Fractionated head and neck irradiation impacts taste progenitors, differentiated taste cells, and Wnt/ß-catenin signaling in adult mice.

Head and neck cancer patients receiving conventional repeated, low dose radiotherapy (fractionated IR) suffer from taste dysfunction that can persist for months and often years after treatment. To understand the mechanisms underlying functional taste loss, we established a fractionated IR mouse model to characterize how taste buds are affected. Following fractionated IR, we found as in our previous study using single dose IR, taste progenitor proliferation was reduced and progenitor cell number declined, leading to interruption in the supply of new taste receptor cells to taste buds. However, in contrast to a single dose of IR, we did not encounter increased progenitor cell death in response to fractionated IR. Instead, fractionated IR induced death of cells within taste buds. Overall, taste buds were smaller and fewer following fractionated IR, and contained fewer differentiated cells. In response to fractionated IR, expression of Wnt pathway genes, Ctnnb1, Tcf7, Lef1 and Lgr5 were reduced concomitantly with reduced progenitor proliferation. However, recovery of Wnt signaling post-IR lagged behind proliferative recovery. Overall, our data suggest carefully timed, local activation of Wnt/ß-catenin signaling may mitigate radiation injury and/or speed recovery of taste cell renewal following fractionated IR.

Effect of Radiation on Sucrose Detection Thresholds of Mice.

Radiotherapy is one of the most common treatments for head and neck cancers, with an almost obligate side effect of altered taste (Conger AD. 1973. Loss and recovery of taste acuity in patients irradiated to the oral cavity. Radiat Res. 53:338-347.). In mice, targeted irradiation of the head and neck causes transient repression of proliferation of basal epithelial cells responsible for taste cell replacement, leading to a temporary depletion of taste sensory cells within taste buds, including Type II taste cells involved in detection of sweet stimuli (Nguyen HM, Reyland ME, Barlow LA. 2012. Mechanisms of taste bud cell loss after head and neck irradiation. J Neurosci. 32:3474-3484.). These findings suggest that irradiation may elevate sucrose detection thresholds, peaking at 7 days postirradiation when loss of Type II cells is greatest. To test this hypothesis, sucrose detection thresholds (concentration detected in 50% of presentations) were measured in mice for 15 days after treatment of: 1) irradiation while anesthetized, 2) anesthetic alone, or 3) saline. Mice were trained to distinguish water from several concentrations of sucrose. Mice were irradiated with one 8 Gy dose (RADSOURCE-2000 X-ray Irradiator) to the nose and mouth while under 2,2,2-tribromethanol anesthesia (Avertin). Unexpectedly, mice given anesthesia showed a small elevation in sucrose thresholds compared to saline-injected mice, but irradiated mice show significantly elevated sucrose thresholds compared to either control group, an effect that peaked at 6-8 days postirradiation. The timing of loss and recovery of sucrose sensitivity generally coincides with the reported maximal reduction and recovery of Type II taste cells (Nguyen HM, Reyland ME, Barlow LA. 2012. Mechanisms of taste bud cell loss after head and neck irradiation. J Neurosci. 32:3474-3484.). Thus, even a single dose of irradiation can significantly alter detection of carbohydrates, an important consideration for patients undergoing radiotherapy.

[Taste dysfunction (dysgeusia) and radioiodine therapy of thyroid cancer - be aware of side effects by antidepressants and sedatives. Vorschädigung durch Antidepressiva und Sedativa beachten]. / Geschmacksstörung (Dysgeusie) und Radioiodtherapie des Schilddrüsenkarzinoms. Vorschädigung durch Antidepressiva und Sedativa beachten.

In addition to xerostomia, taste dysfunction (hypo-, dysgeusia) is an independent side effect of radioiodine therapy of thyroid cancer. Hypogeusia results from damage of the small mucous salivary glands in the vicinity of the taste buds. Particularly in those patients, who are treated with drugs such as antidepressants or sedatives, taste dysfunction becomes frequently clinically symptomatic. If feasible, therapy regimens bearing a potential risk for taste dysfunction should be switched. Additional damage to taste function should be minimalized, including cessation of smoking, change of agents for dental hygiene, and change of toothpaste. If the medical indication for ablative radioiodine therapy is based on the patient's decision, the patient should be informed about alternative strategies. Potential clinical consequences of the sialadenitis (xerostomia, alteration in taste, risk of caries and tooth extraction, lacrimal gland dysfunction, tearing and need of dacryocystorhinostomy) should be revealed completely. Adapted to the initial risk of relapse, the 131I-activity for ablation should be reduced to the latest standard of care. Clinical data are currently too heterogeneous to decide whether rhTSH might reduce the rate of dysgeusia. The specialist in nuclear medicine should be aware of the multifactorial causes of taste dysfunction, in particular if the patient seeks medical advice after radioiodine therapy.

Mechanisms of taste bud cell loss after head and neck irradiation.

Taste loss in human patients following radiotherapy for head and neck cancer is a common and significant problem, but the cellular mechanisms underlying this loss are not understood. Taste stimuli are transduced by receptor cells within taste buds, and like epidermal cells, taste cells are regularly replaced throughout adult life. This renewal relies on progenitor cells adjacent to taste buds, which continually supply new cells to each bud. Here we treated adult mice with a single 8 Gy dose of x-ray irradiation to the head and neck, and analyzed taste epithelium at 1-21 d postirradiation (dpi). We found irradiation targets the taste progenitor cells, which undergo cell cycle arrest (1-3 dpi) and apoptosis (within 1 dpi). Taste progenitors resume proliferation at 5-7 dpi, with the proportion of cells in S and M phase exceeding control levels at 5-6 and 6 dpi, respectively, suggesting that proliferation is accelerated and/or synchronized following radiation damage. Using 5-bromo-2-deoxyuridine birthdating to identify newborn cells, we found that the decreased proliferation following irradiation reduces the influx of cells at 1-2 dpi, while the robust proliferation detected at 6 dpi accelerates entry of new cells into taste buds. In contrast, the number of differentiated taste cells was not significantly reduced until 7 dpi. These data suggest a model where continued natural taste cell death, paired with temporary interruption of cell replacement, underlies taste loss after irradiation.

Taste dysfunction in head and neck malignancy.

Disturbance of taste is common following radiotherapy of head and neck malignancy, that adversely affect systemic health and quality of life. Therapy remains problematic and there is thus a need for effective preventative and curative strategies for radiotherapy-associated taste disturbance. The present article reviews current knowledge of taste dysfunction associated with head and neck malignancy.

Reduction of type II taste cells correlates with taste dysfunction after X-ray irradiation in mice.

BACKGROUND: Taste dysfunction that develops after radiotherapy for head and neck cancer impairs patients' quality of life. Although taste cells have been shown to degenerate after exposure to X-ray irradiation, the alteration in taste cell population is unclear. This study investigated the histopathological change of taste bud structure and the taste cell population in X-ray irradiated mice. METHODS: The head and neck region of C57BL/6J male mice was exposed to a single 15 Gy dose of X-ray irradiation and a chronological histopathological analysis of the circumvallate papilla was performed. Preference for sweet taste was measured using the two-bottle preference method. RESULTS: The histological analysis of the circumvallate papilla revealed that the basal cells had almost disappeared, but that there was not clear change in the spindle-shaped taste cells on day 4 after irradiation. The number of taste cells had decreased on day 8, and then remained unchanged until day 20, after which they increased and recovered to their original number by day 24. There was a more marked decrease in the number of alpha-gustducin-positive type II taste cells than in the number of serotonin-positive type III taste cells. Preference for sweet taste measured by the two-bottle preference method was decreased in parallel with taste cell number. CONCLUSION: These findings suggest that X-ray irradiation disrupts the basal cells, resulting in a decrease of the number of taste cells, particularly type II taste cells, which may be the cause of radiotherapy-induced taste dysfunction.

Effect of superoxide derived from lucifer yellow CH on voltage-gated currents of mouse taste bud cells.

Lucifer yellow CH (LY), a fluorescent membrane-impermeable cell marker dye, has been routinely loaded into cells through recording electrodes to visualize these cells after electrophysiological investigation, without considering its pharmacological effect. Recently, we showed that the exposure of cells loaded with LY to light for microscopy produced unidentified radical species that retarded the inactivation of voltage-gated Na+ currents irreversibly (Higure Y et al. 2003). Here, we show that superoxide dismutase, an enzyme that decomposes superoxide, reverses the retardation effect, which assures that superoxide is the unidentified radical species. The estimated mean lifetime of superoxide in recording electrodes (in the absence of cytoplasm) is approximately 6 min, and hence, the Na+ currents are retarded even in the dark, when LY is exposed to light before being loaded into the cell. Superoxide has no effect on voltage-gated Cl- currents. These results show that superoxide action on ion channels is rather selective. The breakdown of superoxide inside cells and the effect of endogenous superoxide on the superoxide-susceptible channels are discussed.

Functional changes of the gustatory organ caused by local radiation exposure during radiotherapy of the head-and-neck region.

PURPOSE: The aim of this prospective study was to investigate how often and at which dose levels gustatory disturbances appear during radiotherapy of the tongue and to which extent permanent gustatory deficiencies occur. PATIENTS AND METHODS: The study included 44 patients treated by definitive irradiation for malignant head-and-neck tumors. In 22 patients the posterior two thirds of the tongue (group 1), and in the other 22 patients the entire tongue (group 2) were exposed to radiation. The control group comprised 30 patients with non-small cell lung cancer receiving definitive radiation therapy (group 3). The dose distribution in the tongue area was calculated using CT-based three-dimensional planning. Before, during and after irradiation the gustatory function was determined by means of gustometry and correlated with the corresponding results of enoral inspection and the patients' subjective statements on gustatory function. RESULTS: The gustatory ability of the control group was not affected, whereas patients in the locally irradiated groups in parallel with enoral mucositis suffered from loss of gustatory function after a total dose of 20 Gy with a maximum between 40 and 60 Gy. Supportive measures had little influence on acute side effects. The gustatory disturbances regressed within 8 weeks after radiotherapy in patients with partial-tongue irradiation and almost completely after 6 months in patients with entire-tongue irradiation. CONCLUSION: The severity of gustatory disturbances and the longer recovery time in patients with entire-tongue irradiation suggest an influence of the volume exposed. Therefore, reduction of the highly exposed tongue volume by intensity-modulated radiotherapy opens up possibilities for a reduction of this undesirable side effect.

Gustatory impairment in patients undergoing head and neck irradiation.

OBJECTIVES: To determine whether radiation alters taste function and structure. RESEARCH DESIGN: Prospective, longitudinal study. METHODOLOGY: Testing prior to starting radiation, and 2 weeks, 2 months, and 6 months after completing radiation. RESULTS: Relative to controls, patients had lower taste identification test scores for bitter, salty, and sour tastes. Sour taste also showed a significant group-by-time interaction (P = .03). Taste pores were decreased in the irradiated group, with a significant group-by-time interaction (P = .03). CONCLUSION: Head and neck cancer patients have decreased taste function, and radiation adversely affected sour taste and taste pores.

Studies on the relationship between electrogustometry and sour taste perception.

OBJECTIVE: Electrogustometry is used as a measurement of taste perception. The prevailing theory is that the anodal current delivered to the tongue mucosa stimulates the sour taste receptors, but this is not universally accepted. Our aim was to evaluate to what extent electrogustometry relates to an ability to detect sour taste--rather than sweet, salt, or bitter. METHODS: We compared automated electrogustometric thresholds with visual analogue scale (VAS) ratings of various tastant solutions in 114 subjects. The whole mouth, and each side of the tongue were tested separately. VAS scores from the strongest set of solutions, and the lowest electrogustometry thresholds for each location were used for statistics. RESULTS: There was a significant correlation between electrogustometry threshold and the whole mouth perception of the salt taste solution. Electrogustometry correlated significantly but weakly for all taste qualities when testing was confined to left and right oral tongue. The positive predictive values of electrogustometry were no better in relation to sour taste perception than to the other taste qualities. CONCLUSIONS: Our results do not support the theory that electrogustometry is mediated by sour taste receptors or even that it reflects the sour taste quality. We postulate that electrogustometry measures a function of taste perception, which is different from that induced by chemical stimuli.

Taste loss and recovery following radiation therapy.

Previous investigators have reported deficits in taste acuity in patients following radiation therapy for oropharyngeal cancer. In the present longitudinal study, 13 patients (mean age = 51.6 yrs) received conventional or hyperfractionated radiotherapy (63-76.8 Gy) for primary tumors of the oropharynx. One or both parotid glands and at least two-thirds of the tongue were included in the radiation field. Smell recognition and taste detection thresholds were determined at baseline, 1 month, 6 months, and 1 year post-radiation. Differences for smell recognition and the 4 taste qualities were assessed (independently) at the 4 time intervals, with a one-way ANOVA. Smell recognition was unaffected by radiation. There were significant elevations in thresholds for sweet (p < 0.005), salty (p < 0.005), bitter (p < 0.005), and sour (p< 0.001) during radiation therapy that were restored to baseline levels at 6 months and 1 year after radiation. This study demonstrated that radiation-induced taste deficits can be recovered by 6 months.

Taste dysfunction in patients receiving radiotherapy.

BACKGROUND: Taste loss is a major cause of morbidity in patients undergoing head and neck irradiation. METHODS: In a prospective study, 51 patients undergoing radical head and neck irradiation at the Tokyo University Hospital were assessed for taste loss. Taste ability was measured by the taste threshold for the four basic tastes (sweet, sour, salt, and bitter qualities) plus another taste of "umami" quality using a filter-paper-disc method in patients before, during, and after radiotherapy (RT). RESULTS: All tastes declined on the fifth week after the start of RT and improved on the 11th week. Anatomic pathologic analyses in rats revealed that taste buds diminished completely on the sixth day after irradiation of 15 Gy in a single fraction, and the appearance of taste buds returned almost to the preirradiation state on the 28th day. CONCLUSIONS: The main cause of taste disorder resulting from RT was believed to be a disappearance of taste buds and not damage to the taste nerves.

Confocal microscopy of the peripheral gustatory system: comparison between healthy subjects and patients suffering from taste disorders during radiochemotherapy.

OBJECTIVES: Laser-scanning microscopy (LSM) was used to compare taste buds and epithelia of fungiform papillae of healthy subjects with those of patients suffering from taste disorders during/after radiochemotherapy (RCT). Aim of the study was to investigate effects responsible for taste loss at a microscopic level. STUDY DESIGN: Prospective study. METHODS: Data from 12 healthy subjects (mean age 52.4, SD 9.5 years) were compared with those of 12 patients (mean age 54.7, SD 8.5 years) with head and neck cancer suffering from taste disorders during RCT. Four parameters from LSM were selected for analysis: 1) distance between the pore of the taste buds of fungiform papillae and the crest of the papillary vessels; 2) epithelial cells of each taste bud at 34 mum; 3), cell density, and 4) area of the taste pore at 4 mum. These data were correlated to measures of gustatory sensitivity obtained with both the validated "taste strips" test kit and electrogustometry. RESULTS: Patients complaining from taste disorders during RCT exhibited a significant decrease of taste function assessed with both natural and electric stimuli. In these patients, we found thicker epithelia and smaller areas of the taste pores compared with healthy subjects. In 30% of those patients, no taste pores were detectable; in deeper sections, however, normal taste buds were present. CONCLUSIONS: In conclusion, in RCT patients with taste disorders, LSM indicates changes of epithelia of fungiform papilla but no changes of the taste bud structure. Damage of the chorda tympani nerve by scattered rays, direct or indirect mucotoxic effects of chemotherapeutic agents, and covering of taste pores by epithelial cells are likely reasons for taste loss during RCT.

[Changes of taste bud and fungiform papillae after 60Co radiation in rat].

OBJECTIVE: To observe the morphological changes and the regenerating ability of the fungiform papillae and taste buds after 60Co radiation with clinical doses in rats. METHODS: The heads, faces and necks of 30 SD rats were radiated with a large dose and one time of 60Co in the clinical radiation. The general living condition and the number and shape of the fungiform papillae and taste buds of the tongues were observed after the radiation in rats. RESULTS: In the group of 60Co radiation, the animals had wilting, decreasing appetite, losing weight. The heads, faces and necks of animals appeared redness, peeling of hair, increasing of secretions in 5 days after the 60Co radiation. The changes reached the summit in 10 days and the general living condition of the animals recovered in 60 days. The fungiform papillae and taste buds of the animals appeared degeneration, atrophy and collapsing in 5 days after the 60Co radiation. The injuries reached the summit in 10-20 days and the fungiform papillae and taste buds regenerated partially, and the some atrophied fungiform papillae and taste buds were not regenerated in 60 days. CONCLUSION: The damage to fungiform papillae and taste buds of tongue following the 60Co radiation with the clinical doses was very serious. The damaged fungiform papillae and taste buds can regenerate partially, but not completely.

Taste dysfunction in irradiated patients with head and neck cancer.

Taste disorders caused by radiation therapy for head and neck cancer are common. This prospective study of 40 patients with head and neck cancer assessed changes in taste sensations during radiation therapy. The relationship between the time course and the degree of taste disorder was studied. The taste recognition threshold and supra-threshold taste intensity performance for the four basic tastes were measured using the whole-mouth taste method before, during, and after radiation therapy. Bitter taste was affected most. An increase in threshold for sweet taste depended upon whether the tip of tongue was included within the radiation field. The slope of the taste intensity performance did not change during or after radiotherapy. The pattern of salivary dysfunction was different from that of taste dysfunction. The main cause of taste disorders during radiation support the hypothesis that taste dysfunction is due to damage to the taste buds in the radiation field.

Biology of taste buds and the clinical problem of taste loss.

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.

Morphological changes in taste buds of the fungiform papillae after a single dose of x-ray irradiation in rats.

The qualitative and quantitative changes occurring in the taste buds of the fungiform papillae of male Sprague-Dawley rats (aged 51-125 days old) after x-ray irradiation were studied. A single dose of 2000 Roentgen (R) was delivered and observations were made at 0, 3, 7, 14, 21 and 30 days after x-ray irradiation. The changes in taste bud morphology were interpreted first as degenerative and then as regenerative at various stages of the study. The degenerative process appeared at about the third day and reached a peak at 7 days. Regeneration then began after a further week and the taste buds appeared mature at about 30 days. While the number of fungiform papillae remained constant throughout the study, there was a marked loss of taste buds on these papillae at 7 days. At 14 days, the number of taste buds increased from this low level, and by 30 days the number approached the control values. Initial taste bud loss could be attributed to a direct irradiation damage leading to taste bud cell desquamation combined with a concomitant mitotic inhibition of the stratum germinativum.