Abstract
Ionizing radiation is known for its cytotoxic and mutagenic properties. However, recent evidence suggests that chronic sub-lethal irradiation stimulates the growth of melanin-pigmented (melanized) fungi, supporting the hypothesis that interactions between melanin and ionizing photons generate energy useful for fungal growth, and/or regulate growth-promoting genes. There are no quantitative models of how fungal proliferation is affected by ionizing photon energy, dose rate, and presence versus absence of melanin on the same genetic background. Here we present such a model, which we test using experimental data on melanin-modulated radiation-induced proliferation enhancement in the fungus Cryptococcus neoformans, exposed to two different peak energies (150 and 320 kVp) over a wide range of X-ray dose rates. Our analysis demonstrates that radiation-induced proliferation enhancement in C. neoformans behaves as a binary “on/off” phenomenon, which is triggered by dose rates <0.002 mGy/h, and stays in the “on” position. A competing dose rate-dependent growth inhibition becomes apparent at dose rates >5000 mGy/h. Proliferation enhancement of irradiated cells compared with unirradiated controls occurs at both X-ray peak energies, but its magnitude is modulated by X-ray peak energy and cell melanization. At dose rates <5000 mGy/h, both melanized and non-melanized cells exposed to 150 kVp X-rays, and non-melanized cells exposed to 320 kVp X-rays, all exhibit the same proliferation enhancement: on average, chronic irradiation stimulates each founder cell to produce 100 (95% CI: 83, 116) extra descendants over 48 hours. Interactions between melanin and 320 kVp X-rays result in a significant (2-tailed p-value = 4.8×10−5) additional increase in the number of radiation-induced descendants per founder cell: by 55 (95% CI: 29, 81). These results show that both melanin-dependent and melanin-independent mechanisms are involved in radiation-induced fungal growth enhancement, and implicate direct and/or indirect interactions of melanin with high energy ionizing photons as an important pro-proliferative factor.
Highlights
Survival of melanized fungi in environments exposed to high levels of ionizing radiation has been reported for several decades, for example from a nuclear weapons test site in Nevada [1], and from a forest experimentally exposed to chronic irradiation at the Brookhaven National Laboratory [2]
Qe values are more convenient than raw colony-forming units per milliliter (CFU/ml) counts for detecting subtle effects of X-ray peak energy and melanization on cell proliferation, which are of main interest here
By combining quantitative mathematical modeling with Monte Carlo data simulation techniques, and applying them to experimental data on the effects of X-ray dose rates spanning six orders of magnitude, at two different X-ray peak energies, on genetically identical fungi which differ only by melanization status, our study provides new insight into the influence of chronic irradiation on fungal proliferation
Summary
Survival (and sometimes relative predominance) of melanized fungi in environments exposed to high levels of ionizing radiation has been reported for several decades, for example from a nuclear weapons test site in Nevada [1], and from a forest experimentally exposed to chronic irradiation at the Brookhaven National Laboratory [2]. Recent laboratory investigations confirm the conclusion that some melanized fungi are radioresistant, but exhibit enhanced proliferation during chronic sub-lethal irradiation [8,9,10] These findings suggest that the biological effects of ionizing radiation are not limited to cell death, mutagenesis and carcinogenesis [11], but can include growth stimulation of certain life forms. Parameter B represents radiationinduced growth inhibition, which is assumed to be caused by DNA damage response pathways and proportional to dose rate This simple formalism provides a tractable tool for analyzing and mechanistically interpreting experimental data on the influence of chronic sub-lethal irradiation on fungal growth. The effects of cell melanization and other factors on the values of both model parameters (A and B) can be analyzed quantitatively and statistically
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