue from a
second animal is put on a glass slide, and the antibody is applied to it. The antibody will
recognize the antigen in the tissue (the pentagon) and stick to it. In order to visualize where the
antibody is located, a secondary antibody is applied which recognizes the first. The secondary
antibody has a tag on the end (star) which can be seen in a microscope equipped for
fluorescence microscopy.
These descriptors are related to the
function of the anatomical structure.
It would be logical to take the same
approach for the sense of taste and
designate a salt receptor or a bittertaste fiber. However, the details are not
known at a sufficient level to always
determine the functional designations.
Investigators in many laboratories are
improving on the knowledge of the
taste system, so this descriptive system may be realized in the future.
One way to approach this is to identify groups of taste cells or nerve fibers
based on the expression of a particular
protein. With a technique called immunohistochemistry, an antibody is made
which recognizes a particular protein—for example, protein X (Fig. 4).
Simply, an amount of protein X is
injected into a mouse, the host animal.
The immune system of the host generates antibodies directed against protein X. The serum is removed from the
animal, and the new anti-X antibodies
are purified. Thin sections of tissue
from the animal being investigated
(usually not a mouse) are put on slides,
and the anti-X antibodies are added.
The antibodies attach to the X molecules in the tissue. Then a secondary
antibody with a fluorescent tag is attached to the first antibody. A microscope equipped to view the fluorescent
tag is then used to visualize where the
anti-X antibodies attached. The correlation can be made that protein X
resides in the location where fluorescent patterns are seen.
The markers used to identify cells
and nerve fibers can be cell surface
molecules, neurotransmitters, structural proteins, synaptic vesicle proteins, peptides, blood group markers,
enzymes, lectins, or many other types
of proteins. The identification of a
group of taste cells or nerve fibers that
share a given histochemical property
suggests that these cells or nerve fibers
have a common biological characteristic which may be more closely related
to a common function. Taste cells or
nerve fibers classified in this manner
can be studied in various experimental
situations. Often the expression of a
particular protein is found primarily
in a histologically designated type of
taste cell (i.e., light cells), although
only a few of the light cells contain the
protein. Sometimes a few cells from
two groups will express a particular
protein (i.e., a few of the light and
intermediate cells). This suggests that
the histological classifications of light,
intermediate, and dark do not correlate with function.
Examples of various proteins expressed by taste cells include the blood
group antigens,8 the transmembrane
G protein gusducin9 neural cell adhesion molecule (NCAM),10 the calcium
binding protein calbindin,11 and keratins.12 Some are located in specific taste
cell types; others are not. Many other
examples are described in the literature.
Using light and electron microscopic immunohistochemistry, we
demonstrated the presence of NCAM10
and a form of growth associated protein (GAP) in taste cells recognized by
the antibody designated B5013 (Fig. 5).
NCAM appears as smooth, continuous
outlines on long, thin, distinct taste
cells identified as light or intermediate
cells. The B50 antibody produces a
diffuse label throughout taste cells
identified as intermediate or dark cells,
located in the mid to apical portion of
the taste bud. These cells appear different from the thin, elongated cells labeled by the NCAM antibody. Not all
of the intermediate and dark cells label. Experiments with NCAM and B50
together indicate that these proteins
occur on separate populations of taste
cells. No cell in normal taste buds ever
showed reactivity to both of these antibodies together.
ANATOMICAL CONCEPTS BASED
ON NERVE FIBER MARKERS
Nerve fibers can also be described in a
similar fashion. In the construct of a
sensory system, there are nerve fibers
to bring the signal of the perceived
stimulus to the brain (the nerve fibers
which are postsynaptic to the taste
cells, the afferent fibers) and nerve
fibers to bring modulating information to the sensory cells (efferent fibers). There may also be nerve fibers
74 THE ANATOMICAL RECORD (NEW ANAT.)
REVIEW
Fig. 5. Taste bud with antibody-labeled taste cells. After application of an antibody which recognizes NCAM, some of the light to intermediate
taste cells appear bright, having a long, thin outline (taste cells with white dots in illustration). The application of the B50 antibody labels some of
the dark cells with a more diffuse pattern (bright taste cell without dot). In this example, the nerve fibers are not labeled.
Fig. 6. The effects of radiation on taste buds. At the peak of radiation damage (approximately 7 days), some of the light to intermediate taste
cells are degenerating, but the dark cells and all subtypes of nerve fibers remain intact. The nerve fibers containing synaptic vesicle proteins
(red) and the nerve fibers containing peptides (black) remain as they were in the normal taste bud. The overall pattern of degeneration is
different than that seen in the taste buds affected by nerve cut (refer to Fig. 3).
REVIEW
to carry visceral information (hot, cold,
pain, etc.) which may or may not be
located within the taste bud. In an
effort to identify these various types of
nerve fibers, much like the taste cells,
immunohistochemical techniques
were utilized to demonstrate that different nerve fibers express different
proteins. For example, many perigemmal fibers contain the peptide substance P, while others contain calcitonin gene-related peptide (CGRP). The
intragemmal nerve fibers contain synaptic vesicle proteins, like synaptophysin.14 (Of note, even though all of the
types of taste cells, light, intermediate,
and dark, make synaptic contacts with
the intragemmal nerve fibers,4 none of
the synaptic vesicle proteins to date
have been found to label the presynaptic vesicles located within the taste
cells).
Numerous basal plexus nerve fibers
and nerve fibers in the dermis or in the
core of the fungiform papillae also
contain the synaptic vesicle proteins
and peptides. Electron micrographs
show that small vesicles within these
nerve processes, measuring 40–60 nm
in diameter, are the same size as the
vesicles described as containing the
synaptic vesicle proteins in other locations. The nerve fibers that label with
synaptic vesicle proteins are postsynaptic to some taste cells.14 All of the
nerve fibers, both intragemmal and
perigemmal, can be identified with
proteins common to most neurons,
like protein gene product 9.5 (PGP
9.5) and S100.15
When the synaptic vesicle proteincontaining nerve fibers are compared
with those containing peptides or PGP
9.5 using double labeled fluorescence
immunohistochemistry, the two types
of nerve fibers are not distinct groups,
and the location of the proteins does
not correlate exactly with the anatomical classifications. The nerve fibers
containing synaptophysin have a small
subset that also contain CGRP. There
are occasional intragemmal nerve fibers that contain CGRP only. Most
perigemmal nerve fibers show labeling
with either synaptophysin or CGRP.
Analysis of SV2 (another synaptic
vesicle protein16) and CGRP gives
slightly different results. For both the
intragemmal and perigemmal nerve
fibers, there is a group of fibers that
contain both proteins, and there is a
THE ANATOMICAL RECORD (NEW ANAT.) 75
group of fibers that contain SV2 only
and CGRP only. All synaptophysin
nerve fibers are also PGP 9.5 nerve
fibers, but the reverse is not true. Even
though there is some overlap in the
described categories of gustatory nerve
fibers, the results of examining the
distribution of these proteins in the
gustatory nerve fibers allows their division into functional groups: postsynaptic intragemmal (labeled with synaptic
vesicle proteins), nonpostsynaptic intragemmal (labeled with peptides),
perigemmal (labeled with peptides),
and nerve fibers around the taste pore
(labeled with SV2). This gives us a tool
to follow what happens to these categories of nerve fibers during experimental manipulation, as described below.
TASTE LOSS IN HUMANS
While not discussed widely in the biochemical literature, ageusia (taste loss)
and hypogeusia (decrease in taste) and
dysgeusia (abnormal taste) are widespread and associated with a variety of
illnesses, from common to obscure.
Taste loss occurs as a natural phenomenon of aging and also in response to
normal changes such as pregnancy
and menopause.17 Poor dentition and
hygiene are common oral conditions
that affect taste. Patients with xerostomia (dry mouth), Sjögren syndrome
(inflammation of the salivary glands
resulting in a dry mouth), and zinc
deficiency may also experience taste
loss. Other conditions in which taste
loss may occur include liver and kidney disorders, diabetes mellitus, depression, and surgical procedures
around the chorda tympani or glossopharyngeal nerve. Patients with head
trauma and epilepsy may also experience taste loss. Taste loss can range
from mild to severe, resulting in subsequent decrease in nutritional intake.
(Many investigators contributed to the
accumulation of this knowledge. The
reader is referred to the many chapters that cover these topics in more
detail in Getchell et al.18)
Various types of therapy can also
induce taste loss. Numerous drugs are
associated with taste loss. However, an
incomplete understanding of how the
taste system works and the interaction
of drug compounds with the taste
system make it difficult to assign the
taste loss to a drug alone. One cannot
rule out that the taste loss is caused by
the underlying disease process. Most
of the drugs associated with taste loss
affect the turnover of cells, as is seen
in other systems, but other mechanisms are possible. Drugs usually induce a temporary effect which diminishes after the drug is discontinued.
Chemotherapy employs drugs associated with taste loss. A few examples
include methotrexate and dexamethasone, antihypertensives, antimicrobial
agents, and antiproliferative agents.18
RADIATION THERAPY–INDUCED
TASTE LOSS
Radiation is often used either alone or
in addition to surgery to treat various
types of cancers. The typical dose for
patients with head and neck cancer or
oral cancer is 5,000–7,000 cGy. (A centiGrey (cGy) is the deposition of 1 erg
of energy per 100 g of tissue.) It is
administered in divided doses of about
180 cGy/week until the desired dose is
achieved. Radiation is composed of
charged particles that disrupt the electron orbital structure of the atoms in
the tissue, causing tissue destruction.19 The theory behind the therapy
is to disrupt the proliferative capacity
of the tumor, thus destroying it, while
doing as little damage as possible to
the normal tissue. Since the tissue
lining the mouth and the gastrointestinal tract divides at a faster rate than
tissues of other organs (e.g., liver),
they are more susceptible to radiation
damage. The resulting side effects to
the oral cavity include mucositis (swelling and tenderness of the oral mucosa
with sloughing off of dead cells), xerostomia, and taste loss.
Of particular interest is the taste
loss that occurs with the administration of radiation therapy, termed postirradiation gustatory dysfunction. It
occurs following administration of radiation to the region of the oral cavity
and thus the taste buds. In some patients, the taste loss can be severe. The
loss of taste has been reported in the
literature only as case reports and as
occasional small studies. The loss of
taste due to radiation therapy is a
common problem which is underrepresented in the literature. In patients
who lose their sense of taste, one result is a marked decrease in the ability
to eat and thus a decrease in nutrition
REVIEW
76 THE ANATOMICAL RECORD (NEW ANAT.)
intake. These patients experience
greater weight loss than those patients
who do not report a change in taste,20
and it has been well documented that
these patients have a worse outcome
than the patients who do not lose their
sense of taste and are able to maintain
their food intake and nutritional support.21 Nutritional supplements have
been shown to positively impact cancer therapy when administered in addition to the therapy for the disease.22
The changes in the taste thresholds
for all tastes (sweet, sour, bitter, salty)
varies among treated patients. Quinine taste (bitter) is most consistently
lost, but the loss of sugar and salt taste
varies considerably among patients.
Decreases in taste thresholds begin
from treatment with as little as 200–
400 cGy.23 Also, a discrepancy is noted
between the speed with which taste
sensation is lost and the deterioration
of the taste cells. The taste buds degenerate 6–7 days after irradiation, but
taste alteration is seen as early as 2–3
days after irradiation. In mice, following a single radiation dose between
1,000 and 4,000 cGy, taste buds are
either entirely destroyed or, if they
remain, lose 30–50% of their cells. The
taste bud degeneration peaks at 9 days
after injury, and then the taste buds
begin to regenerate.24 In another
study,25 single doses of 850 cGy cause
a smaller number of taste buds to
degenerate, and recovery begins
sooner. At a single dose of 2,200 cGy,
the taste buds degenerate much faster.
This illustrates that the number of
taste buds that degenerate is related to
the size of the dose. When permanent
damage occurs, it is usually with accumulated doses exceeding 6,000 cGy.
Long-term effects include lowered
taste detection and threshold levels as
well as xerostomia. The maximum tolerance dose giving a 50% complication rate is approximately 4,000–6,500
cGy for xerostomia and 5,000–6,500
cGy for taste loss.26 The loss of taste
does not vary by type of radiation (i.e.
neutron vs. photon radiation).27
Radiation affects elements of cells
that cannot easily be repaired or replaced, namely the DNA. As a consequence, proliferative cells are most
sensitive to the effects of radiation.
Inside the taste buds are the nondividing nerve fibers and a proliferative
population of taste cells. This suggests
two possible sites of radiation damage
leading to taste loss: (1) the intragemmal nerve fibers and (2) the taste cells.
If the nerve fibers are the site of damage, one possibility could be a significant physical loss in the population of
postsynaptic intragemmal nerve fibers. Since the neurons are a nondividing population of cells, they are
thought to be generally radioresistant.
However, disruption of the functional
integrity of the neuron could lead to
the symptom of taste loss. Synaptic
uncoupling or disruption of membrane integrity leading to a disruption
in the contact between the taste cells
and nerve fibers, resulting in the inability to conduct action potentials, is a
possibility. A similar finding was demonstrated in the disruption of neuromuscular junctions in mouse tongues
following a single dose of radiation.28
Other investigators have actually proposed the nerve fiber as the site of
damage leading to taste loss but mostly
incidentally.24,25
Radiation affects
elements of cells that
cannot easily be
repaired or replaced,
namely the DNA.
The second possible site of damage
is the taste cells. Previously it has been
demonstrated that following irradiation the cells within the taste bud lose
their characteristic histological appearances (light, intermediate, and dark)
and all appear as intermediate cells.25
The disruption of the proliferative capacity of the taste cells would cause
stem cells to stop dividing, and, once
the current receptors die off, no new
ones would be there to replace them.
This would be experienced as a loss of
taste. It does not, however, account for
the changes in taste measured at 2–3
days following irradiation in both animals and humans. This is more likely
to be a disruption of the current receptor cells, possibly via membrane damage causing loss of structural integrity,
or loss of the synaptic contacts. Other
possibilities suggested include radiation-induced changes in metabolism,
possibly associated to depleted zinc
stores.20
In an attempt to test these various
hypotheses, the projects described
herein use a novel approach of combining histological evaluation with behavioral assessment in an effective model
of radiation-induced taste loss in rats,
as well as extending the studies to
human cancer patients receiving radiation therapy. In this model, hypotheses about the function of taste cells
and nerve fibers can be formulated
based on quantitative behavioral data.
The tool we have designed to direct
the radiation to the surface of the
tongue results in a method of radiation which eliminates the problematic
side effects encountered with conventional radiation, typically mucositis
and xerostomia. In addition, the labels
for the various subpopulations of taste
cells and nerve fibers make it possible
to follow what happens to each of
these components of the taste system
following radiation. The eventual goal
of this model is to understand the
biological mechanisms underlying radiation-induced taste loss so that methods to prevent taste loss can be developed and thus improve the quality of
life and treatment outcome of these
cancer patients.
RADIATION-INDUCED TASTE LOSS
IN ANIMALS
In studies described previously,29 the
effects of radiation on the taste system
were examined in rats given a single
dose (1,700 cGy) of radiation to the
oral cavity. Behavioral measurements
were made based on the consumption
of either a 1.8% NaCl (salt) solution
or a quinine-HCl (bitter) solution
and correlated with the histological
changes in two groups of nerve fibers
and two groups of taste cells at various
time points after radiation. The nerve
fibers followed were labeled with either synaptophysin or CGRP, and the
taste cells followed were labeled with
either NCAM antibodies or B50.
Briefly, following irradiation, two
changes in the consumption of 1.8%
NaCl are noted: (1) a decrease in the
total volume of fluid consumed and (2)
an increase in the amount of NaCl
consumed. Both of these changes begin to occur on day 4 (day 0 is the day
the animals received radiation), peak
REVIEW
at days 7–8, and return to preirradiation levels by day 11. The statistical
analysis showed no significant difference prior to radiation between the
two groups of animals (experimental
and control). Following irradiation, a
significant difference was seen for the
NaCl consumption on days 7 and 8.
Following the dose of radiation, the
distribution of the nerve fibers labeled
with synaptophysin or CGRP does not
change. However, the NCAM-labeled
cells show a dramatic change in appearance. At 6 days, the NCAM cells
appear normal, with one or possibly
two cells demonstrating label only in
small patches. At day 7 there is a
dramatic change. Only rare, abnormalappearing cells labeled with NCAM
remain. Also, the rare cells with any
NCAM are also immunoreactive with
the GAP antibody B50. The normal
pattern of NCAM labeling begins to
return at 11 days, and NCAM-labeled
cells are more numerous by 16 days.
The change in the pattern of labeling for antibody B50 is different from
that observed for NCAM. Unlike NCAM
antibody labeling, B50 labeling retains
its normal pattern until 11 days. At
this time, the B50-labeled cells begin
to appear irregular in shape and remain so throughout 21 days. Again,
the two proteins begin to appear in the
same taste cells at day 7.
These findings, which are summarized in Figure 6, indicate that changes
in taste acuity do indeed occur and
can be measured effectively and correlated with histological changes. The
loss of the NCAM-labeled taste cells
correlates with the noted changes in
consumption of 1.8% NaCl. However,
the B50-labeled cells remains intact.
This suggests that NCAM-labeled cells
could be NaCl receptors, while the
B50-labeled cells are not. Clearly the
division of these two groups of taste
cells is altered by the radiation when
the two proteins begin to colocalize.
The biology of the cells is altered by
the radiation, but its meaning is not
yet understood.
CAN TASTE LOSS BE TREATED?
Two questions arise naturally out of
these findings. Can the same type of
behavioral and histological measurements be done in humans? And how
THE ANATOMICAL RECORD (NEW ANAT.) 77
will this information impact taste loss
in human cancer patients? Psychophysical measurements of taste acuity
and taste thresholds have been reviewed extensively in the literature
(see Bartoshuk30) Detection thresholds are stable over time (M. Linschoten, personal communication) and can
be measured using a two alternative
forced choice procedure.31 The premise is to offer the subject two solutions (one water, one containing a
tastant) to taste, and the subject
chooses which one has a taste different from water. When the patient cannot distinguish between correct and
incorrect for a given tastant concentration, the patient is believed to be at his
or her threshold for that tastant. As
patients receive radiation or chemotherapy, the changes that occur in the
taste thresholds of any or all of the
four tastants (sweet, sour, bitter, salty)
can be followed. It is even possible to
monitor the recovery, or lack thereof,
of taste thresholds in these patients
over long periods of time.
The purpose of this entire area of
study is twofold: to improve on the
quality of life of cancer patients receiving radiation therapy and to improve
the outcome of therapy by maximizing the patients’ ability to eat and
maintain nutritional support. Once the
biology of the taste loss is understood—including the degree of taste
loss and what taste qualities are lost—
modifications to the way the patient
receives treatment can be made. One
possibility is to design a diet that
maximizes on the remaining abilities
to taste, resulting in the most palatable diet available to the patient. This
would require individual diet management, depending on the thresholds
that change for that patient. This is
similar to other specialized diets, such
as diabetic diets. Another approach
would be to protect the taste cells from
the radiation damage. A fine balance
has to be made between using enough
radiation to kill the tumor cells and
keeping damage to normal tissue at a
tolerable level. A local application of a
molecular substance in a foam or gel
vehicle applied to the oral mucosa and
tongue to impart a temporary resistance to the penetrating photons may
reduce the damage to taste cells. Such
a compound is only theoretical at the
present.
In summary, radiation-induced taste
loss is a real problem that has a significant effect on the treatment of cancer.
With information gathered from the
animal model and human studies, we
hope to achieve a better understanding of the function of the taste system
and to positively impact the treatment
outcome of cancer patients receiving
radiation therapy.
ACKNOWLEDGMENTS
I would like to thank Drs. Mary J.C.
Hendrix, Richard Lynch, and Thomas
E. Finger for their support and encouragement. Also thanks to Jolene Redvale for review of the manuscript and
especially Ken Nelson for the invaluable assistance with the computer
graphics. The clip art in Figures 1 and
4 was provided by the Corel Corporation.
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