Sergey E. Pigarev

Введение. Изучение феномена трансгенерационных эффектов ионизирующего излучения насчитывает не один десяток лет. Одним из возможных последствий облучения родителей может быть изменение частоты и спектра развития злокачественных новообразований у потомства, при этом данный вопрос освещается в небольшом числе публикаций экспериментальных и эпидемиологических исследований. Целью данного обзора было определить влияние преконцептивного облучения отцов и матерей на риск развития опухолевой патологии у их потомства. Материалы и методы. В базах данных PubMed и eLIBRARY.RU проведен поиск без ограничений по дате с использованием терминов: «трансгенерационный канцерогенез», «радиационный канцерогенез» в eLIBRARY.RU и transgeneration AND irradiation в PubMed; всего были найдены 236 публикаций. После первоначального ознакомления с названием и аннотацией исключены 161. Для детального анализа отобраны 75 работ, из которых исключены 63 как не соответсвующие критериям, включая одну дублирующую результаты и 22 обзорные публикации. Дополнительный анализ списков литературы в обзорных работах позволил идентифицировать еще 18 публикаций. Всего в систематический обзор включены 30 публикаций. Результаты. В основном, исследования заболеваемости у потомства облученных людей не выявили каких-либо значимых рисков для здоровья. В то же время эксперименты, выполненные на мышах, свидетельствуют в пользу наличия увеличенного риска, как спонтанного, так и индуцированного дополнительным воздействием канцерогенеза у потомства облученных животных. Выводы. В целом совокупность эпидемиологических данных у людей и экспериментальных у мышей не позволяет исключить того, что воздействие облучения на зародышевую линию вызывает слабые прямые онкогенные эффекты, а также сопровождается гиперчувствительностью потомства к последующим канцерогенным воздействиям в постнатальном периоде.

This paper summarises data from studies of transgenerational effects of preconceptual exposure to ionising radiation (IR) of animals across various taxa. We have conducted search in PubMed, a database on medical and biomedical topics, using “transgeneration AND irradiation” as search terms, and, have additionally reviewed papers cited in the original documents. For the analysis we have selected 103 original papers, including 39 published in the last decade. The following living objects were used for studying transgenerational effects of ionizing radiation: Protostomes, including Nematoda, Annelida, Crustaceans and insects (21 papers), Deuterostomes, including fish, Amphibia, birds and mammals (82 papers). With regard to transgenerational effects in humans, we have reviewed 31 paper discussing effects of preconceptual exposure of parents to IR. Reported results come from the analysis of effects of ionizing radiation such as X-ray, gamma, neutrons (corpuscular), of incorporated radionuclides (Pu, U, U, U, Fe), alongside data from radiation incidents and atomic bombings. Reported transgenerational effects of preconceptual exposure of parents to a wide range of doses of IR include teratogenic effects, prenatal death, different birth defects, reduced conception rates, both in vivo and in vitro, genomic instability, and mutations (excess deletions). Besides, an increased hazard of carcinogenic events resulting from mutational variance and instability of germline genome is reported, though it is shown to be relatively low in descendants of irradiated parents. Transgenerational effects of IR may play a significant role on reproductive health of animals and humans, particularly in radiation-contaminated regions. We suggest that future research incorporate an integrated approach to assess condition of genome across multiple genetic parameters, including detection of transgenerational genomic instability in descendants of irradiated parents.

We studied the effects of polyphenolic composition BP-C2, comprising molybdenum with lignin derivatives, on lung carcinogenesis induced by urethane in the progeny of F₀ male BALB/c mice preconceptionally exposed to radiation in a dose of 1 Gy. The multiplicity of lung tumors in the progeny of irradiated mice was higher than in the progeny of non-irradiated male parents by 50% in females and 43% in males (p1 mice (progeny of irradiated F₀ male parents treated with BP-C2), the multiplicity of lung tumors was also higher, but this increase was less pronounced: 35% in females (p=0.3852) and 23% in males (p=0.0766). We have demonstrated that administration of BP-C2 to irradiated parents (F₀) efficiently inhibits carcinogenesis in their F₁ progeny. The use of BP-C2 in irradiated male parents and their progeny not only reduced the multiplicity of tumors, but also normalized body weights in the F₁ progeny. Our study demonstrates potential of the polyphenolic composition BP-C2 for chemoprophylaxis of radiation-induced transgenerational carcinogenesis.

Introduction. Genomic instability caused by ionizing radiation or chemical carcinogens of anticancer therapy poses a potential threat not only to the patients themselves, but also possibly to their offspring. Aim. To investigate the risk of transgenerational transmission of increased susceptibility to chemical carcinogenesis of the lung in the offspring of irradiated male BALB/c mice. Materials and methods. Male mice were subjected to whole-body gamma irradiation at a dose of 0 or 1 Gy. Thirty days after irradiation, they were mated with intact females of the same strain to produce F1 offspring. At 3 months of age, F1 offspring of both sexes were injected with urethane (600 mg/kg, four times with a 7-day gap). Results. After 9 months of administering the carcinogen, macroscopically detected lung tumor incidence in the offspring of irradiated males was significantly higher than in the offspring of non-irradiated males, with a 49% increase (p < 0.05) in females and 43% increase (p < 0.01) in males. The majority of the tumors were adenocarcinomas. The mean number of adenocarcinomas per tumor-bearing mouse in the offspring of irradiated fathers was 83% higher (p < 0.05) in males and 53% higher (p < 0.05) in females compared to the offspring of non-irradiated fathers. Conclusion. This study confirms that male mice exposed to whole-body gamma irradiation are at risk of transgenerational transmission of increased susceptibility to carcinogenesis. Введение. Геномная нестабильность, возникшая под влиянием ионизирующей радиации или химических канцерогенов противоопухолевой терапии представляет потенциальную угрозу не только для самих пациентов, но возможно и для их потомства. Цель исследования. Изучение риска трансгенерационной передачи повышенной чувствительности к химическому канцерогенезу легкого у потомков облученных отцов на мышах BALB/c. Материалы и методы. Самцов мышей подвергали общему гамма-облучению в дозе 0 или 1 Гр, спустя 30 сут после облучения спаривали с интактными самками этой же линии и получали потомство F1. В возрасте 3 мес потомкам F1 обоего пола вводили уретан (600 мг/кг, четыре раза с интервалом 7 дней). Результаты. Через 9 мес от начала введения канцерогена среднее количество макроскопически выявленных опухолей легких у потомков облученных самцов было выше, чем у потомков необлученных самцов, у самок — на 49 % (р<0,05), у самцов — на 43 % (р<0,01). Большинство выявленных опухолей представляли аденокарциномы. Среднее число аденокарцином на мышь-опухоленосителя у потомства облученных отцов было больше, чем у потомства необлученных на 83 % (р < 0,05) и 53 % (р < 0,05) у самцов и самок, соответственно. Заключение. Результаты исследования подтверждают риск трансгенерационной передачи повышенной чувствительности к канцерогенезу после равномерного общего гамма-облучения самцов мышей.

Natural products (e.g., polyphenols) have been used as biologically active compounds for centuries. Still, the mechanisms of biological activity of these multicomponent systems are poorly understood due to a lack of appropriate experimental techniques. The method of tritium thermal bombardment allows for non-selective labeling and tracking of all components of complex natural systems. In this study, we applied it to label two well-characterized polyphenolic compounds, peat fulvic acid (FA-Vi18) and oxidized lignin derivative (BP-Cx-1), of predominantly hydrophilic and hydrophobic character, respectively. The identity of the labeled samples was confirmed using size exclusion chromatography. Using ultra-high resolution Fourier transform ion cyclotron resonance mass spectrometry (FT ICR MS), key differences in the molecular composition of BP-Cx-1 and FA-Vi18 were revealed. The labeled samples ([³H]-FA-Vi18 (10 mg/kg) and [³H]-BP-Cx-1 (100 mg/kg)) were administered to female BALB/c mice intravenously (i.v.) and orally. The label distribution was assessed in blood, liver, kidneys, brain, spleen, thymus, ovaries, and heart using liquid scintillation counting. Tritium label was found in all organs studied at different concentrations. For the fulvic acid sample, the largest accumulation was observed in the kidney (C_max 28.5 mg/kg and 5.6 mg/kg, respectively) for both routes. The organs of preferential accumulation of the lignin derivative were the liver (C_max accounted for 396.7 and 16.13 mg/kg for i.v. and p.o. routes, respectively) and kidney (C_max accounted for 343.3 and 17.73 mg/kg for i.v. and p.o. routes, respectively). Our results demonstrate that using the tritium labeling technique enabled successful pharmacokinetic studies on polyphenolic drugs with very different molecular compositions. It proved to be efficient for tissue distribution studies. It was also shown that the dosage of the polyphenolic drug might be lower than 10 mg/kg due to the sensitivity of the ³H detection technique.

Identification of molecular targets and mechanism of action is always a challenge, in particular - for natural compounds due to inherent chemical complexity. BP-Cx-1 is a water-soluble modification of hydrolyzed lignin used as the platform for a portfolio of innovative pharmacological products aimed for therapy and supportive care of oncological patients. The present study describes a new approach, which combines in vitro screening of potential molecular targets for BP-Cx-1 using Diversity Profile - P9 panel by Eurofins Cerep (France) with a search of possible active components in silico in ChEMBL - manually curated chemical database of bioactive molecules with drug-like properties. The results of diversity assay demonstrate that BP-Cx-1 has multiple biological effects on neurotransmitters receptors, ligand-gated ion channels and transporters. Of particular importance is that the major part of identified molecular targets are involved in modulation of inflammation and immune response and might be related to tumorigenesis. Characterization of molecular composition of BP-Cx-1 with Fourier Transform Ion Cyclotron Resonance Mass Spectrometry and subsequent identification of possible active components by searching for molecular matches in silico in ChEMBL indicated polyphenolic components, nominally, flavonoids, sapogenins, phenanthrenes, as the major carriers of biological activity of BP-Cx-1. In vitro and in silico target screening yielded overlapping lists of proteins: adenosine receptors, dopamine receptor DRD4, glucocorticoid receptor, serotonin receptor 5-HT1, prostaglandin receptors, muscarinic cholinergic receptor, GABAA receptor. The pleiotropic molecular activities of polyphenolic components are beneficial in treatment of multifactorial disorders such as diseases associated with chronic inflammation and cancer.

BP-C3 is a formulation, which comprises lignin-derived polyphenolic composition of benzenepolycarboxylic acids (BP-Cx-1) with iron complex, selenium, ascorbic acid and retinol, and possesses geroprotective activity. The present study examined the effect of BP-C3 (80 mg/kg, administered 18 times in total by gavage) on the development of haematological and intestinal manifestations of toxicity following 5-fluorouracil (5-FU; 150 mg/kg, administered once via intravenous injection) administration in outbred male Swiss-H Rappolovo (SHR) mice. The use of BP-C3 on therapeutic and preventative/therapeutic schedules demonstrated that it was protective against the toxic effect of 5-FU exerted on the lymphopoietic organs. Administering BP-C3 24 h after 5-FU (therapeutic schedule) had an effect on the recovery of leukopoiesis and prevented anaemia in the mice. In the mice that received 5-FU and 5-FU with BP-C3 prior to and following administration of the chemotherapeutic agent (preventative/therapeutic schedule), mild anaemia developed by day 7. Administration of BP-C3 without 5-FU did not affect blood cell differentiation in the mice. Thus, BP-C3, depending on the administration schedule, had different effects on the haematological parameters of haematopoietic organs and peripheral blood in mice exposed to 5-FU. BP-C3 promoted intestinal crypt survival when administered on the preventative/therapeutic and therapeutic schedules, suggesting that the formulation protects the epithelium of the small intestine against damage by 5-FU.