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Effects of radioactive iodine (131I) on the thyroid of newborn, pubertal and adult rats
International Congress Series 1236 (2002) 127 – 131
Effects of radioactive iodine (131I) on the thyroid of newborn, pubertal and adult rats Yumiko Nitta*, Masaharu Hoshi, Kenji Kamiya Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami, Hiroshima 734-8553, Japan
Abstract Age is a potent modifier of thyroid cancer. The short latency for the development of thyroid cancer in the post-Chernobyl cases proposes that we need to be sure of the thyroid susceptibility to internal exposure, especially at young ages. We started a large-scale carcinogenesis project 6 years ago with the purpose to evaluate the carcinogenic potential of 131I when irradiated at young ages. First, we established a method to estimate the absorbed doses in the thyroid of different age groups. Irradiation at 1 week of age caused heavier exposure than at 4 and 9 weeks of age by eight times, while damages of the thyroid tissue were more obvious in the 4-week-old groups than in the 1-weekold groups. Second, we tested the responsiveness of thyroid epithelium to radiation. Apoptosis was not detected in the 1-week-old-thyroid epithelium, however, it did appear in the 4-week-old thyroid epithelium. While the proliferating cell nuclear antigen (PCNA)-labeling index was vice versa. Third, the carcinogenesis of 131I has been tested. Papillary carcinomas have developed in rats internally irradiated with 131I at the age of 1 week. A very low dose rate of irradiation by 131I could induce thyroid carcinomas with a short latency. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Chernobyl; Thyroid cancer;
131
I; Internal exposure; Rat
1. Introduction Medical internal exposures to 131I showed no age-dependency in the risk of thyroid cancer. However, the short latency for the development of thyroid cancer in children of the post-Chernobyl cases signals to us to make sure of the thyroid’s susceptibility to radiation at young ages. We started a large-scale carcinogenesis project for the purpose of re-evaluating the carcinogenic potential of 131I when irradiated at young ages. First, we established a method to estimate the doses of 131I in the thyroid at different ages [1,2]. Second, we *
Corresponding author. Tel./fax: +81-82-257-5877. E-mail address: [email protected] (Y. Nitta).
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 1 ) 0 0 8 5 6 - 1
128
Y. Nitta et al. / International Congress Series 1236 (2002) 127–131
compared the thyroid susceptibility to radiation at different ages [3]. Third, the carcinogenesis experiment is on going.
2. Materials and methods For the internal and external irradiation experiments, female rats of the Fischer 344 strain of the 1-, 4- and 9-week-old groups at irradiation were set up. Each age group was composed of the standard diet (SD) and the iodine-deficient diet (IDD) group [1,2]. 131I was injected with activities to give 3.0 Gy as the thyroid dose for the SD-rats for the internal irradiation [1,2]. The 60Co-rays were applied externally to the rat thyroid with a dose of 3.0 Gy. The rats
Fig. 1. Epithelial atrophy post-radiation exposure (IDD groups). HE staining of the thyroid irradiated at the age of 1 week (left column) or at the age of 4 weeks (right column). (a) and (d) were the section just before the irradiation, (b) and (e) were those at 6-h post-irradiation, and (c) and (f) at 48-h post-irradiation.
Y. Nitta et al. / International Congress Series 1236 (2002) 127–131
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were autopsied at 0-, 6-, 12-, 24-, 48-, 96-, 192- and 384-h post-irradiation. Using the paraffin-embedded thyroid section, the proliferation profile of the epithelium was expressed by labeling the index of the proliferating cell nuclear antigen (PCNA), and the apoptosis was detected by the TdT-mediated dUTP-biotin nick end labeling (TUNEL) method.
Fig. 2. (A) Epithelial responsiveness to radiation exposure (SD groups). Columns indicate the PCNA labeling index (nuclei/follicle). The bar indicates standard error. (B) Epithelial responsiveness to radiation exposure (IDD groups). HE staining (a, b) and PCNA immunostaining (c, d). (a) and (c) were the thyroid at 48-h post-irradiation of the 1-week-old group.(b) and (d) were the thyroid at 48-h post-irradiation of the 4-week-old group. The arrow indicates PCNA positive blood vessel’s endothelium. The arrowhead indicates PCNA positive foliclar epithelium.
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Y. Nitta et al. / International Congress Series 1236 (2002) 127–131
3. Results 3.1. Kinetics of the thyroid treated with
131
I
The kinetics of 131I in the thyroid and the whole body showed that IDD-treatment increased the exposure to 131I by 4.2, 2.4 and 2.1 for the 1-, 4- and 9-week-old groups, respectively [2]. The epithelial atrophy 6 h after irradiation was prominent in the IDDtreated thyroid after the injection (Fig. 1). 3.2. Epithelial apoptosis and proliferating responsiveness post-irradiation When 131I was irradiated, no TURNEL-positive cell was found in the thyroid, however, it was found in the spleen. When 60Co was irradiated, severe apoptosis was observed in the external granular cells in the cerebellum, however, not in the thyroid. When irradiated with 131 I or 60Co, there were lots of PCNA-positive nuclei in the 4- but not in the 1-week-old thyroid (Fig. 2A, B).
4. Discussion The 1-week-old groups were exposed more heavily than the 4- and 9-week-old groups when irradiated internally, and both internal and external irradiations caused atrophy on the thyroid epithelium 6 to 12 h later [2]. However, the atrophic cells did not show apoptosis in all the three age groups. Cell proliferation started after 48 h of irradiation in the 4-week-old groups, however, it did not start at that time in the 1-week-old groups. This attenuation of the epithelial proliferation post-irradiation in the 1-week-old groups might contribute to thyroid cancer development. One year has passed since we set up a large-scale carcinogenesis experiment for the induction of thyroid cancer by radiation. At the moment, multiple carcinomas developed in the rats whose thyroids were exposed to 3.6, 8.9 or 21.4 Gy of 131I at the age of 1 week with the latency of 36 weeks. Pathologically, most of the cancers were diagnosed as papillary carcinomas. In conclusion, papillary carcinomas are found to be inducible in rats by the combined treatment of 131I and an iodine deficient diet with a short latency, when the exposure to radiation is at a young age. Finally, a low dose rate of the moderate dose irradiation could induce thyroid cancer in rats. Acknowledgements This work was supported by a Grant-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan (Y.N. 09788107). References [1] S. Endo, Y. Nitta, M. Ohtaki, J. Takada, V. Stepanenko, K. Komatsu, H. Tauchi, S. Matsuura, E. Iaskova, M. Hoshi, Estimation of dose absorbed fractions in rat thyroid, J. Radiat. Res. 39 (1998) 223 – 230.
Y. Nitta et al. / International Congress Series 1236 (2002) 127–131
131
[2] Y. Nitta, S. Endo, N. Fujimoto, K. Kamiya, M. Hoshi, Age-dependent exposure to radioactive iodine (131I) in the thyroid and total body of newborn, pubertal and adult Fischer 344 rats, J. Radiat. Res. 42 (2001) 143 – 155. [3] Y. Nitta, K. Kamiya, M. Hoshi, Thyroid susceptibility to radioactive iodine (131I) in newborn, pubertal and adult rats, Proceedings of the 2nd International Symposium for Low Dose and Very Low Dose of Radiation on Human Health, Dublin, 27th f 29th, June, 2001.
Effects of radioactive iodine (131I) on the thyroid of newborn, pubertal and adult rats Yumiko Nitta*, Masaharu Hoshi, Kenji Kamiya Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami, Hiroshima 734-8553, Japan
Abstract Age is a potent modifier of thyroid cancer. The short latency for the development of thyroid cancer in the post-Chernobyl cases proposes that we need to be sure of the thyroid susceptibility to internal exposure, especially at young ages. We started a large-scale carcinogenesis project 6 years ago with the purpose to evaluate the carcinogenic potential of 131I when irradiated at young ages. First, we established a method to estimate the absorbed doses in the thyroid of different age groups. Irradiation at 1 week of age caused heavier exposure than at 4 and 9 weeks of age by eight times, while damages of the thyroid tissue were more obvious in the 4-week-old groups than in the 1-weekold groups. Second, we tested the responsiveness of thyroid epithelium to radiation. Apoptosis was not detected in the 1-week-old-thyroid epithelium, however, it did appear in the 4-week-old thyroid epithelium. While the proliferating cell nuclear antigen (PCNA)-labeling index was vice versa. Third, the carcinogenesis of 131I has been tested. Papillary carcinomas have developed in rats internally irradiated with 131I at the age of 1 week. A very low dose rate of irradiation by 131I could induce thyroid carcinomas with a short latency. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Chernobyl; Thyroid cancer;
131
I; Internal exposure; Rat
1. Introduction Medical internal exposures to 131I showed no age-dependency in the risk of thyroid cancer. However, the short latency for the development of thyroid cancer in children of the post-Chernobyl cases signals to us to make sure of the thyroid’s susceptibility to radiation at young ages. We started a large-scale carcinogenesis project for the purpose of re-evaluating the carcinogenic potential of 131I when irradiated at young ages. First, we established a method to estimate the doses of 131I in the thyroid at different ages [1,2]. Second, we *
Corresponding author. Tel./fax: +81-82-257-5877. E-mail address: [email protected] (Y. Nitta).
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 1 ) 0 0 8 5 6 - 1
128
Y. Nitta et al. / International Congress Series 1236 (2002) 127–131
compared the thyroid susceptibility to radiation at different ages [3]. Third, the carcinogenesis experiment is on going.
2. Materials and methods For the internal and external irradiation experiments, female rats of the Fischer 344 strain of the 1-, 4- and 9-week-old groups at irradiation were set up. Each age group was composed of the standard diet (SD) and the iodine-deficient diet (IDD) group [1,2]. 131I was injected with activities to give 3.0 Gy as the thyroid dose for the SD-rats for the internal irradiation [1,2]. The 60Co-rays were applied externally to the rat thyroid with a dose of 3.0 Gy. The rats
Fig. 1. Epithelial atrophy post-radiation exposure (IDD groups). HE staining of the thyroid irradiated at the age of 1 week (left column) or at the age of 4 weeks (right column). (a) and (d) were the section just before the irradiation, (b) and (e) were those at 6-h post-irradiation, and (c) and (f) at 48-h post-irradiation.
Y. Nitta et al. / International Congress Series 1236 (2002) 127–131
129
were autopsied at 0-, 6-, 12-, 24-, 48-, 96-, 192- and 384-h post-irradiation. Using the paraffin-embedded thyroid section, the proliferation profile of the epithelium was expressed by labeling the index of the proliferating cell nuclear antigen (PCNA), and the apoptosis was detected by the TdT-mediated dUTP-biotin nick end labeling (TUNEL) method.
Fig. 2. (A) Epithelial responsiveness to radiation exposure (SD groups). Columns indicate the PCNA labeling index (nuclei/follicle). The bar indicates standard error. (B) Epithelial responsiveness to radiation exposure (IDD groups). HE staining (a, b) and PCNA immunostaining (c, d). (a) and (c) were the thyroid at 48-h post-irradiation of the 1-week-old group.(b) and (d) were the thyroid at 48-h post-irradiation of the 4-week-old group. The arrow indicates PCNA positive blood vessel’s endothelium. The arrowhead indicates PCNA positive foliclar epithelium.
130
Y. Nitta et al. / International Congress Series 1236 (2002) 127–131
3. Results 3.1. Kinetics of the thyroid treated with
131
I
The kinetics of 131I in the thyroid and the whole body showed that IDD-treatment increased the exposure to 131I by 4.2, 2.4 and 2.1 for the 1-, 4- and 9-week-old groups, respectively [2]. The epithelial atrophy 6 h after irradiation was prominent in the IDDtreated thyroid after the injection (Fig. 1). 3.2. Epithelial apoptosis and proliferating responsiveness post-irradiation When 131I was irradiated, no TURNEL-positive cell was found in the thyroid, however, it was found in the spleen. When 60Co was irradiated, severe apoptosis was observed in the external granular cells in the cerebellum, however, not in the thyroid. When irradiated with 131 I or 60Co, there were lots of PCNA-positive nuclei in the 4- but not in the 1-week-old thyroid (Fig. 2A, B).
4. Discussion The 1-week-old groups were exposed more heavily than the 4- and 9-week-old groups when irradiated internally, and both internal and external irradiations caused atrophy on the thyroid epithelium 6 to 12 h later [2]. However, the atrophic cells did not show apoptosis in all the three age groups. Cell proliferation started after 48 h of irradiation in the 4-week-old groups, however, it did not start at that time in the 1-week-old groups. This attenuation of the epithelial proliferation post-irradiation in the 1-week-old groups might contribute to thyroid cancer development. One year has passed since we set up a large-scale carcinogenesis experiment for the induction of thyroid cancer by radiation. At the moment, multiple carcinomas developed in the rats whose thyroids were exposed to 3.6, 8.9 or 21.4 Gy of 131I at the age of 1 week with the latency of 36 weeks. Pathologically, most of the cancers were diagnosed as papillary carcinomas. In conclusion, papillary carcinomas are found to be inducible in rats by the combined treatment of 131I and an iodine deficient diet with a short latency, when the exposure to radiation is at a young age. Finally, a low dose rate of the moderate dose irradiation could induce thyroid cancer in rats. Acknowledgements This work was supported by a Grant-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan (Y.N. 09788107). References [1] S. Endo, Y. Nitta, M. Ohtaki, J. Takada, V. Stepanenko, K. Komatsu, H. Tauchi, S. Matsuura, E. Iaskova, M. Hoshi, Estimation of dose absorbed fractions in rat thyroid, J. Radiat. Res. 39 (1998) 223 – 230.
Y. Nitta et al. / International Congress Series 1236 (2002) 127–131
131
[2] Y. Nitta, S. Endo, N. Fujimoto, K. Kamiya, M. Hoshi, Age-dependent exposure to radioactive iodine (131I) in the thyroid and total body of newborn, pubertal and adult Fischer 344 rats, J. Radiat. Res. 42 (2001) 143 – 155. [3] Y. Nitta, K. Kamiya, M. Hoshi, Thyroid susceptibility to radioactive iodine (131I) in newborn, pubertal and adult rats, Proceedings of the 2nd International Symposium for Low Dose and Very Low Dose of Radiation on Human Health, Dublin, 27th f 29th, June, 2001.