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Microarray Studies on 211At Administration in BALB/c Nude Mice Indicate Systemic Effects on Transcriptional Regulation in Non-Thyroid Tissues

Artikel i vetenskaplig tidskrift
Författare Britta Langen
Nils Rudqvist
Khalil Helou
Eva Forssell-Aronsson
Publicerad i Journal of Nuclear Medicine
Volym 58
Nummer/häfte 2
Sidor 346-353
ISSN 0161-5505
Publiceringsår 2017
Publicerad vid Sahlgrenska Cancer Center
Institutionen för kliniska vetenskaper, sektionen för onkologi, radiofysik, radiologi och urologi, Avdelningen för radiofysik
Institutionen för kliniska vetenskaper, sektionen för onkologi, radiofysik, radiologi och urologi, Avdelningen för onkologi
Sidor 346-353
Språk en
Länkar dx.doi.org/10.2967/jnumed.116.17695...
Ämnesord Molecular Biology, Radiobiology/Dosimetry, Radionuclide Therapy, astatine-211, normal tissue response, radiogenomics, radionuclide therapy, systemic effects
Ämneskategorier Strålningsbiologi, Radiofysik, Bioinformatik och systembiologi, Molekylärbiologi

Sammanfattning

Introduction: Targeted α-therapy is a promising treatment option for various types of malignant tumors. Radiolabeled cancer-seeking agents, however, undergo degradation resulting in a certain percentage of free radionuclide in the body. The radiohalogen 211At accumulates in various tissues with specifically high uptake in the thyroid. When normal thyroid function is disturbed due to ionizing radiation (IR) exposure, deleterious effects can occur in tissues that depend on thyroid hormone (TH) regulation for normal physiological function. However, knowledge of systemic effects is still rudimentary. We previously reported similarities in transcriptomic regulation between the thyroid and other tissues despite large differences in absorbed dose from 211At (Langen et al. JNM, 2013). Here, we present supportive evidence on systemic effects after 211At administration. Methods: Expression microarray data from kidney cortex and medulla, liver, lungs, and spleen were used from previous studies where mice were i.v. injected with 0.064–42 kBq 211At and killed after 24 h, or injected with 1.7 kBq 211At and killed after 1, 6, or 168 h. Controls were mock-treated and killed after 24 h. Literature-based gene signatures were used to evaluate the relative impact from IR- or TH-induced regulation. Thyroid- and TH-associated upstream regulators as well as thyroid-related diseases and functions were generated using functional analysis software. Results: Responses in IR- or TH-associated gene signatures were tissue-specific, varied over time, and the relative impact of each gene signature differed between the investigated tissues. The liver showed a clear dominance of TH-responding genes. In the kidney cortex, kidney medulla, and lungs, the TH-associated signature was detected to at least similar extent as the IR-associated signature. The spleen was the single tissue showing regulation of only IR-associated signature genes. Various thyroid-associated diseases and functions were inferred from the data: L-triiodothyronine, TH, TH receptor, and triiodothyronine (reverse) were inferred as upstream-regulators with differences in incidence and strength of regulation depending on tissue type. Conclusion: These findings indicate that transcriptional regulation in various non-thyroid tissues was–in part–induced by thyroid (hormone)-dependent signaling. Consideration of the systemic context between tissues could contribute to normal tissue risk assessment and planning of remedial measures.

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