Gene expression, telomere and cognitive deficit analysis as a function of Chornobyl radiation dose and age: from in utero to adulthood

Probl Radiac Med Radiobiol. 2015 Dec;20:283-310.
[Article in En, Ukrainian]

Abstract
in En , Ukrainian

Objective - to estimate the possible effects of low dose ionizing radiation on human cognitive function in adult hood and in utero.

Materials and methods: Cognitive tests, telomere length and expression of genes regulating telomere function were studied in Chornobyl cleanup workers who were exposed to doses under 500 mSv (n = 326) and subjects exposed in utero during the first days after the accident Prypiat town (n = 104). The neurocognitive assessment covered mem ory, attention, language, executive and visiospatial functions. In young adults after prenatal exposure a relation ship was analyzed between a cognitive function and radiation dose to foetus, brain and thyroid gland. Internal con trols were used for both groups - the group of Chornobyl cleanup workers exposed in doses less than 20 mSv and an age matched comparison group from radioactively contaminated areas for subjects exposed in utero.

Results: Cognitive functions in cleanup workers exposed to ionizing radiation at adulthood are characterized by symptoms of a mild cognitive impairment according to the MMSE (mean group score 25,58 ± 2,95) and a significant ly higher level of mental disorders according to the BPRS in a dose related manner. Cleanup workers exposed to doses over 500 mSv demonstrate a significant cognitive deficit in comparison with those exposed below 500 mSv and espe cially non exposed patients. Subjects exposed in utero during the check at age of 25-27 years exhibit an excess of the disorders of autonomic nervous system (ICD 10: G90). Neurological microsymptoms as well as neurotic, stress relat ed and somatoform disorders (F40-F48) dominate. Relationship were revealed between the TERT, TERF1, TERF2 genes expression, relative telomere length (RTL),cognitive deficit and cerebrovascular pathology, radiation dose and age. Telomere length in cleanup workers is sreduced after 50 years (6.1 %). The most significant reduction in telomere length is shown after 70 years (11.7 %). Negative correlation was found between telomere length and degree of cog nitive deficit (MMSE scale) and between age and degree of cognitive deficit. The RTL is significantly decreased in groups of persons with cognitive deficit compared to a comparison group. Telomere length at the late period after low dose radiation exposure is downregulated by the high TERF2 gene expression combined with low expression of TERT gene. After exposure to doses over 250-500 mSv a cognitive deficit and dementia were associated with a substantial increase in TERT gene expression, overexpression of TERF1 and decrease in expression of TERF2 gene. A relationship was revealed between the TERF2 gene expression and CD95+ cell fraction susceptible to apoptosis.

Conclusions: This study shows that cognitive deficit in humans at a late period after radiation exposure is influ enced by dose, age at exposure and gene regulation of telomere function.

Meta doslidzhennia – vyvchyty mozhlyvi efekty nyz'kykh doz ionizuiuchogo vyprominiuvannia na kognityvni funktsiI doroslykh i oprominenykh vnutrishn'outrobno.Materialy i metody. Provedeno doslidzhennia kognityvnykh testiv, dovzhyny telomer i ekspresiI geniv, shcho regu liuiut' funktsiiu telomer v uchasnykiv likvidatsiI naslidkiv avariI na Chornobyl's'kiy AES (ULNA), oprominenykh u dozi menshe 500 mZv (n = 326) ta osib, oprominenykh vnutrishn'outrobno v pershi dni pislia avariI u m. Pry’piati (n = 104). Neyrokognityvna otsinka vkliuchala osnovni kognityvni funktsiI: pam’iat' uvagu, movu, vykonavchi funktsiI ta vizual'no prostorove spryyniattia. U molodykh doroslykh pislia prenatal'nogo oprominennia analizuvaly zv’iazok mizh kognityvnymy funktsiiamy i dozoiu oprominennia na plid, mozok ta shchytopodibnu zalozu. Analiz psykho nevrologichnykh testiv uchasnykiv likvidatsiI naslidkiv avariI na Chornobyl's'kiy AES ta osib, oprominenykh vnutrishn'outrobno, z riznym rivnem kognityvnykh porushen' provodyly v porivnianni z vnutrishnim kontrolem: grupoiu uchasnykiv likvidatsiI avariI na ChAES oprominenykh v mezhakh do 20 mZv, ta grupy osib vidpovidnogo viku z radioaktyvno zabrudnenykh terytoriy dlia vnutrishn'outrobno oprominenykh.Rezul'taty. Kognityvni funktsiI ULNA pislia oprominennia v doroslomu vitsi, kharakteryzuvalysia symptomamy pomirnogo kognityvnogo defitsytu za indeksamy MMSE (seredniy grupovyy indeks 25,58 ± 2,95) ta dostovirno vy shchym dozozalezhnym rivnem psykhichnykh porushen' za shkaloiu BPRS. V ULNA pislia oprominennia v dozakh > 500 mZv vyznachaiet'sia bil'sh vyrazhenyy kognityvnyy defitsyt, porivniano z grupamy oprominenykh do 500 mZv ta, osobly vo, neoprominenykh patsiientiv. U sub’iektiv, oprominenykh in utero, pry obstezhenni u vitsi 25–27 rokiv diagnostuvaly zakhvoriuvannia avtonomnoI nervovoI systemy (ICD 10: G90) ta dominuvannia nevrologichnoI mikrosymptomatyky, nevrotychnykh, pov’iazanykh zi stresom ta somatofornykh porushen' (F40–F48). Vstanovleno zv’iazok mizh ekspresiieiu geniv TERT, TERF1, TERF2, vidnosnoiu dovzhynoI telomer (RTL), kognityvnym defitsytom, tserebrovaskuliarnoiu pato logiieiu, dozoiu oprominennia ta vikom. Vidnosna dovzhyna telomer u zagal'niy kogorti uchasnykiv likvidatsiI avariI na ChAES znyzhuvalas' pislia 50 rokiv (6,1 %) z naybil'sh suttievym znyzhenniam pislia 70 rokiv (11,7 %). Negatyvnu koreliatsiiu vstanovleno mizh RTL ta kognityvnym defitsytom (MMSE), mizh vikom ta stupenem kognityvnogo defitsy tu. U sub’iektiv z kognityvnym defitsytom RTL bula dostovirno znyzhenoiu vidnosno grupy porivniannia. V intervali malykh doz skorochennia RTL pov’iazano z giperekspresiieiu gena TERT2 pry nyz'kiy ekspresiI TERT. Pry dozakh vyshche 250–500 mZv prodemonstrovano giperekspresiiu geniv TERF1, TERT ta znyzhennia ekspresiI gena TERF2, asotsiyovani z kognityvnymy rozladamy ta dementsiieiu. Vstanovleno negatyvnyy koreliatsiynyy zv’iazok mizh ekspresiieiu gena TERF2 ta ekspresiieiu proapoptotychnogo markera CD95.Vysnovky. Vstanovleno zalezhnist' kognityvnogo defitsytu u viddalenomu periodi pislia oprominennia vid dozy, viku na moment oprominennia ta gennoI reguliatsiI funktsiI telomer.

Keywords: Chornobyl; cognitive deficit; gene expression; low dose radiation; telomeres.