T-cell immunosenescence and inflammatory response in atomic bomb survivors

In this paper we summarize the long-term effects of A-bomb radiation on the T-cell system and discuss the possible involvement of attenuated T-cell immunity in the disease development observed in A-bomb survivors. Our previous observations on such effects include impaired mitogen-dependent proliferation and IL-2 production, decreases in naive T-cell populations, and increased proportions of anergic and functionally weak memory CD4 T-cell subsets. In addition, we recently found a radiation dose-dependent increase in the percentages of CD25(+)/CD127(-) regulatory T cells in the CD4 T-cell population of the survivors. All these effects of radiation on T-cell immunity resemble effects of aging on the immune system, suggesting that ionizing radiation might direct the T-cell system toward a compromised phenotype and thereby might contribute to an enhanced immunosenescence. Furthermore, there are inverse, significant associations between plasma levels of inflammatory cytokines and the relative number of na?ve CD4 T cells, also suggesting that the elevated levels of inflammatory markers found in A-bomb survivors can be ascribed in part to T-cell immunosenescence. We suggest that radiation-induced T-cell immunosenescence may result in activation of inflammatory responses and may be partly involved in the development of aging-associated and inflammation-related diseases frequently observed in A-bomb survivors.     

Stable chromosome aberrations in atomic bomb survivors: results from 25 years of investigation

Frequencies of stable chromosome aberrations from more than 3,000 atomic bomb survivors were used to examine the nature of the radiation dose response. The end point was the proportion of cells with at least one translocation or inversion detected in Giemsa-stained cultures of approximately 100 lymphocytes per person. The statistical methods allow for both imprecision of individual dose estimates and extra-binomial variation. A highly significant and nonlinear dose response was seen. The shape of the dose response was concave upward for doses below 1.5 Sv but exhibited some leveling off at higher doses. This curvature was similar for the two cities, with a crossover dose (i.e. the ratio of the linear coefficient to the quadratic coefficient) of 1.7 Sv (95% CI 0.9, 4). The low-dose slopes for the two cities differed significantly: 6.6% per Sv (95% CI 5.5, 8.4) in Hiroshima and 3.7% (95% CI 2.6, 4.9) in Nagasaki. This difference was reduced considerably, but not eliminated, when the comparison was limited to people who were exposed in houses or tenements. Nagasaki survivors exposed in factories, as well as people in either city who were outside with little or no shielding, had a lower dose response than those exposed in houses. This suggests that doses for Nagasaki factory worker survivors may be overestimated by the DS86, apparently by about 60%. Even though factory workers constitute about 20% of Nagasaki survivors with dose estimates in the range of 0.5 to 2 Sv, calculations indicate that the dosimetry problems for these people have little impact on cancer risk estimates for Nagasaki.     

A chromosome study of 6-thioguanine-resistant mutants in T lymphocytes of Hiroshima atomic bomb survivors

Cytogenetic characterizations were made of lymphocyte colonies established from somatic mutation assays for 6-thioguanine (TG) resistance in Hiroshima atomic bomb survivors. G-banded chromosomes were analyzed in both TG-resistant (TGr) and wild-type colonies. Included were 45 TGr and 19 wild-type colonies derived from proximally exposed A-bomb survivors, as well as colonies from distally exposed control individuals who did not receive a significant amount of A-bomb radiation (18 TGr and 9-wild type colonies). Various structural and numerical chromosome abnormalities were observed in both TGr and wild-type colonies. Aberrations of the X chromosome, on which the hypoxanthine guanine phosphoribosyl transferase (HPRT) locus is present, were found in 6 colonies: 2 resistant colonies from controls (45,X/46,XX; 46,X,ins(X)), 3 resistant colonies (45,X/46,XX/46,X, + mar; 46,X,t(Xq +;14q-); 46,Y,t(Xq-;5q +)), and 1 wild-type colony (45,X/47,XXX) from proximally exposed persons. In cases with exchange aberrations, each of the break points on the X chromosome was situated proximally to band q26 where the HPRT locus is known to be assigned. DNA-replicating patterns were also studied, and it was found that abnormal X chromosomes showed early replicating patterns, while normal X chromosomes showed late replicating patterns.     

Hyperparathyroidism among atomic bomb survivors in Hiroshima.

To determine the effect of exposure to atomic bomb radiation on the occurrence of hyperparathyroidism, the prevalence was determined among a population of 3,948 atomic bomb survivors and their controls in Hiroshima. The diagnosis of hyperparathyroidism was based upon histopathological findings or the presence of consistent hypercalcemia and elevated levels of serum parathyroid hormone. Primary hyperparathyroidism was diagnosed in 19 persons (3 males, 16 females). Females had approximately a threefold higher overall prevalence of hyperparathyroidism than males (P less than 0.05). The prevalence rates of hyperparathyroidism increased with radiation dose (chi2(1) = 12, P less than 0.001) after adjusting for sex and age at the time of the bombing. The estimated relative risk was 4.1 at 1 Gy (95% confidence limits 1.7 to 14). There was some evidence that the effect of radiation was greater for individuals who were younger at the time of the bombing. In conclusion, exposure to atomic bomb radiation affected the occurrence of hyperparathyroidism, suggesting that doses of radiation lower than those used in radiotherapy may also induce this disorder.     

Organ doses from radiation therapy in atomic bomb survivors

Previous surveys of radiation therapy among the Life Span Study (LSS) population at the Radiation Effects Research Foundation (RERF) revealed that 1,670 (1.4%) of the LSS participants received radiation treatments before 1984. The data on therapeutic radiation doses are indispensable for studying the relationship between radiation treatments and subsequent cancer occurrences. In this study, the radiation treatments were reproduced experimentally to determine the scattered radiation doses. The experiments were conducted using a female human phantom and various radiation sources, including a medium-voltage X-ray machine and a (60)Co gamma-ray source. Doses were measured using thermoluminescence dosimetry and ionization chambers. Radiation doses were determined for the salivary glands, thyroid gland, breast, lung, stomach, colon, ovary and active bone marrow. The results have been used for documenting the organ doses received by patients in previous surveys. The contribution of therapeutic irradiation to the occurrence of chromosome aberrations was studied using data on doses to active bone marrow from both radiation treatments and atomic bomb exposures in 26 RERF Adult Health Study participants. The results suggest that radiation treatments contributed to a large part of their frequencies of stable-type chromosome aberrations. The therapeutic radiation doses determined in the present study are available for investigating the effects of therapeutic irradiation on the subsequent primary cancers among atomic bomb survivors who received radiation treatments.     

Mortality of atomic bomb survivors predicted from laboratory animals

Exposure, pathology and mortality data for mice, dogs and humans were examined to determine whether accurate interspecies predictions of radiation-induced mortality could be achieved. The analyses revealed that (1) days of life lost per unit dose can be estimated for a species even without information on radiation effects in that species, and (2) accurate predictions of age-specific radiation-induced mortality in beagles and the atomic bomb survivors can be obtained from a dose-response model for comparably exposed mice. These findings illustrate the value of comparative mortality analyses and the relevance of animal data to the study of human health effects.     

In vivo mutant T cell frequency in atomic bomb survivors carrying outlying values of chromosome aberration frequencies

Frequencies of HPRT- mutant T cells were determined by means of a direct clonal assay in atomic bomb survivors who showed outlying values of chromosome aberration frequencies. The studied survivors consisted of 2 groups: those whose aberration frequency was near the higher end of the distribution (high-aberration group) and those whose aberration frequency was near the lower end of the distribution (low-aberration group). The mean radiation doses (T65D) of the high-aberration group (13 people) and low-aberration group (17 people) were 248 and 273 rad, respectively. The mean mutant frequency (Mf) of the high-aberration group was 6.7 X 10(-6), which was significantly higher than that of the low-aberration group (3.7 X 10(-6)) or that of 17 controls (3.4 X 10(-6)). When all the samples were combined, the correlation between Mf and radiation dose was not significant using either dose estimation system, T65D or DS86. However, the correlation coefficient was higher when DS86 doses were used. Mf correlated significantly with increasing aberration frequencies. The tendency that Mf correlates better with chromosome aberration frequency than with estimated radiation dose was stronger in this study than in a previous study where the samples were selected randomly.     

Effects of radiation on the longitudinal trends of hemoglobin levels in the Japanese atomic bomb survivors

The late effects of radiation on the hematopoietic system have not been fully evaluated. We examined the long-term effects of radiation exposure on hemoglobin levels in the Japanese atomic bomb survivors over a 40-year period from 1958 to 1998. Compared to the unexposed survivors, the mean hemoglobin levels for those exposed to a bone marrow dose of 1 Gy were significantly reduced by 0.10 g/dl (95% CI: 0.04 to 0.16) or 0.67% at 40 years of age (P < 0.0001) and by 0.24 g/dl (95% CI: 0.08 to 0.40) or 1.8% at 80 years of age. Radiation effects are greater for smokers than for nonsmokers at age less than 35 years (P < 0.01), although cigarette smoking was associated with increased hemoglobin levels. Sex and birth cohort differences in radiation effects were not found after adjusting for smoking. The radiation-induced reduction in hemoglobin levels could not be explained by the presence of certain anemia-associated diseases.     

Prevalence of hepatitis B virus infection among atomic bomb survivors

The aim of this study was to determine whether the prevalence of hepatitis B virus (HBV) carriers increased with atomic bomb radiation dose, and whether radiation decreased the ability to clear HBV among the atomic bomb survivors. The study subjects were 6,121 participants in the Adult Health Study of atomic bomb survivors in Hiroshima and Nagasaki. After adjustment for age, sex, city and potential confounders, the rates of seropositivity for hepatitis B surface antigen (HBsAg), indicating current HBV infections, and anti-hepatitis B core antibody, indicating either cured or current infections, increased with radiation dose. However, no relationship was observed between radiation and anti-hepatitis B surface antibody (indicating cured infection). The proportion of persons who were unable to clear the virus, as the proportion of HBsAg-positive persons among those ever infected by HBV (positive for HBsAg or surface or core hepatitis B antibody), increased significantly with radiation dose among those receiving blood transfusions. This proportion was not related to dose among those who reported no such transfusions. The findings may suggest a lower likelihood of clearance after HBV infection among those who were more likely to have been infected with HBV as adults after atomic bomb irradiation rather than as infants or adults prior to irradiation.     

Noncancer disease incidence in atomic bomb survivors, 1958-1998

We examined the relationships between the incidence of noncancer diseases and atomic bomb radiation dose using the longitudinal data for about 10,000 Adult Health Study (AHS) participants during 1958-1998. The current report updates the analysis we presented in 1993 with 12 additional years of follow-up. In addition to the statistically significant positive linear dose-response relationships detected previously for the incidence of thyroid disease (P < 0.0001), chronic liver disease and cirrhosis (P = 0.001), and uterine myoma (P < 0.00001), we also found a significant positive dose response for cataract (P = 0.026), a negative linear dose-response relationship for glaucoma (P = 0.025), and significant quadratic dose-response relationships for hypertension (P = 0.028) and for myocardial infarction among survivors exposed at less than 40 years of age (P = 0.049). Significant radiation effects for calculus of the kidney and ureter were evident for men but not for women (test of heterogeneity by sex: P = 0.007). Accounting for smoking and drinking did not alter the results. Radiation effects for cataract, glaucoma, hypertension, and calculus of the kidney and ureter in men are new findings. These results attest to the need for continued follow-up of the aging A-bomb survivors to fully elucidate the effects of radiation exposure on the occurrence of noncancer diseases.     

Solid cancer incidence in atomic bomb survivors: 1958-1998

This is the second general report on radiation effects on the incidence of solid cancers (cancers other than malignancies of the blood or blood-forming organs) among members of the Life Span Study (LSS) cohort of Hiroshima and Nagasaki atomic bomb survivors. The analyses were based on 17,448 first primary cancers (including non-melanoma skin cancer) diagnosed from 1958 through 1998 among 105,427 cohort members with individual dose estimates who were alive and not known to have had cancer prior to 1958. Radiation-associated relative risks and excess rates were considered for all solid cancers as a group, for 19 specific cancer sites or groups of sites, and for five histology groups. Poisson regression methods were used to investigate the magnitude of the radiation-associated risks, the shape of the dose response, how these risks vary with gender, age at exposure, and attained age, and the evidence for inter-site variation in the levels and patterns of the excess risk. For all solid cancers as a group, it was estimated that about 850 (about 11%) of the cases among cohort members with colon doses in excess of 0.005 Gy were associated with atomic bomb radiation exposure. The data were consistent with a linear dose response over the 0- to 2-Gy range, while there was some flattening of the dose response at higher doses. Furthermore, there is a statistically significant dose response when analyses were limited to cohort members with doses of 0.15 Gy or less. The excess risks for all solid cancers as a group and many individual sites exhibit significant variation with gender, attained age, and age at exposure. It was estimated that, at age 70 after exposure at age 30, solid cancer rates increase by about 35% per Gy (90% CI 28%; 43%) for men and 58% per Gy (43%; 69%) for women. For all solid cancers as a group, the excess relative risk (ERR per Gy) decreases by about 17% per decade increase in age at exposure (90% CI 7%; 25%) after allowing for attained-age effects, while the ERR decreased in proportion to attained age to the power 1.65 (90% CI 2.1; 1.2) after allowing for age at exposure. Despite the decline in the ERR with attained age, excess absolute rates appeared to increase throughout the study period, providing further evidence that radiation-associated increases in cancer rates persist throughout life regardless of age at exposure. For all solid cancers as a group, women had somewhat higher excess absolute rates than men (F:M ratio 1.4; 90% CI 1.1; 1.8), but this difference disappears when the analysis was restricted to non-gender-specific cancers. Significant radiation-associated increases in risk were seen for most sites, including oral cavity, esophagus, stomach, colon, liver, lung, non-melanoma skin, breast, ovary, bladder, nervous system and thyroid. Although there was no indication of a statistically significant dose response for cancers of the pancreas, prostate and kidney, the excess relative risks for these sites were also consistent with that for all solid cancers as a group. Dose-response estimates for cancers of the rectum, gallbladder and uterus were not statistically significant, and there were suggestions that the risks for these sites may be lower than those for all solid cancers combined. However, there was emerging evidence from the present data that exposure as a child may increase risks of cancer of the body of the uterus. Elevated risks were seen for all of the five broadly classified histological groups considered, including squamous cell carcinoma, adenocarcinoma, other epithelial cancers, sarcomas and other non-epithelial cancers. Although the data were limited, there was a significant radiation-associated increase in the risk of cancer occurring in adolescence and young adulthood. In view of the persisting increase in solid cancer risks, the LSS should continue to provide important new information on radiation exposure and solid cancer risks for at least another 15 to 20 years.     

Effects of radiation on the longitudinal trends of total serum cholesterol levels in the atomic bomb survivors.

The effects of radiation on the long-term trends of the total serum cholesterol levels of the Hiroshima and Nagasaki atomic bomb survivors were examined using data collected in the Adult Health Study over a 28-year period (1958-1986). The growth-curve method was used to model the longitudinal age-dependent changes in cholesterol levels. For each sex, temporal trends of cholesterol levels were characterized with respect to age, body mass index, city and birth year. We then examined whether the temporal trends differed by radiation dose. We showed that the mean growth curve of cholesterol levels for the irradiated subjects were significantly higher than that for the unirradiated subjects, and that the increase was greater for women than for men. No difference in dose response was detected between Hiroshima and Nagasaki. An increased mean level of cholesterol was evident for irradiated women in general, but a notable increase was apparent in males only for the youngest birth cohort of 1935-1945. The difference in the mean cholesterol levels between the irradiated and unirradiated subjects diminished past 70 years of age. It is not known whether this is due to natural progression or is an artifact of nonrandom variation in the rate of participation in the examinations. The maximum predicted increase at 1 Gy for women occurred at age 52 years for the 1930 cohort: 2.5 mg/dl (95% CI 1.6-3.3 mg/dl) for Hiroshima and 2.3 mg/dl (95% CI 1.5-3.1 mg/dl) for Nagasaki. The corresponding increase for men occurred at age 29 years for the 1940 cohort: 1.6 mg/dl (95% CI 0.4-2.8) for Hiroshima and 1.4 mg/dl (95% CI 0.3-2.6) for Nagasaki. Controlling for cigarette smoking did not alter the dose-response relationship. Although the difference in the mean growth curves of the irradiated and unirradiated groups was statistically significant, there was a considerable overlap in the individual growth curves of the two groups. The significant sex difference and the greater magnitude of radiation effects in women suggest that hormonal changes resulting from radiation exposure, such as accelerated menopause, is an area worth investigating to delineate the mechanisms underlying the increased cholesterol levels of the irradiated female subjects. This increase may also partially explain the increased rate of coronary heart disease seen in the atomic bomb survivors.     

The F value for chromosome aberrations in atomic bomb survivors does not provide evidence for a primary contribution of neutrons to the dose in Hiroshima.

Brenner and Sachs (Radiat. Res. 140, 134-142, 1994) proposed that the ratio of interchromosomal to intrachromosomal exchanges, termed the F value, can be a cytogenetic fingerprint of exposure to radiations of different linear energy transfer (LET). Using published data, they suggested that F values are over 10 for low-LET radiations and approximately 6 for high-LET radiations. Subsequently, as F values for atomic bomb survivors were reported to be around 6, Brenner suggested that the biological effects of atomic bomb radiation in Hiroshima are due primarily to neutrons. However, the F values used for the survivors were means from individuals exposed to various doses. As the F-value hypothesis predicts a radiation fingerprint at low doses, we analyzed our own data for the survivors in relation to dose. G-banding data for the survivors showed F values varying from 5 to 8 at DS86 doses of 0.2 to 5 Gy in Hiroshima and around 6 in Nagasaki with no evidence of a difference between the two cities. The results are consistent with our in vitro data that the F values are invariably around 6 for X and gamma rays at doses of 0.5 to 2 Gy as well as two types of fission-spectrum neutrons at doses of about 0.2 to 1 Gy. Thus, apart from a possible effect at even lower doses, current data do not provide evidence to support the proposition that the biological effects of atomic bomb radiation in Hiroshima are caused mainly by neutrons.     

Plasma levels of kisspeptins in postmenopausal Chinese women do not show substantial elevation

The menopause, defined as the permanent cessation of menstruation resulting from ovarian failure, is characterized by elevated levels of serum gonadotropins. Recent studies have demonstrated that the gonadotropin hypersecretion in postmenopausal women is secondary to increase of KiSS-1 mRNA from the hypothalamus neurons, which encoded kisspeptin peptides. The present study was designed to determine whether plasma kisspeptins levels are altered in postmenopausal women. Blood samples were taken from 145 postmenopausal women, 35 young women and 30 pregnant women control in the first trimester. The plasma concentration of kisspeptins, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E₂) was measured using immunoassay kits. Results indicated that plasma kisspeptins levels in postmenopausal women had higher than those in young women (5.25 ± 0.36; 4.48 ± 0.34 pmol/L), but no significant difference was found between the two groups (p = 0.179). Plasma FSH and LH levels were significantly higher in postmenopausal women (124.67 ± 12.78, 57.14 ± 3.57 mIu/mL) than those in young women (9.23 ± 2.78, 7.56 ± 2.71 mIu/mL, p < 0.001). However, Plasma kisspeptins levels were not significantly correlated to FSH and LH in postmenopausal women (r = ?0.23, 0.324; p = 0.927, 0.176, respectively), and also there was no any correlation between plasma kisspeptins and E₂ in postmenopausal women (r = ?0.065; p = 0.792). Collectively, there was no significant difference in plasma kisspeptins levels between postmenopausal and young women. Our result suggested that kisspeptins’ role during menopause might mainly act in central rather than peripheral system and it could not be currently used as a clinical marker for menopause.