Cellular mechanisms of cyclophosphamide-induced taste loss in mice

Abstract

Many commonly prescribed chemotherapy drugs such as cyclophosphamide (CYP) have adverse side effects including disruptions in taste which can result in loss of appetite, malnutrition, poorer recovery and reduced quality of life. Previous studies in mice found evidence that CYP has a two-phase disturbance in taste behavior: a disturbance immediately following drug administration and a second which emerges several days later. In this study, we examined the processes by which CYP disturbs the taste system by examining the effects of the drug on taste buds and cells responsible for taste cell renewal using immunohistochemical assays. Data reported here suggest CYP has direct cytotoxic effects on lingual epithelium immediately following administration, causing an early loss of taste sensory cells. Types II and III cells in fungiform taste buds appear to be more susceptible to this effect than circumvallate cells. In addition, CYP disrupts the population of rapidly dividing cells in the basal layer of taste epithelium responsible for taste cell renewal, manifesting a disturbance days later. The loss of these cells temporarily retards the system’s capacity to replace Type II and Type III taste sensory cells that survived the cytotoxic effects of CYP and died at the end of their natural lifespan. The timing of an immediate, direct loss of taste cells and a delayed, indirect loss without replacement of taste sensory cells are broadly congruent with previously published behavioral data reporting two periods of elevated detection thresholds for umami and sucrose stimuli. These findings suggest that chemotherapeutic disturbances in the peripheral mechanisms of the taste system may cause dietary challenges at a time when the cancer patient has significant need for well balanced, high energy nutritional intake.

The Mystery of “Metal Mouth” in Chemotherapy

“…Second, it has been reported that chemotherapy is toxic to taste receptor cell progenitors (Mukherjee et al, 2013;Mukherjee et al, 2017;Jewkes et al, 2018;Delay et al, 2019).…”

“…It is unclear whether the length-dependence of chemotherapy-induced neurotoxicity in the somatosensory system applies to the chorda tympani, with its tortuous length through the petrous part of the temporal bone; but there is evidence that the pattern of gustotoxicity on the tongue roughly follows the distribution of the chorda tympani, with taste receptor cells on the anterior portion of the tongue potentially worst-affected by cyclophosphamide. After cyclophosphamide is injected into mice, anterior (fungiform) papillae are diminished faster, such that type II (PLCβ2 + ) taste cells tend to die sooner after cyclophosphamide injection if situated more anteriorly on the tongue (see Figure 5) (Mukherjee & Delay, 2011;Mukherjee et al, 2013;Mukherjee et al, 2017). Because the posterior part of the tongue is disproportionately dedicated to bitter taste (e.g., Adler et al, 2000;Matsunami, Montmayeur, & Buck, 2000;Voigt et al, 2012;Feeney & Hayes, 2014), this suggests that bitter taste faculties might be preferentially preserved under chemotherapy.…”

Cyclophosphamide and the taste system: Effects of dose fractionation and amifostine on taste cell renewal

“…This makes CYP particularly toxic to cells engaged in cell renewal, such as cancerous cells or normal cells with short life spans requiring frequent renewal. Previous research with mice has shown that CYP can disrupt taste functions by increasing taste thresholds and decreasing the ability to discriminate different tastes [16–19], killing taste sensory cells within taste buds, and suppressing cell renewal involved in replacement of aging taste sensory cells [16, 19]. Several types of cells are found within a taste bud [20, 21].…”

“…The rate of cell cycling of the proliferating cells is relatively high [31], making these cells especially vulnerable to the effects of CYP. A single dose of 75 mg/kg can kill cells within taste buds and severely depress the rate of cell cycling within the basal layer for several days [16, 19]. When mature cells die and there are inadequate replacement cells, additional disruptions in behavioral taste functions occur [16, 18].…”

“…Because fractionated dosing of CYP altered behavioral thresholds for salt differently than a single large dose, we wanted to compare the effects of two dosing regimens of CYP on populations of different cell types of murine circumvallate taste buds over days post injection. While the time course of the behavioral effects of CYP are well characterized, the effects of CYP on taste cells are not as well delineated since cellular effects have only been observed after a single dosing at 4 and 8, 10, 12 and 16 days post injection [16, 18, 19]. To address this question more accurately we examined taste buds at two-day intervals following either a single large dose of CYP or five smaller doses of CYP.…”