THE HIGH background-radiation area (HBRA) of Yangjiang, located in southwest Guangdong, China, is composed of two closely adjacent regions, Dong-anling and Tongyou. The annual dose from natural radiation in this HBRA varies from 5.06 mSv y−1 to 6.86 mSv y−1. HBRAs provide a unique opportunity to study the effects of chronic low-dose radiation on humans.
The Yangjiang HBRA covers a total area of approximately 540 km2. The 80,000 inhabitants largely belong to families who have lived there for two generations or more. The control area (CA) is located relatively near the HBRA and has a similar population size. In general, the HBRA and CA are comparable with respect to factors other than natural radiation level. The annual dose from natural radiation in the CA varies from 1.8 mSv y−1 to 2.3 mSv y−1.
The high background radiation in the HBRA is due to the surface granites of the nearby mountain, from which monazite particles are washed down continually by rain and deposited in the surrounding basin regions. The concentrations of 238U, 232Th, and 226Ra in the soil of the HBRA are approximately three to five times higher than those in the CA, where the nearby rocks are limestone, and the natural radiation levels are normal.
Based on the difference in radiation levels between the HBRA and CA, extensive epidemiological studies have been carried out in the HBRA of China since 1972 for the purpose of studying the human health effects of exposure to high background levels of radiation in the natural environment (HBRRG 1980). These studies have shown that cancer mortalities in the HBRA are lower than those in the CA, while the reactivity of T-lymphocytes and the DNA repair system among young people in the HBRA was higher than that in the CA, which contradicts the linear nonthreshold theory of carcinogenesis and indicates a possible adaptive response (AR) in the HBRA (HBRRG 1985 ; Tao et al. 2004, 2008, 2012).
AR is well known in many biological systems and results from exposure to certain environmental stresses at very low intensity. In the case of low-dose ionizing irradiation, AR acts as a biological defense mechanism that elicits cellular resistance to the genotoxic effects of subsequent irradiation (Mohammadi et al. 2006). The concept of AR was derived from studies of the health effects of ionizing radiation, based on findings that living organisms possess the ability to respond to low-dose radiation in a sophisticated way (Seong and Kim 1994 ; Su 2003 ; Liu 2008). The molecular mechanisms of AR can be described by a systems biology approach using several pathways: the DNA repair system, regulation of the cell cycle, the antioxidative stress defense system, and heat shock proteins. Upon stimulation, organism functions including DNA repair capacity, apoptosis, and immune defense can be enhanced to produce AR. Such responses, in which acquired radioresistance is induced by low-dose radiation, have been reported mostly in experimental animal studies, and much less evidence is available from human investigations (Durante and Manti 2008).
The present study aimed to investigate the effects of low-dose radiation, at the molecular level, on DNA oxidative damage, DNA damage repair, antioxidation, and apoptosis in the human population inhabiting the HBRA of Guangdong. The results could provide experimental molecular biological evidence to further elucidate the potential AR mechanisms of cancer epidemiology in the HBRA.
MATERIALS AND METHODS
A total of 53 male inhabitants between 50 and 59 y old were selected from the HBRA in Yangjiang as the exposure group, while 53 male inhabitants of the same ages from Enping were selected as the control group. Those with a family history of tumors, medical radiation exposure within the last half year, chronic disease, medicine taken within one month, and acute infectious diseases were excluded.
Informed consent was obtained from all subjects. The study protocol was approved by the Ethics Committee of our institute.
Questionnaires were conducted to collect information on the following traits: (1) personal status (age, social level, economic status); (2) food and nutrients consumed; (3) smoking history (never smoked, previously smoked, currently smokes with median packs/year); (4) alcohol-drinking status (never drinks, drinks occasionally, drinks regularly); (5) habitation conditions (house type, construction materials, ventilation); (6) medical radiation history; and (7) stressful life events such as surgery, accident with blood loss, death of family members, or divorce.
All subjects were monitored by wearing a thermoluminescent dosimeter (TLD) at the waist for 90 d with inspection every month.
The external radiation dose per year was calculated by the following formula: external radiation dose per year = external radiation dose for 90 d × 4. The internal radiation dose was derived according to our previous studies (Yuan et al. 2004). The effective dose per year was the sum of the internal and external radiation doses.
Measurement of antioxidative capacity in serum samples
The peripheral blood of subjects was sampled and centrifuged at 3,000 rpm for 10 min to segregate blood serum (radius of centrifuge is 12.4 cm). An aliquot of 30 μL serum was used for measurement of superoxide dismutase (SOD) activity, 100 μL for glutathione hormone (GSH) activity, 100 μL for catalase (CAT) activity, and 100 μL for total antioxidant capacity (T-AOC) content with commercial kits using chemical colorimetry (supplied by Nanjing Jiancheng Bioengineering Institute, Jiangsu Sheng, China).
The peripheral blood of subjects was sampled with a negative-pressure tube containing sodium ethylenediaminetetraacetic acid (Na2 EDTA) as an anticoagulant and was brought back to the laboratory on ice. Total RNA was extracted from the peripheral blood using TRIzol reagent (Takara Biotechnology Co., Ltd., Dalian, China) following the manufacturer’s instructions. Briefly, the blood was centrifuged at 3,000 rpm for 10 min to remove plasma and washed with phosphate-buffered saline (PBS) twice. Leukocytic cream was collected in a safety cabinet and then transferred to a 2 ml RNase-free Eppendorf tube, and 1 ml TRIzol was added. Total RNA was extracted according to the kit directions (Gibco BRL, Grand Island, NY, U.S.), and cDNA was synthesized using the M-MLV Reverse Transcription Kit (Promega, Madison, WI, U.S.).
Reverse transcription-PCR of MGMT
O6‐methylguanine-DNA methyltransferase (MGMT) polymerase chain reaction (PCR) primers were synthesized by Shanghai Sangon Company as listed in Table 1, and 35 cycles of amplification were performed. The PCR product was separated using agarose gel electrophoresis (containing 0.5 μg mL−1 ethidium bromide) and photographed with a gel imaging system (Vilber, Lourmat, France). The PCR density was represented by the integral of optical density × area. Beta-actin was used as an internal control, and the expression of MGMT mRNA was represented as the ratio of MGMT density to beta-actin density.
Real-time quantitative PCR of hOGG1, hMTH1, TP53, BCL2, BAX, HSPB1, MT-COX2
PCR primers for hOGG1, hMTH1, TP53, BCL2, BAX, HSPB1, and MT-COX2 were synthesized by Takara Biotechnology Co., Ltd., as listed in Table 2. The total RNA of each sample was reverse transcribed to cDNA using the PrimeScript II 1st Strand cDNA Synthesis Kit (Takara Biotechnology Co., Ltd.). All quantitative real-time PCR was performed with Takara SYBR Premix Ex TaqTM II (Tli RNase H Plus) according to the following program: 95°C for 3 min; 40 cycles of 95°C for 5 s; and 60°C for 34 s. Beta-actin was used as an internal control. The relative expression levels of mRNA were calculated using the ΔCt and 2−ΔΔCt methods.
Quantitative detection of 8-OHdG, TrxR, HSP27, and MT-COX2
Quantitative detection of 8-OHdG, TrxR, HSP27, and MT-COX2 in plasma were performed using enzyme-linked immunosorbent assay (ELISA) kits (8-OHdG and TrxR: CUSABIO, Wuhan, China; HSP27 and MT-COX2: Bluegene, Shanghai, China) according to the manufacturers’ instructions.
Statistical analysis was performed using the SAS software package (version 8.1; SAS Institute, Cary, NC, U.S.). Data were expressed as the mean values with standard deviations according to the normal distribution or as medians with interquartile ranges. Differences among experimental groups were examined by t-test or the Mann-Whitney U test. The chi-squared test method was adapted to the qualitative data. Values of p < 0.05 were considered of significance.
Estimation of effective dose per year
A total of 85 TLDs were reclaimed, of which 40 were from the CA group (a reclamation rate of 75%) and 45 were from the HBRA group (85%). The external radiation dose ranges were within 0.72–1.96 mSv and 2.20–4.84 mSv per year in the CA and HBRA, respectively, with averages of 0.92 mSv and 2.96 mSv per year, respectively. The overall effective radiation dose to HBRA inhabitants was 6.24 mSv y−1, and that to CA inhabitants was 1.95 mSv y−1, representing a three-fold difference.
Distribution of influential factors in the two populations
Data from the questionnaire were used to analyze the modifying factors in the two groups. No statistically significant differences were found in variables such as age, smoking status, alcohol drinking, and stressful life events between the two populations (p > 0.05, Table 3), indicating the comparability of the two groups.
Comparison of antioxidative capacity in the two populations
The activities of the antioxidative enzymes SOD, GSH, and CAT and the T-AOC in the CA group were 50.23 ± 26.19 U mL−1, 23.17 ± 4.33 U mL−1, 2.20 ± 1.65 U mL−1, and 11.41 ± 3.78 U mL−1, respectively, while those in the HBRA group were 65.93 ± 38.50 U mL−1, 28.81 ± 6.36 U mL−1, 4.48 ± 2.19 U mL−1, and 14.39 ± 3.06 U mL−1, respectively. A significant difference was present between the two groups (p < 0.05, Table 4).
mRNA Expression levels of DNA repair genes in the two populations
A representative image of MGMT and beta-actin mRNA expression is shown in Fig. 1. As shown in Table 5 and Fig. 2, in the peripheral blood leukocytes of the HBRA and CA inhabitants, the relative mRNA expression levels (ΔCt; greater values indicate lower levels of expression) of the DNA repair gene MGMT were 0.60 ± 0.12 and 0.41 ± 0.11, with a significant difference between the two groups (p < 0.05). The relative mRNA expression level of hOGG1 was significantly higher in the HBRA group than in the CA group [10.58 (9.07, 13.43) vs. 10.31 (7.23, 11.96), p < 0.05]. These results indicated that the capacity for DNA repair of HBRA inhabitants might be higher than that of CA inhabitants.
mRNA Expression levels of proapoptotic genes and an antiapoptotic gene in the two populations
Table 6 shows the mRNA expression levels of proapoptotic genes and an antiapoptotic gene in the peripheral blood leukocytes of HBRA and CA inhabitants. Compared with those in the CA, the mRNA expression levels of the proapoptotic genes TP53 and BAX were significantly lower in the HBRA, and both the expression level of the antiapoptotic gene BCL2 and the ratio of BCL2/BAX were higher in the HBRA. The differences in BCL2 level and BCL2/BAX ratio between the two groups were statistically significant (p < 0.05). These results indicated that cells tended to exhibit antiapoptotic programs under conditions of naturally high background radiation.
mRNA Expression levels of oxidative-stress-related genes in the two populations
As shown in Table 7, the relative mRNA expression levels (ΔCt) of HSPB1 were 1.68 (1.33, 2.35) and 3.08 (2.13, 4.47) in the HBRA and CA, and those of MT-COX2 were −5.04 ± 1.75 and 3.21 ± 1.54, respectively. Compared with those in CA, the relative mRNA expression levels of HSPB1 and MT-COX2 were higher in HBRA, and all differences between the two groups were statistically significant (p < 0.05).
Comparisons of 8-OHdG, TrxR, HSP27, and MT-COX2 in the two populations
In the plasma of the inhabitants of the HBRA and CA, the concentrations of the DNA oxidative damage index 8-OHdG were 270.98 ± 107.46 ng mL−1 and 315.39 ± 111.87 ng mL−1, respectively. The concentrations of the antioxidant index TrxR were 0.49 ± 0.05 ng mL−1 and 0.46 ± 0.06 ng mL−1, respectively. The differences between the two groups were statistically significant (p < 0.05). These results indicated that less DNA oxidative damage and higher oxidation resistance were present in the inhabitants of the HBRA. HSP27 concentrations, which reflect the oxidative stress index, were 1.92 ± 1.17 ng mL−1 in the HBRA and 1.94 ± 1.40 ng mL−1 in the CA, and the concentrations of the indicator MT-COX2 were 1.87 ± 3.01 ng mL−1 and 2.29 ± 5.10 ng mL−1, respectively. The differences in HSP27 and MT-COX2 in the two groups showed no statistical significance (p > 0.05), as shown in Table 8.
Hormesis was proposed first by Luckey (1980), who held that low-dose radiation was beneficial to human health. Subsequently, Olivieri found that low-dose irradiation with tritiated thymidine (3H-TdR) could induce an adaptive cytogenetic response (Olivieri et al. 1984). Radiation-induced AR is described as a reduced effect of radiation received at a challenging dose under conditions of induction by a previous low radiation dose (Tapio and Jacob 2007). Many animal studies have indicated a possible role of radioadaptive responses in the development of various cancers, and it is now widely accepted that low-dose exposure to either radiation or chemicals may induce in vivo AR (Mohammadi et al. 2006). Radiation-induced AR provides a new scope for the risk assessment and medical application of ionizing radiation (Sakai 2006).
Regarding the mechanisms underlying AR, an enhanced capacity for DNA damage repair and antioxidation have largely been considered the main contributing factors (Chae et al. 1999 ; Yang et al. 2000). The defense system of the human body functions through enzymatic reactions catalyzed by SOD and CAT and nonenzymatic reactions involving GSH, which scavenges reactive oxygen species (ROS) and free radicals. Low antioxidant capacity has been found to be related to diseases such as cancer, diabetes, and immune deficiency. On the other hand, antioxidative enzyme activity can be activated by low-dose irradiation in immune cells such as lymphocytes. After exposure to gamma irradiation at a low dose of 0.02 Gy, human lymphoblast AHH‐1 cells were then exposed to a high dose of 3 Gy gamma irradiation for 6 h, and the activities of Mn-superoxide dismutase (M-SOD), glutathione S transferase (GST), glutathione peroxidase (GPX), and CAT increased promptly, suggesting the role of antioxidation in the mechanism of AR (Bravard et al. 1999). Evidence also exists of increased activities of SOD and Se-GPX in the thymus and spleen after whole-body low-dose irradiation. In clinical practice, patients with bronchial asthma often show increased SOD activity and decreased lipid peroxidation after short-term low-dose radiation. Epidemiological investigation has shown that SOD activity in residents near a hot spring (with a radon concentration of 54 Bq m−3) was higher than that in residents of the control area (Yamaoka et al. 2004).
In this study, an increased antioxidative capacity was confirmed in the inhabitants of the HBRA, consistent with the report by Yamaoka et al. (2004, 2005). The reinforced antioxidative capacity might account for the lower mortality rate from cancer in the HBRA (Pohl-Rüling and Hofmann 2002), as it could lead to more effective free radical removal and inhibition of lipid peroxidation, protecting cells from oxidative damage and malignant transformation.
Activation of DNA repair enzymes by low-dose radiation could be another mechanism underlying AR. Olivieri and Wolff (Olivieri et al. 1984 ; Wolff 1996, 1998) reported that the repair system in cells was stimulated by long-term exposure to low-dose radiation, and stimulated cells could endure a high dose of radiation, suggesting the importance of DNA damage repair in the mechanisms of AR. DNA repair is a complicated process in which MGMT produces a key repair enzyme for alkylation damage and is very sensitive to radiation (Wang et al. 2005 ; Kaina et al. 2007). Alkylation induced by radiation could be repaired by MGMT to increase the tolerance of organisms to radiation (Zhang et al. 2010). The present study found a stimulated antioxidative capacity and a higher level of MGMT expression in the HBRA, indicating the roles of enhanced immune function and DNA repair in response to high background radiation.
The hOGG1 gene on chromosome 3p25‐26, composed of seven exons and six introns, plays an important role in DNA repair by various processes (Dianov et al. 2001). The protein hOGG1, encoded by the hOGG1 gene, is a key enzyme in oxidative damage repair that can specifically excise and repair the 8‐OHdG caused by ROS. Analyses of 8‐OHdG in human leukocyte DNA and in urine are new approaches to the assessment of an individual’s cancer risk due to oxidative stress. 8‐OHdG is one of the major forms of oxidative DNA damage and a useful marker of cellular oxidative stress (Kasai 1997). Trx (thioredoxin) is an important protein regulating redox equilibrium by eliminating ROS and regulating some proteins. Trx, TrxR, and NADPH constitute the Trx system, which can repair oxidized proteins and eliminate oxygen free radicals in vivo. Compared to those in the CA group, the relative mRNA expression level of hOGG1 and the concentration of the antioxidant index TrxR were significantly higher in the HBRA group, and the concentration of the DNA oxidative damage index 8‐OHdG was significantly lower. These results suggest that the DNA oxidative-damage-repair capacity of HBRA inhabitants, who live with long-term naturally high background-radiation levels, might be enhanced, allowing them to clear and repair the oxidative DNA damage product 8‐OHdG in a timely manner. This ability leads to a decreased plasma level of 8‐OHdG as a result of adaptation stimulated by long-term exposure to high background radiation, consistent with the results of epidemiological studies in the HBRA.
Cells can survive when DNA damage repair is performed completely. However, if DNA damage repair fails, the body causes the cells to undergo apoptosis, and the mRNA expression levels of apoptosis-related genes will change. Cellular apoptosis is regulated by multiple genes, of which the p53 and Bcl‐2 gene families are the best known. The p53 gene, which is also known as a tumor suppressor gene, is an important apoptosis induction gene. Its high expression can promote cellular apoptosis and inhibit tumor formation. Moreover, the p53 protein is involved in repair of double-stranded DNA breaks through multiple signal-transduction pathways. The Bcl‐2 gene family and its related proteins are the most important gene family in the regulation of apoptosis. The Bcl‐2 gene family, including Bcl‐2, Bcl-xl, Bax, Bak, Bik, and Bid, plays an important regulatory role in the mitochondrial pathway of cellular apoptosis, and Bcl‐2 and Bcl-xl are its major antiapoptotic factors (Azad et al. 2010). The function of Bcl‐2 is to extend the life of the cell and increase cellular resistance to apoptosis-stimulating factors. Heterodimers formed by Bax and Bcl‐2 can inhibit the activity of Bcl‐2 and promote apoptosis. The ratio of Bcl‐2 to Bax (Bcl‐2/Bax) is the key factor that determines the strength of apoptosis inhibition, regulating the balance of cell proliferation and apoptosis (Korsmeyer et al. 1993 ; Yu et al. 2001). The greater the ratio is, the greater the antiapoptotic ability will be. Compared with those in CA inhabitants, the mRNA expression levels of the proapoptotic genes TP53 and BAX were significantly lower in HBRA inhabitants, and both the expression of the inhibitory apoptotic gene BCL2 and the ratio of BCL2/BAX were higher in the HBRA group. The differences in BCL2 and BCL2/BAX between the two groups were statistically significant. The results above are consistent with those of previous animal studies. Under long-term low-dose ionizing radiation, the body may repair damaged cells by improving its capacity for DNA damage repair and antioxidation, and the expression levels of genes that inhibit apoptosis will be elevated, while those of genes that promote apoptosis will be reduced. Because cellular apoptosis is closely related to DNA damage repair, antioxidation, and the occurrence of cancer, our results serve as a partial explanation of the AR mechanism from the perspective of cellular apoptosis.
Heat shock protein beta‐1 gene (HSPB1) is located on chromosome 7 at q11.23 and contains three exons and two introns. Heat shock protein (HSP) 27, encoded by HSPB1, is an adenosine triphosphate-independent molecular chaperone that can facilitate the repair or degradation of damaged proteins to protect against protein aggregation in stressed cells (Haslbeck 2002 ; Parcellier et al. 2003). Furthermore, HSP27 can relieve the toxic effects of oxidized proteins and enhance the antioxidant defense capacity of cells (Arrigo et al. 2005 ; Lopez Guerra et al. 2011). These characteristics of HSP27 may be of particular importance in the process of AR, because ROS are important in the induction of apoptosis in cells exposed to radiation (Pinthus et al. 2007). Compared with that in CA inhabitants, the relative mRNA expression level of HSPB1 was significantly higher in HBRA inhabitants. This result suggested that long-term high background radiation, as an external environmental stimulation factor, might induce AR in HBRA residents. The HSP27 protein protects the cell mainly through restraining the aggregation of denatured or misfolded proteins, promoting the irreversible degradation of these proteins by hydrolysis, regulating the production of ROS, and inhibiting cellular apoptosis. Our previous studies have found that the antioxidant capacity and apoptosis inhibition of HBRA inhabitants might be higher than that of CA inhabitants. Overall, these results indicated that the increased expression of HSP27 might play an important role in AR as part of the ROS generation and cellular apoptosis signal-transduction pathways.
The mitochondrial membrane, which is rich in polyunsaturated fatty acids, is susceptible to attack by reactive oxygen radicals, and cytochrome C oxidase (COX) can then cause changes in the morphology and function of mitochondria (Das et al. 2012). COX is involved in mitochondrial oxygen utilization and energy production, playing a key role in maintaining mitochondrial antioxidant mechanisms and cellular energy metabolism (Hescot et al. 2013 ; Bourens et al. 2014). COX is also closely related to apoptosis. Reduction in COX activity can initiate apoptosis by decreasing adenosine triphosphate levels in the cell and collapsing the inner mitochondrial membrane potential. Abnormal expression of COX2 can directly damage the function of COX. Thus, our study selected COX2 to reflect the overall expression of COX. The relative mRNA expression level of MT-COX2 was higher in HBRA than in CA, and the difference between the two groups was statistically significant. This result suggests that low-dose radiation can enhance the antioxidative capacity of HBRA inhabitants. However, the difference in the level of the MT-COX2 protein in plasma was not statistically significant.
This study comprehensively assesses the evidence for AR in the inhabitants of the HBRA of Yangjiang, China. In conclusion, under conditions of long-term, naturally high, background ionizing radiation differing from the natural radiation background of the control area, the DNA damage-repair capacity and antioxidant ability of the inhabitants of the HBRA may be enhanced. Additionally, HBRA residence could induce up regulation of gene expression related to cell survival and down regulation of apoptotic gene expression. In summary, the lower mortality rate of cancer in the residents of HBRA may be attributable to AR.
The first two authors, Shibiao Su and Shanyu Zhou, contributed equally to this work. This study was supported by grants from the Medicine Scientific Research Foundation of Guangdong Province (A2007057), the Open Fund from Provincial Key Lab of Soochow University (KJS0718), Guangdong Province Hospital for Occupational Disease Prevention and Treatment–Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment (2017B030314152), and the National Natural Science Foundation of China (81602804).
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