Global Gene Expression Responses to Low- or High-Dose Radiation in a Human Three-Dimensional Tissue Model

Abstract

Accumulating data suggest that the biological responses to high and low doses of radiation are qualitatively different, necessitating the direct study of low-dose responses to better understand potential risks. Most such studies have used two-dimensional culture systems, which may not fully represent responses in three-dimensional tissues. To gain insight into low-dose responses in tissue, we have profiled global gene expression in EPI-200, a three-dimensional tissue model that imitates the structure and function of human epidermis, at 4, 16 and 24 h after exposure to high (2.5 Gy) and low (0.1 Gy) doses of low-LET protons. The most significant gene ontology groups among genes altered in expression were consistent with effects observed at the tissue level, where the low dose was associated with recovery and tissue repair, while the high dose resulted in loss of structural integrity and terminal differentiation. Network analysis of the significantly responding genes suggested that TP53 dominated the response to 2.5 Gy, while HNF4A, a novel transcription factor not previously associated with radiation response, was most prominent in the low-dose response. HNF4A protein levels and phosphorylation were found to increase in tissues and cells after low- but not high-dose irradiation.

Low Dose Radiation Causes Skin Cancer in Mice and Has a Differential Effect on Distinct Epidermal Stem Cells

“…The direct effect of LDR in this setting has not been studied, but the authors showed that when LDR preceded high dose, this led to a resistance to high dose radiation . Gene expression profiling of cultured cells and 3D in vitro models showed that the transcriptional response differs between administration of high and low doses of radiation, with high doses leading to p53 and apoptotic signatures in most tissues, while response to LDR was cell type specific . Transcriptomic analysis upon LDR of the EPI‐200 human 3D skin model identified as key modulated pathways the cell cycle, metabolism, unfolded protein response, pH regulation, oxidative stress, and chromatin organization .…”

The effect of low dose ionizing radiation on homeostasis and functional integrity in an organotypic human skin model

“…The majority of cells damaged by radiation will undergo a limited number of abortive divisions resulting in near-normal differentiated daughter cells which counteract radiation-induced cell loss [30]. For a human skin model consisting of keratinocytes alone, enhanced proliferation activity in the basal layer was reported at 48 h and 72 h post exposure to 10 cGy low LET protons and a lack of a continuous basal layer at 72 h post exposure to 250 cGy of protons [31]. Similarly, in the results presented in this study, we found fluence dependent effects on basal cell numbers post exposure to low doses of high LET O, Si and Fe ions and corresponding changes in the thickness of the viable epidermis.…”

Effects of Low Doses of Ionizing Radiation Exposures on Stress-Responsive Gene Expression in Human Embryonic Stem Cells

“…Previous studies were focused upon both HD and LD IR transcriptional responses in vitro [15–19], ex vivo [20,21], and in vivo settings in humans [22]. What emerges from these and other reports is that LD IR responses, including gene expression alterations, are highly genotype, cell type, and tissue-dependent, with a remarkable degree of variability both between individuals and different cell types [23–28].…”