Chronic low dose-rate radiation down-regulates transcription related to mitosis and chromosomal movement similar to acute high dose in prostate cells

Abstract

Purpose: Despite concerns over risks from exposure to low-dose ionizing radiations encountered in the environment and workplace, the molecular consequences of these exposures, particularly at representative doses and dose-rates, remains poorly understood.

Materials and methods: Using a novel flood source construct, we performed a direct comparison of genome-wide gene expression regulations resulting from exposure of primary human prostate fibroblast cultures to acute (10 cGy and 200 cGy) and longer-term chronic (1.0–2.45 cGy cumulative over 24 h) exposures.

Results: Expression profiling showed significant differential regulation of 396 genes with no measureable changes in the acute 10 cGy dose. However, there were 106 genes in common between samples given an acute 200 cGy dose compared to those given chronic doses, most of which were decreased and related to cell cycle or chromosomal movement in M-phase. Biological pathway analysis showed decreases in cell cycle, chromosomal movement, cell survival and DNA replication, recombination and repair as well as a predicted activation of transcriptional regulators TP53, RB1 and CDKN2A. In agreement with these results, prostate epithelial cells given 200 cGy or chronic doses displayed functional decreases in proliferation and mitotic cells.

Conclusions: In summary, we showed a contrast to the common observation of constant or reduced effect per unit dose as the dose (acute) was diminished, that even very low total doses delivered chronically could rival the perturbing effect of acute doses 100 times as intense. Underscored is the importance of the means of dose delivery, shown to be as important as dose size when considering biologic effect.

Keywords::

• Low-dose effects
• low dose-rate
• risk assessment
• ionizing radiation
• prostate
• gene expression

Acknowledgements

We thank Phil Hahnfeldt and Melissa Klumpar for manuscript editing.

Financial disclosure

This research was supported by the Office of Science (BER), U.S. Department of Energy, under the Award Number DE-SC0002606 (to L.H.). J.T.M. was also supported by the National Institutes of Health under the Loan Repayment Program from the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contributions: J.T.M. and L.H. designed the research; J.T.M., H.S., and M.P. performed the research; C.B., D.S., A.P., G.L.K. and I.T. contributed new reagents, materials or analytic tools; J.T.M. and C.B. analyzed data; and J.T.M. and L.H. wrote the paper.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.