TERF1 and TERF2 downregulate telomere length in cognitive deficit at the late period after low-dose exposure

Probl Radiac Med Radiobiol. 2014 Sep;19:170-85.
[Article in English, Ukrainian]

Abstract

Purpose - to explore the role of radiation dose on gene regulation of telomere length and its influence on the patho-genesis of cerebrovascular neurocognitive deficit at the remote period of low-dose irradiation as a result of the Chornobyl accident. Materials and methods. We performed a study of TERF1, TERF2 and TERT genes expression (GE) by RT-PCR, and relative telomere length (RTL) by flow-FISH in 258 clean-up workers of Chornobyl accident divided by radiation dose groups (range 22-2800 mSv) and 78 controls with vascular cognitive deficit. Detailed psychometric interviews were performed to obtain quantitative data on the stage of cognitive deficit. Results. Statistically significant telomere shortening was demonstrated in groups of clean-up workers with radiation doses in 100-250 mSv and 250-500 mSv range (subsequently M ± SD: 15.85 ± 0.27; p< 0.02; 15.89 ± 0,33; p< 0.02; control: 17.21 ± 0,23). A decrease in RTL was in parallel to radiation dose increase and overexpression of negative telomere length regulators: TERF2 genes and, to a lesser extent TERF1; the opposite tendency was demonstrated for TERT GE. In exposed over 500 mSv a significant TERT overexpression was combined with decreased TERF1 and TERF2 GE, and absence of significant RTL changes in comparison with clean-up workers exposed to lower doses indicating a certain independency between gene expression and telomere length changes and possible threshold effects at this dose range. Analysis of the group of exposed in comparison with non-exposed demonstrated a significant decrease (p = 0.03) both of the mean MMSE and RTL parameters suggesting influence of previous exposure. Conclusion. This study shows parallel changes in decline of cognitive function and telomere length and differences in TERF2, TERT and TERF1 gene regulation at the late period after low dose and over 500 mSv exposure.

Meta: vyvchyty rol' vplyvu ionizujuchogo vyprominjuvannja u diapazoni malyh doz na gennu reguljaciju dovzhyny telomer ta patogenez cerebrovaskuljarnogo kognityvnogo deficytu u viddalenomu periodi pislja avarii' na Chornobyl's'kij AES. Materialy i metody. Provedene doslidzhennja ekspresii' geniv TERF1, TERF2 ta TERT za dopomogoju polimeraznoi' lancjugovoi' reakcii' u real'nomu chasi ta vidnosnoi' dovzhyny telomer za dopomogoju metodu fljuorescentnoi' gibrydyzacii' in situ ta protochnoi' cytometrii'. Obstezheno 258 uchasnykiv likvidacii' naslidkiv avarii' na Chornobyl's'kij AES, rozpodilenyh na grupy v zalezhnosti vid dozy oprominennja (diapazon 22–2800 mZv) ta 78 neoprominenyh osib grupy porivnjannja z sudynnym kognityvnym deficytom. Kil'kisni dani pro tjazhkist' kognityvnogo deficytu vyznachaly za danymy psyhometrychnyh interv’ju. Rezul'taty. Bulo vstanovlene statystychno dostovirne ckorochennja dovzhyny telomer u grupah likvidatoriv oprominenyh u diapazonah doz 100–250 ta 250–500 mZv (M±SD: 15,8 5±0,27; p < 0,02; 15,89±0,33; p < 0,02; kontrol': 17,21±0,23). Pokazano, shho vidnosna dovzhyna telomer (RTL) zmenshuvalas' iz zrostannjam dozy oprominennja ta giperekspresijeju negatyvnyh reguljatoriv dovzhyny telomer: genu TERF2 i, v menshij miri TERF1; protylezhna tendencija bula prodemonstrovana dlja ekspresii' genu TERT. U grupi oprominenyh v dozi bil'sh nizh 500 mZv dostovirna giperekspresija genu TERT pojednuvalas' iz znyzhennjam ekspresii' geniv TERF1 i TERF2 ta vidsutnistju istotnyh zmin RTL u porivnjanni iz grupoju uchasnykiv likvidacii' naslidkiv avarii', jaki zaznaly vplyvu nyz'kyh doz, shho vkazujut' na pevnu nezalezhnist' mizh ekspresijeju geniv i zminoju dovzhyny telomer i najavnist' mozhlyvyh porogovyh efektiv u c'omu diapazoni doz. Analiz danyh grupy oprominenyh osib porivnjano iz neoprominenymy osobamy prodemonstruvav znachne znyzhennja (r = 0,03) serednih pokaznykiv MMSE i RTL, shho imovirno pov’jazano z poperednim oprominennjam. Vysnovky. Doslidzhennja prodemonstruvalo paralel'ni zminy u znyzhenni kognityvnyh funkcij i dovzhyny telomer ta vidminnosti u TERF2, TERT ta TERF1 gennij reguljacii' u viddalenomu periodi pislja oprominennja u diapazoni malyh doz ta pry radiacijnomu oprominenni ponad 500 mZv.

Keywords: Chornobyl; TERF1; TERF2; TERT; cognitive deficit; gene expression; low-dose radiation; telomeres.