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7 October 2022 Life Span, Cause of Death and Neoplasia in B6C3F1 Mice Exposed In Utero to Low- and Medium-Dose-Rate Gamma Rays
Ignacia B. Tanaka III, Rei Nakahira, Jun-ichiro Komura, Satoshi Tanaka
Author Affiliations +

Previously, we reported that while low-dose-rate (LDR) gamma-ray exposure to 20 mGy/day for the entire gestation period (gestation days 0–18) did not result in any significant effect in B6C3F1 pups up to 10 weeks of age when compared to the non-irradiated controls, exposure to medium-dose-rates (MDR, 200 and 400 mGy/day) resulted in growth retardation and gonadal hypoplasia, in addition to delayed ossification (only at 400 mGy/day). In the present work, we investigated the late effects of continuous in utero exposure to gamma rays at LDRs (0.05, 1.0 and 20 mGy/day) and at an MDR of 400 mGy/day, on life span, causes of death, neoplastic and non-neoplastic disease incidences in B6C3F1 mice. Reproductive parameters such as litter size and weaning rates was not significantly different among the LDR groups, but was significantly decreased in the MDR group, when compared to the non-irradiated controls. Mean life spans were not significantly different among the LDR exposed groups compared to the non-irradiated controls, whereas the life spans of those exposed to the MDR were significantly shorter than the non-irradiated controls. There was no significant difference in tumor spectra between the non-irradiated and LDR nor MDR irradiated groups. In mice exposed to MDR in utero, the over-all incidence rates shifted with increased incidences in the number of neoplasms of liver (both sexes) and endocrine (adrenals, pituitary and ovaries in females) origin with corresponding decreases in the incidence of malignant lymphomas (both sexes) and lung neoplasms (males). Multiple primary neoplasms were significantly increased only in females exposed to MDR. Results show that B6C3F1 mice exposed to gamma-rays in utero at LDRs of 0.05, 1 and 20 mGy/day for the entire gestation period (18 days) does not significantly alter lifespan, cause of death, neoplasm incidence rates and tumor spectra.


Radiation exposure during pregnancy is a health concern for both the mother and the unborn child and is a source of anxiety in pregnant women. Except for radiation therapy, fluoroscopy-guided interventional procedures and some computed tomography (CT) scans, diagnostic medical imaging procedures such as CT, conventional fluoroscopy and nuclear medicine expose the embryo or fetus to absorbed doses of 0.1 Gy or less (1, 2). X-ray exposures of ≤5 rad (≤5 mGy) at any stage of pregnancy show no measurable risk (3), neither birth defects or miscarriage (1).The maximum permissible dose to the fetus is 0.5 mSv (0.05 rem)/month and a dose of 0.1 Gy (10 rad) to the embryo during the sensitive period of gestation (10 days to 25 weeks) is frequently considered as the cutoff point above which therapeutic abortion should be considered to avoid the possibility of an abnormal child (4).

The biological effects of in utero radiation exposure depend on many factors such as radiation quality, dose and dose-rate, gestation age at the time of exposure, and are further confounded by maternal factors (age, health status) and genetic predilection (5), all of which need to be taken into consideration when assessing risk.

The effects of ionizing radiation exposure on the fetus are broadly classified as either deterministic effects (tissue reactions), such as death (pregnancy loss = miscarriage/stillbirth), congenital malformations, growth/developmental disturbances, microcephaly and intellectual disability and increased cancer risks, or as stochastic effects, such as cancer induction as in childhood cancers (6). In humans, doses to the fetus above 0.10 Gy (100 mGy, 10 rads) increases the risk of tissue reactions (deterministic effects) (6) in addition to neurobehavioral dysfunction, growth retardation, fetal death and increased cancer risk. Evidence on the detrimental effects of radiation on the fetus have been obtained primarily from animal studies, nuclear accidents (e.g., Chernobyl disaster) and from the atomic bomb survivors of Hiroshima and Nagasaki (6).

Surviving animal fetuses exposed in utero to acute high doses of radiation result in growth retardation, congenital anomalies, including those of the central nervous system, cognitive and behavioral abnormalities (79), and increased cancer incidences (10) depending on the gestation age at the time of exposure as well as on the mouse strain.

Animal studies on in utero radiation exposures at low (LDR) (11) or medium (MDR) dose-rates (12) and at fractionated doses (13) has been briefly reviewed previously (14). Depending on the gestation age at the time of exposure, acute doses from 0.5–5.7 Gy result in preimplantation loss, embryonic death, decreased litter sizes (8, 15), increased fetal mortality, increased incidences of congenital malformations and growth retardation, and decreased body size and brain weight (8). Growth retardation, delay in the appearance of physiological markers such as pinna detachment, fur development, eye opening, vaginal opening, and testicular descent have also been reported (16). Studies in both rats (17) and mice (12, 18) on in utero exposures for the entire gestation period (days 1 to 18) using gamma rays from 25 mGy/day to 124 mGy/day reported no effect. In rats, the no observed adverse effect level (NOAEL) for lethal effects of radiation is approximately 0.15–0.20 Gy (15–20 rad) at 0–8 days post conception (equivalent to 0–16 days post conception in humans) (19) with no increased risk of growth retardation in surviving embryos receiving 0.20 Gy or less. Sasaki (10) reported that mice exposed to γ rays at acute doses of 1.9 to 5.7 Gy during the late-fetal period shortened the average lifespan and increased solid tumor incidence in the lungs, liver, pituitary, ovaries, and uterus in adulthood. Radiation exposure during organogenesis and fetal development have been reported to result in behavioral changes, impairments in learning and memory, effects on the central nervous system, delay in the appearance of physiological markers of development, low birth weight and growth reduction (9), but it is not clear however, whether these behavioral changes, attributed to radiation exposure during organogenesis, persist later in life (9).

Previously, we (14) showed that in utero exposure to a LDR of 20 mGy/day for the entire gestation period did not cause any significant effect in pups up to 10 weeks of age when compared to age-matched non-irradiated controls, whereas, increased post implantation loss, due to early embryonic deaths (early resorption), dose-related growth retardation with delayed ossification (400 mGy/day) and gonadal hypoplasia/atrophy in both sexes were observed at MDRs of 200 or 400 mGy/day. Further investigation by Nakahira et al. (20) verified the absence of germ cells in gestation day (GD) 18 fetuses exposed to MDRs of 200 and 400 mGy/day, confirming gonadal hypoplasia. Exposure to acute high dose-rate (HDR) of 2 Gy at GD11 increased the incidence rates for external abnormalities at birth and failed to survive to 10 weeks of age (14).

The need to investigate the long-term/late effects on offspring exposed in utero at low dose and low-dose-rate exposures leads to the present work on the effects continuous in utero to gamma-ray exposure, for the entire gestation period (gestation day 0–18) at LDR (0.05, 1 and 20 mGy/day) and MDR (400 mGy/day) in B6C3F1 mice on lifespan, neoplasm and non-neoplastic disease incidences exposed.


Mice and Animal Husbandry

Six-week-old specific pathogen free (SPF) C57BL/6JJcl females and C3H/HeNJcl males purchased from CLEA Japan were used as parent stock. C3H/HeNJcl males were housed individually in plastic cages (218 × 320 × 133 mm). Virgin C57BL/6JJcl females, housed in groups (up to 20 to a cage, 267 × 426 × 150 mm), were transferred into the cages housing the males (1:1) in the afternoon and allowed to mate overnight. Females with confirmed vaginal plugs the following morning were considered pregnant at gestation day (GD) 0 and were transferred to individual cages and randomly assigned to nonirradiated control (n = 34) or irradiated dose groups (n = 140). The number of pregnant females required per dose group was estimated (based on previous breeding experience) to produce at least 100 pups per sex per dose group.

The entire study was conducted under SPF environmental conditions as described in the life span study (21). Husbandry (cage changes, feed and water and health monitoring or clinical inspection), monitoring of SPF status and irradiation has been described previously (21).


Pregnant C57BL/6JJcl dams assigned to irradiated groups were continuously exposed to whole-body gamma-ray radiation for 22 h/day from GD 0 to GD 18 to LDRs of 20 mGy/day (n = 33), 1 mGy/day (n = 32) and 0.05 mGy/day (n = 31), and to an MDR of 400 mGy/day (n = 44), to total doses of 360, 18, 0.9 and 7,200 mGy, respectively. After completion of the radiation exposure at GD 18, the pregnant females were moved back to the animal rooms with the nonirradiated pregnant females and allowed to give birth.

Justification for selected radiation dose and dose rates. Based on previous work (14, 2122), LDRs of 0.05, 1 and 20 mGy/day were selected with an MDR of 400 mGy/day as positive control (14, 20)

Dosimetry. The absorbed doses by the pregnant dam are based on measurements made using thermoluminesence dosimeters (TLDs) inserted into the abdomen of mice as described by Shiragai et al. (23).

Monitoring and Pathological Examination

Pups were carefully counted (total n = 1,184; 614 males and 570 females) as soon as possible after birth and were allowed to stay with their dams until weaning at day 21 (3 weeks of age), at which time they were individually identified with ear notches, weighed, separated by sex and group caged (4 mice/cage). The pups were allowed to die a natural death upon which they were subjected to necropsy (gross examination) and organs collected, weighed and fixed in 10% neutral buffered formalin for histopathological examination based on a standard protocol (22). When deemed necessary, additional tissue samples were collected from neoplasms and from organs or tissues with gross abnormalities, and special histochemical procedures performed for diagnostic purposes.

Histopathological examination was performed blind and neoplasms were classified based on proposed nomenclatures of WHO/IARC (24) and the NTP (25) as described previously (22).

A cause of death (COD) was assigned, as described by Tanaka IB et al. (22) in the life span study, to all animals in the study.

Multiple primary neoplasms and pathologies were treated as in the previous life span study (22) wherein multiple (including multiple or metastatic foci) neoplasms of the same type were counted only once. All neoplasms were counted into the overall incidence.

After the pups were weaned at 3 weeks of age, all the dams were sacrificed in a similar manner, necropsied, examined for gross pathological changes and the uteri collected. The uteri were clarified (26), and the number of implantation sites counted and recorded accordingly.

All experiments were conducted according to legal regulations in Japan and following the Guidelines for Animal Experiments of the Institute for Environmental Sciences.

Statistical Analyses

Fischer's exact tests were used to analyze the crude mortality rates, causes of death, non-neoplastic lesions and neoplasm incidence. Neoplasm multiplicity was analyzed using the Wilcoxon test. Analyses of mean life span and body weights were done using Steel test. Levels of significance for mortality rates and incidence rates of non-neoplastic lesions and neoplasms were chosen as P = 0.05 and P = 0.01.


Reproduction Parameters

Reproduction parameters including the number of implantation sites, litter sizes and weaning rates, are summarized in Table 1. The number of implantation sites/dam was not significantly different between the nonirradiated and irradiated groups. Litter size was significantly (<0.05) decreased in those exposed to 400 mGy/day, with a significant (<0.05) decrease in the number of female pups, compared to the non-irradiated controls. Although there was no significant difference in the average number of pre-weaning losses/litter and weaning rates among the LDR- and non-irradiated pups, the average number of weaned pups/litter in those exposed to 400 mGy/day was significantly decreased as a secondary consequence to the significantly small litter size.


Reproductive Parameters (95% Confidence Interval) in B6C3F1 Mice Continuously Exposed to Low- and Medium-Dose-Rate Gamma Rays for 18 Days In Utero


Pathological changes were not observed in any of the dams at the time of necropsy and collection of uteri.

Body Weights

Body weights were monitored by weighing a representative number (n = 60–69) of animals/group every 4 weeks from weaning (3 weeks of age), up to 179 weeks as shown in Fig. 1. There was no significant difference in body weights and rate of body weight gain between the nonirradiated control and LDR irradiated groups. Mean body-weights of male mice exposed to 400 mGy/day in utero were significantly (P < 0.01) lower compared to the nonirradiated controls, weighing less from 7 to 147 weeks of age (heaviest between 51–67 weeks of age), whereas females exposed to the same dose weighed significantly (P < 0.01) heavier from 15–87 weeks of age (heaviest between 67–87 weeks of age), subsequently declining significantly (P < 0.01, from 111 to 143 weeks of age) as the mice aged.

FIG. 1

Average body weights of B6C3F1 mice exposed to low- (LDR) and medium-(MDR) dose-rate gamma rays for 18 days in utero. *P < 0.01


Survival Curves

Lifespans of mice exposed to LDRs 20 mGy/day and below were not significantly different from the nonirradiated controls. Survival curves (Fig. 2) of males and females exposed to 400 mGy/day show a significant shift towards the left. Mean lifespans of both males (862.6 ± 209 days, P = 0.0462) and females (794 ± 136.2 days, P < 0.0001) in the 400 mGy/day group showed a significant lifespan shortening (Steel test) (Table 2).

FIG. 2

Survival curves of B6C3F1 mice exposed to low- (LDR) and medium-(MDR) dose-rate gamma rays for 18 days in utero.



Mean Life Spans of B6C3F1 Mice Continuously Exposed to Low- and Medium-Dose-Rate Gamma Rays for 18 Days In Utero


Causes of Death (COD)

The causes of death with their corresponding incidence rates, classified according to tissue/organ of origin (in alphabetical order) are shown in Table 3. Majority (79.6–93.8%) of the mice died from neoplasms regardless of radiation exposure.


Causes of Death in B6C3F1 Mice Continuously Exposed to Low- and Medium-Dose-Rate Gamma Rays for 18 Days In Utero









Extended. Continued.


Male mice died mostly from malignant lymphomas (25.6–33.3%) and liver tumors (23.1–31.0%) with no significant difference in the incidence rates among the non-irradiated and low dose-rate (0.5, 1 and 20 mGy/day) groups. At 400 mGy/day exposure however, COD from liver neoplasms (42.9%, P < 0.01) was significantly increased with a corresponding decrease in malignant lymphomas (15.0%, P < 0.01) as COD.

Females also died mostly from malignant lymphomas (44.4–48.8%) and from soft tissue neoplasms (9.3–11.4%), with no significant differences in incidence rates among the non-irradiated and irradiated groups (0.5 to 20 mGy/day). At 400 mGy/day, there was a significant decrease in the number of female mice dying from malignant lymphoma (24.8%, P < 0.01), and significantly increased numbers of mice dying from neoplasms originating from the pituitary gland (pars distalis) (15.9%, P < 0.01) and the ovaries (14.2%, P < 0.01), mainly malignant granulosa cell tumors (9.7%, P < 0.01).

Non-neoplastic causes of death, including interstitial pneumonia, dental dysplasia, malocclusion, hyaline glomerulopathy, systemic arteritis and amyloidosis, etc., accounted for 2.7–15.7% of all CODs and were not significantly different between non-irradiated controls and irradiated groups. Undetermined/unknown CODs comprised 2.4–6.0% of all deaths in both sexes.

For other causes of death, no significant differences were observed in the incidence rates between the non-irradiated and irradiated groups in neither sex.

Mean Survival of Causes of Death

Kaplan-Meier estimates of mean survival of the major causes of death with results of a log-rank test are shown in Table 4. There was no significant life shortening for malignant lymphoma as COD in all groups. In males exposed to 400 mGy/day, significant life shortening (P < 0.01) was observed only for liver neoplasms. For females exposed to 400 mGy/day, significant life shortening (P < 0.01) was observed for liver, lung, soft tissue, and pituitary gland neoplasms.


Kaplan-Meier Estimates of Mean Survival of Major Causes of Death in B6C3F1 Mice


Neoplasm Incidence

All the neoplasms, fatal (caused death) and incidental, are listed in Table 5, classified according to organ/tissue (in alphabetical order) of origin. Overall, there was no significant differences in the incidence rates of neoplasms between the non-irradiated and low-dose irradiated groups.


Incidence of Neoplasms in B6C3F1 Mice Continuously Exposed to Low- and Medium-Dose-Rate Gamma Rays for 18 Days In Utero









Extended. Continued.


Digestive system. There was a significant increase (P < 0.001) in the total incidence of neoplasms originating from the digestive tract in both sexes (35.4% in females, 67.7% in males) exposed to 400 mGy/day, mainly due to the significant (P < 0.001) increase in the number of neoplasms arising from the liver (34.5% in females and 66.9% in males). Hepatocellular adenoma incidence in females (21.2%, P < 0.01), but not in males (21.1%, n.s.), was significantly increased in the 400 mGy/day group. Incidence rates of hepatocellular carcinomas in both sexes (11.5% in females and 44.4% in males) exposed to 400 mGy/day were significantly increased (P < 0.01). Incidence rates for other neoplasms originating from the digestive system were low (<2%).

Endocrine system. A significant over-all increase (P < 0.001) in the incidence of endocrine neoplasms was observed in both sexes (85.0% in females and 30.1% in males) exposed to 400 mGy/day. The increase in female mice is attributed to neoplasms originating from the adrenal (15.9%, P < 0.01), pituitary [55.8%, P < 0.01, mostly adenomas of the pars distalis (54.0%, P < 0.01)] and the thyroid (12.4%, not statistically significant) glands. In males, the overall increase is attributed to the increases in the numbers of adrenal (9.0%, P = 0.0737) and thyroid (16.5%, P = 0.0942) neoplasms compared to the nonirradiated controls.

Reproductive system. An overall increase in the incidence rate of neoplasms originating from the reproductive tract (112.4 %, P < 0.01) in females exposed to 400 mGy/day due to significant increases in the numbers ovarian neoplasms mainly, tubulostromal adenomas (61.9%, P < 0.01) and malignant granulosa cell tumors (14.2%, P < 0.01). Solitary primary ovarian neoplasms were found in 75.22 % (n = 85) of the animals while 14.15% (n = 16) had 2 primary ovarian neoplasms. The remaining ovaries in 12 females with no neoplasms were either hypoplastic or cystic.

Testes of males in 400 mGy/day group were all hypoplastic. There was no significant increase in the number of neoplasms originating from the male reproductive tract was observed.

Harderian gland. Incidence rates for Harderian gland neoplasms were low (maximum of 9%) and were not significantly different between the non-irradiated controls and irradiated groups.

Hematopoietic System. A large majority of the neoplasms originated from the hematopoietic system, mostly malignant lymphomas and was highest in the non-irradiated controls (females = 54.5%; males = 39.2%), decreasing as the radiation dose increased. Incidence rates for malignant lymphoma were significantly decreased in both sexes (females = 29.2%, P < 0.01; males = 22.6%, P < 0.01) exposed to 400 mGy/day.

Respiratory system. Although overall incidence rates for respiratory neoplasms were not significantly different between LDR and nonirradiated controls. Incidence rate for males were higher than the females but significantly decreased as the radiation dose increased only in males (19.5%, P < 0.01) exposed to 400 mGy/day and is due to decreases in the incidences of both bronchiolo-alveolar adenoma (11.3%, P < 0.01) and carcinoma (8.3%, n.s.).

Other organs/tissues. Incidence rates for neoplasms originating from the mesothelium, skin, soft tissues, urinary system, vascular system and the Zymbal gland were low and were not significantly different between the nonirradiated controls and irradiated groups.

Multiple primary neoplasms. The frequencies of multiple primary neoplasms are shown in Table 6. Over 91.7% of the animals died with more than 1 primary neoplasm with a few animals having as many as 6 neoplasms. A significant increase in the average number of primary neoplasms was observed only in female mice (3.11, P < 0.01) exposed to MDR of 400 mGy/day in utero with almost half (42.5 %) of the animals having 3 neoplasms each. The maximum number of 6 primary neoplasms were observed in female mice exposed to 1 mGy/day (n = 1, 0.8%) and 400 mGy/day (n = 5, 4.4%), and in 1 (0.8%) male mouse exposed to 400 mGy/day.


Frequencies of Multiple Primary Neoplasms in B6C3F1 Mice Continuously Exposed to Low- and Medium-Dose-Rate Gamma Rays for 18 Days In Utero






Reproductive parameters. The results of the breeding parameters in the present study are similar to that previously reported, such as average number of implantation sites/dam (14, 20), and average number of pups born/litter (14), and are comparable across all matching dose groups, nonirradiated control and irradiated (20 mGy/day and 400 mGy/day). As in a previous study (14), the significant reduction in mean litter size of dams (average number of pups born/litter) alongside the significant increase in the number of resorbed fetuses exposed to MDR of 400 mGy/day, indicates significant fetal loss between post implantation (from GD 6) and birth. Overall, the average weaning rates in the present study were higher in all dose groups compared to a previous report (14) wherein the group exposed to MDR of 400 mGy/day had an exceptionally low-average weaning rate. This difference in weaning parameters may be attributed to batch differences and the larger number of litters examined in the present study (44 vs. 23 litters). Analyses of the reproductive parameters in the present study show that in utero LDR γ-ray exposures of 0.05, 1.0 and 20 mGy/day from GD 0-18 were not significantly different from the non-irradiated controls.

Body weight and growth retardation. The difference in the pattern of body weight gain between sexes was striking in pups exposed to 400 mGy/day in utero where male pups appeared to “catch-up” from 3 to 7 weeks of age but showed slower and smaller gains in weight thereafter (persistent growth retardation). Female pups similarly exposed however, continued to gain weight at a rate faster than the non-irradiated controls and the LDR groups until 87 weeks of age, after which they started to lose weight progressively, until body weight monitoring was discontinued at 187 weeks of age. It is interesting to note that this pattern of weight loss in females exposed to 400 mGy/day is similar to the females in the lifespan study (22) exposed to 20 mGy/day.

Our previous reports (14, 20) on in utero exposures showed similar results where GD18 pups exposed to MDRs of 200 and 400 mGy/day had significantly lower body weights than the non-irradiated controls that prevailed (persistent growth retardation) only in male pups until the end point at 10 weeks of age (14). The same report (14) also showed that while the pups (both sexes) exposed to MDRs appeared to “catch-up” in growth, observed as an increase in body weight, the organ weights (absolute and relative) at 10 weeks of age showed that this increase was due to increased fat deposition. Sreetharan et al. (27) reported similar reductions in body weights of male C57Bl/6J mice exposed to a total of 1,000 mGy at HDRs in utero. Jauhari et al. (28) exposed pregnant Swiss mice to 800 mGy (at both high- and low-dose rates) of gamma rays on day 18 post conception resulted in a biphasic weight loss in male offspring but a monophasic weight loss in female offspring. Coppenger et al. (29) reported similar results in rats exposed to 50 r daily during the entire gestation period, wherein males were sterile and gained weight slower, whereas females demonstrated higher weight gains, than the nonirradiated controls and attributed this to the “castrated” condition in females. Rugh and Wohlfromn (30) attributed the decrease in body weight to radiation-induced cell death, resulting in growth retardation as a permanent consequence of prenatal radiation exposure (31). In our previous studies (14, 20), small GD18 fetuses exposed to MDRs of 200 and 400 mGy/day for the entire gestation period also had placentas that were smaller in size and weight (unpublished data) but preliminary histopathological examination did not reveal any abnormalities.

In human infants, fetal growth restriction (FGR)/in utero growth restriction/retardation (IUGR) and short/small for gestational age (SGA) are often used interchangeably in clinical practice even though they are not synonymous (3235), the differences, however, are beyond the scope of this work (and these terms will be used interchangeably in this paper for convenience). Regardless of etiology (32, 36), FGR/IUGR or SGA cause a spectrum of both short- (37) and long-term complications (3840), many of which are amplified by postnatal weight gain (41, 42) or spontaneous catch-up growth (35) requiring different interventions or treatment (34) and monitoring/surveillance duration (33). Associated morbidities and severity also depend on the onset of placental dysfunction and gestation age at birth and with the degree of severity dependent on numerous factors (such as dose, dose-rate and gestation age at the time of exposure in the case of in utero exposure.

It is also possible that the vascular damage (43), caused by chronic MDR exposure, may lead to placental insufficiency that ultimately results in FGR. At high-dose exposures to the human uterus, such as those used in cancer therapy, increased risks of unfavorable pregnancy and neonatal outcomes [e.g. premature birth, low-birth weights, small for gestational age (SGA) and in some cases perinatal mortality] has been attributed to radiation-induced uterine damage (44, 45). Most studies in humans show that obesity is associated with elevated estradiol both in men (46) and in women after menopause (47). Similar findings were reported by Gulay et al. (14) in 10-week-old males and females exposed MDR of 400 mGy/day and in females exposed to MDR of 200 mGy/day where significant increases in fat deposits (based on relative organ weights) were observed. Although we did not observe FGR/IUGR in mice exposed to a LDR of 20 mGy/day, hypogonadism, associated with IUGR in both humans and animals regardless of etiology, with significantly greater prevalence in obese human males (46), may need to be considered as a late effect. Evaluation and long-term management of FGR/IUGR and/or SGA that result from in utero exposure must take into consideration these long-term consequences, in addition to any secondary effects, that may result from hypogonadism and other hormone imbalances that affect the growth of the fetus, including cancer. Further investigation is needed to determine whether in utero radiation exposure is additive or synergistic to the effects of FGR/IUGR or SGA.

Nakahira et al. (20) confirmed that the gonadal hypoplasia observed at 10 weeks of age by Gulay et al. (14) in pups exposed in utero to 400 mGy/day was present at GD 18 and that the lesion was irreversible/permanent (no recovery observed in adults). In the present study, we also confirmed (data not shown) gonadal hypoplasia histopathologically in all male pups exposed in utero to 400 mGy/day.

The disparity in the weight gain between sexes in the pups exposed in utero to 400 mGy/day suggest that there are other contributing factors and/or mechanisms that affect growth, or as in this study, weight gain, other than gonadal hypoplasia, particularly in males. Factors, or a combination of several (possibly additive and/or synergistic), include disruptions (of the normal hormonal feedback system) in the hypothalamic-pituitary-gonadotropin axis in both the irradiated dam and pups exposed in utero, transgenerational effects as a phenotypic outcome of developmental programming (also known as Barker's hypothesis) resulting from maternal stress (in this case, radiation exposure), which are fetal sex and temporal specific (48), during pregnancy (27), cell killing in embryonic/fetal organs and tissues as a direct result of radiation exposure and radiation-induced uterine damage (44, 45). Gender differences in response to chronic low dose exposure have not been investigated in detail, but it has been suggested that the differences may be due to intrinsic differences in gametogenesis such as differences in the duration of meiosis and age at exposure (49). Nakamura et al. (50) showed that female B6C3F1 mice exposed continuously to a low-dose rate of 20 mGy/day for 400 days had significantly increased body weights due to adiposity accompanied by increased serum leptin and liver lipid content, but with no increase in feed consumption.

Life span. No life span shortening was observed in pups exposed to low-dose rates of 0.05,1 and 20 mGy/day, and this may be attributed to the very low-dose rates and very low-total-accumulated doses over the short irradiation period of 18 days. At 400 mGy/day however, the life span was significantly shorter in both males and females since the total accumulated dose over the 18-day in utero exposure was much higher at 7,200 mGy (7.2 Gy). It is interesting to note that the mean lifespans (862.6 days in males; 794.9 days in females) and rates of lifespan shortening (7.8% in males and 14.0% in females) of mice exposed in utero to 400 mGy/day, were comparable to the results of life span study (21) in B6C3F1 mice exposed to 20 mGy/day for 400 days [total dose 8 Gy; (mean life spans = 812.0 days in males; 740.9 days in females) and (rates of lifespan shortening = 11.03% in males; 13.9% in females)] despite the large difference in the number of mice examined as well as a shift in the causes of death and neoplasm incidence rates as discussed below.

Neoplasm incidence. Carcinogenic effects are often seen in animal studies when radiation exposure occurs during the late stages of fetal development (6). Our results show no significant differences in the incidence rates of neoplasms that caused death among the non-irradiated controls and those exposed in utero to LDRs of 0.05, 1 and 20 mGy/day in either sex.

At MDR exposure, a shift, based on incidence rates, in the major COD was observed in males, from malignant lymphomas at LDRs to liver neoplasms, with significant life span shortening (Table 2). This shift towards liver neoplasms is likely due to the genetic predilection of male B6C3F1 mice for developing liver neoplasms, that is inherited as a dominant trait from its C3H sire (25), in combination with in utero exposure to 400 mGy/day of gamma rays resulting in both initiation (increased incidence) and progression (shorter life spans). Although not statistically significant, Sasaki et al. (51) showed a similar increase in liver neoplasms in B6WF1 males exposed to 200R of X rays at 16–18 days post coitus (dpc) compared to the non-irradiated controls whereas those exposed at 12 dpc did not develop any liver neoplasms at all. Nitta et al. (52) reported similar an overall increase in liver neoplasms incidence in both male and female B6C3F1 mice acutely exposed in utero on GD 16.5 to neutrons (Cf: 1 Gy), but not in mice similarly exposed to gamma rays (Co: 1 and 2.7 Gy).

In females exposed to 400 mGy/day, there was a huge reduction (50.8%) in the rate at which malignant lymphomas caused death, and shifted to an increase in the incidence of neoplasms with endocrine function originating from the pituitary (with significant lifespan shortening) and the ovaries. Using B6C3F1 females exposed in utero to 3.8 Gy of gamma rays, Sasaki (10) reported similar increases in the neoplasm incidence rates originating from the liver, pituitary and the ovaries when exposed during the late fetal stage (day 17 post coitus) but did speculate on possible pathogenetic mechanisms. Acute in utero exposure to neutrons (Cf: 1Gy) and gamma-rays (Co: 2.7 Gy) on GD 16.5 has also been shown to increase the incidence of pituitary and mammary gland tumors (52) in female B6C3F1 mice. In the current study these shift in neoplasm incidence rates could also be related to the some of the same factors that contribute to the differences in growth (weight gain) such as disruptions in the normal hormonal feedback system of the hypothalamic-pituitary-gonadotropin axis in both the irradiated dam and pups exposed in utero. The hormonal insufficiency/imbalance resulting from ovarian hypoplasia is also a huge factor that contributes to the increase in the incidence of ovarian neoplasms.

It is also of interest to note the absence of any significant change in the incidence rates for Harderian gland neoplasms among the non-irradiated, LDR- and MDR-in-utero-irradiated groups in the present study. Although it might be reasonable to assume that at LDRs the total accumulated dose is too low to induce Harderian gland tumors, there was no increase incidence in the MDR group despite the relatively high total accumulated dose at 7.2 Gy suggesting other factors may influence its development and sensitivity to radiation exposure.

The over-all incidence rates of endocrine neoplasms in both sexes exposed to 400 mGy in utero were significantly increased compared to the non-irradiated controls. When classified based on organ of origin, only neoplasms originating from the adrenals, pituitary and ovaries were significantly increased in females and this may be partly related to the hormone imbalance brought about by gonadal hypoplasia and disruptions (of the normal hormonal feedback system) in the hypothalamic-pituitary-gonadotropin axis. Intrinsic differences in the hormone regulation in the endocrine system between sexes may account for some of the differences in neoplastic incidence rates.

In the present study, no change in tumor spectra was observed in mice exposed to both LDRs and MDRs in utero. The average tumor burden, reflected as the number of multiple primary tumors, however, was significantly increased only in females exposed in utero to MDR of 400 mGy/day despite the shorter lifespan due to increased incidence rates of neoplasms originating from liver, pituitary and the ovaries.

None of the neoplasms observed in the present study correspond to what may be considered as childhood cancer (often affecting children at ages 0 to 14 years). Stewart et al. (53) was first to report on childhood cancers resulting from prenatal diagnostic and assessment X-ray exposure in 1956, but a follow-up of the Hiroshima and Nagasaki atomic bomb survivors exposed in utero (n = 1,630) reported only 2 childhood cancers without a single case of leukemia (54). In the present study, we found only 3 animals with myeloid leukemia, 2 females (non-irradiated and 20 mGy/day) and 1 male (1 mGy/day). While ICRP (55) concluded that evidence for solid tumors, particularly childhood brain cancer, was not strong due to lack of evidence of increased risk in cohort studies (atomic bomb survivors) as well as the unusual homogeneity of the relative risk of all childhood cancers in the Oxford survey of childhood cancers, NCRP (56) stated that in utero exposure maybe of concern. Although an analysis of epidemiological studies on prenatal x-ray exposure to about 10 mGy show a consistent relative risk of 1.4 for childhood cancer, the individual probability for childhood cancer would be very low since the background incidence is so low (about 0.2-0.3%) (5). Based on absolute risks for childhood cancer deaths exposed to 1,000 mGy in utero has been estimated to be around 0.06% per 10 mGy or equivalent to 1 cancer death per 1,700 children exposed to 10 mGy in utero (5). Uncertainties remain regarding the contribution of in utero diagnostic radiology studies to leukemia induction until its mechanism is understood (3).

A number of studies (57, 58) report neurocognitive deficits and behavioral changes (58) such as aggressive behavior (57) in several strains of mice as well as in rats (5961) exposed acutely to high doses of radiation at various gestation ages. Structural changes in the cortical layer of juvenile rats with behavioral changes suggest that long-term effects of fetal exposure are not only due to cell loss during development but also due to an overall perturbation of regulatory systems responsible for growth and development (61). The standard twice daily cage-side observations in the resent study failed to detect neither abnormal neurobehavioral symptoms (data not shown) nor histo-morphological changes (histopathology) in the brains of non-irradiated nor irradiated mice. Behavioral testing is beyond the scope and objectives of present study design as this would require a separate group of animals, space and manpower. Studies on the effect(s) of in utero exposures to chronic low dose rates of radiation on behavior and neurocognitive changes are needed.

Biological response(s) to radiation exposure, particularly its chronic and late effects, should be examined with a holistic approach and at whole organism level (62) as it is more complex than the LNT relationship between health risk and dose where radiation always induces gene mutations in direct proportion to radiation dose (63). The possibility that the same low-dose radiation that induces epigenetic mechanisms that contribute to cancer induction, also induces a hormetic response (63). In vitro studies show that low doses may not induce efficient repair of double-strand breaks (6465). While the current report focuses on the effect of in utero radiation exposure on life span, cause of death and neoplasm incidences in mice, other responses to radiation exposure such as DNA damage repair, bystander effects, and, non-neoplastic diseases, and their contribution to life span shortening and cause of death require further investigation.

It is also necessary to differentiate the effects of in utero radiation exposure from the heritable effects that result from radiation exposure of germ cells (oocytes or spermatocytes) that cause chromosomal aberrations and/or mutations in genes themselves (66). Our previous reports (14, 20) on in utero exposures at MDRs of 200 and 400 mGy/day have shown severe hypoplasia of both the ovaries and testes in GD 18 fetuses and at 10 weeks of age (no recovery = irreversible), indicating that these mice are sterile and therefore it is reasonable to assume that any radiation injury incurred at these doses will not be passed on to future progeny/generations. As mentioned in the results, all males exposed to 400 mGy/day in utero had testicular hypoplasia and a large majority of females had ovarian neoplasms with a few having more than one primary ovarian neoplasm. Nakahira et al. (20) reported a slight, but not statistically significant, decrease in germ cell counts in mice exposed in utero to a LDR of 20 mGy/day. Further investigation is required to determine whether the surviving germ cells in these mice exposed in utero to LDRs (20 mGy/day and below) carry heritable defects that could be passed on to future progeny/generations.

The results of the present work show that in utero exposure of mice to LDRs (0.05, 1 and 20 mGy/day) for the entire gestation period (GD 0 to 18) did not significantly alter any of the parameters (life span, cause of death, neoplasm incidence) examined when compared to the nonirradiated controls suggest that the effect on the irradiated embryo/fetus and the pregnant dam (uterine physiology) may be too small to be detected statistically. As mentioned, our previous life span study (22), the absence of an observable effect in the present in utero exposure study, particularly at LDR exposures of 20 mGy/day, does not mean that increased risk does not exist (67), since the probability of observing any effect as statistically significant would be limited by the magnitude of the effect and the sample size. In the previous in utero exposure study (LDR = 20 mGy/d; MDR = 200 and 400 mGy/d; and an acute high dose rate 0.77/Gy/min) (14), several parameters showed significant trends (e.g., increasing post-implantation loss; decreasing body sizes, weaning rates, body and organ weights, etc.) as the dose-rate increased. In the present study, there was no significant trend in the mean life spans within the LDR group (data not shown).

Extrapolation of the current results to in utero exposures in humans should take into consideration the dose rates and the total accumulated dose the mice were exposed to over the entire gestation period of 18 days as compared to the length of the human gestation period of 280 days. Total doses at LDRs of 0.05 and 1 mGy/day were still very low at 0.9 and 18 mGy, respectively. At the LDR of 20 mGy/day however, the total dose of 360 mGy for the entire gestation period exceeds 200 mGy, the maximum dose considered by UNSCEAR (1986, 1993) (67) as low dose.

Further studies however are necessary to determine whether or not chronic in utero radiation exposure to low dose and low dose rates will affect future reproductive capabilities of in utero exposed mice and their exposed dams (effect on succeeding pregnancies, life span, neoplasia and non-neoplastic diseases).


We are indebted to the technical and animal care staff of the IES for their support during the conduct of the study. We appreciate the useful discussions with the advisors of the Department of Radiobiology. The work was performed under contract with the Aomori Prefectural Government, Japan.



Preconception and prenatal radiation exposure: Health effects and Protective Guidance (2013), National Council on Radiation Protection and Measurements (NCRP) Report No. 174 (2013). Google Scholar


Brent RL. Protection of the gametes embryo/fetus from prenatal radiation exposure. Health Phys 2015: 108; 242–274. Google Scholar


Brent RL. Counseling women and men regarding exposures to reproductive and developmental toxicants before conception or women during pregnancy. Semin Fetal Neonatal Med 2014: 19; 203–213. Google Scholar


Hall EJ, Giaccia A. Radiobiology for the radiologist. 6th ed. Philadelphia. Lippincott Williams & Wilkins; 2006. Google Scholar


5. Valentin J, editor. Annals of the International Commission on Radiological Protection. Publication 84. Pregnancy and Medical Radiation. London: Elsevier Science Ltd; 2000. Google Scholar


Kumar R, de Jesus O. Radiation Effects on the Fetus. 2022 Apr 30. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. PMID: 33232028. ( Scholar


Devi PU, Suresh R, Hande MP. Effect of fetal exposure to ultrasound on the behavior of the adult mouse. Radiat Res 1995:141; 314–317. Google Scholar


Kim SH, Kim SR, Lee YS, Kim TH, Jo SK, Lee CS Influence of gestational age at exposure on the prenatal effects of gamma-radiation. J Vet Sc 2001: 2; 27–42 Google Scholar


Sreetharan, S, Thome C, Tharmalingan S, Jones, DE, Kulesza AV, Khaper N et al. Ionizing radiation exposure during pregnancy: Effects on postnatal development and life. Radiat Res 2017: 187; 647–58. Google Scholar


Sasaki S. Influence of the age of mice at exposure to radiation on life- shortening and carcinogenesis. J Radiat Res 1991: 32 (Suppl.); 73e85 Google Scholar


Stadler J, Gowan JW 1964. Observations on the effects of continuous irradiation over ten generations on reproductivities of different strains of mice. pp. 111–122. Effects of Ionizing Radiation on the Reproductive System. Edited by Carlson WD, Gassner FX. Pergamon Press, London. Google Scholar


Konermann G. Die Die Keimesentwicklung der Maus nach Einwirkung kontinuierlicher Co60 Gammabestrahlung während der Blastogenese, der Organogenese und der Fetalperiode. Strahlentherapie 1969: 137; 451–466 Google Scholar


Coppenger C, Brown SO. Postnatal manifestations in albino rats continuously irradiated during prenatal development. Tex Rep Biol Med 1965; 23: 45–65. Google Scholar


Gulay KCM, Tanaka IB III , Komura J, Tanaka S. Effects of continuous gamma-ray exposure in utero inB6C3F1 mice on gestation day18 and at 10 weeks of age. Radiat Res 2018; 189: 425–440. Google Scholar


Gu Y, Kai, M, Kusama T. The embryonic and fetal effects in ICR mice irradiated in the various stages of the preimplantation period. Radiat Res 1997: 147; 735–40. Google Scholar


Devi PU, Hossain M. Effect of early fetal irradiation on the postnatal development of mouse. Teratology 2001; 64(1): 45–50. Google Scholar


Vorisek P. Einfluss der kontinuierlichen intrauterinen Bestrahlung auf die perinatale Mortalität der Frucht. Strahlentherapie 1965: 127; 112–120. Google Scholar


Russell LB, Badgett SK, Saylors CL. Comparison of the effects of acute, continuous and fractionated irradiation during embryonic development. In Buzzati-Traverso AA, editor. A Special Supplement to International Journal of Radiation Biology: Immediate and Low Level Effects of Ionizing Radiation. Proceedings of a conference held in Venice. London. Taylor & Francis; 1959. p. 343–359. Google Scholar


Brent RL. Saving lives and changing family histories: appropriate counseling of pregnant women and men and women of reproductive age, concerning the risk of diagnostic radiation exposures during and before pregnancy. Am J Obstet Gynecol 2009; 200: 4–24. Google Scholar


Nakahira R, Ayabe Y, Braga-Tanaka I, Tanaka S, Komura J. Effects of continuous in utero low- and medium-dose-rate gamma ray exposure on fetal germ cells. Radiat Res 2021; 195: 235–243. Google Scholar


Tanaka S, Tanaka IB III , Sasagawa S, Ichinohe K, Takabatake T, Matsushita S, et al. No lengthening of life span in mice continuously exposed to gamma rays at very low dose rates. Radiat Res 2003; 160: 376–379. Google Scholar


Tanaka IB III , Tanaka S, Ichinohe K, Matsushita S, Matsumoto T, Otsu H, et al. Cause of death and neoplasia in mice continuously exposed to very low dose rates of gamma rays. Radiat Res 2007; 167: 417–437. Google Scholar


Shiragai A, Saitou M, Kudo I, Kanaiwa-Kudo S, Matsumoto T, Furuse T, et al. Estimation of the absorbed dose to mice in prolonged irradiation by low-dose rate -rays from 137Cs sources. Radioisotopes 1997; 46: 904–911. Google Scholar


Mohr U. International Classification of Rodent Tumors: The Mouse. Springer-Verlag, Berlin, Heidelberg, 2001. Google Scholar


25. Maronpot RR (Ed.) Pathology of the Mouse: Reference and Atlas. Vienna, Illinois, USA: Cache River Press; 1999. Google Scholar


Yamada T, Hara M, Ohba Y, Inoue T, Ohno H. Studies on Implantation Traces in Rats. I. Size, Observation Period and Staining. Jikken Dobutsu 1985; 34 (1): 17–22. Google Scholar


Sreetharan S, Stoa L, Cybulski ME, Jones DE, Lee AH, Kulesza AV, et al. Cardiovascular and growth outcomes of C57Bl/6J mice offspring exposed to maternal stress and ionizing radiation during pregnancy. Int J Radiat Biol 2019; 95:1085–1093. Google Scholar


Jauhari S, Nandchahal KK, Dev PK. Postnatal survival and growth of mouse irradiated in utero with low dose. Indian J Exp Biol 1996; 34: 883–886. Google Scholar


Coppenger CJ, Brown SO. Postnatal manifestations in albino rats continuously irradiated during prenatal development. Tex Rep Biol Med 1965; 23: 45–55. Google Scholar


Rugh R, Wohlfromm M. Prenatal x-irradiation and postnatal mortality. Radiat Res 1965; 26: 493–506. Google Scholar


Martin PG. The postnatal response of four organs to prenatal irradiation as measured by changes in nucleic acids and protein. Radiat Res 1971; 48: 368–376. Google Scholar


Sharma D, Sharma P, Shastri S. Postnatal Complications of Intrauterine Growth Restriction. J Neonatal Biol 2016; 5: 232. Google Scholar


Easter SR, Eckert LO, Boghossian N, Spencer R, Oteng-Ntim E, Ioannou C, et al. Fetal growth restriction: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine 2017; 35: 65466554. Google Scholar


Beune IM Bloomfield FH, Ganzevoort W, Embleton ND, Rozance PJ, van Wassenaer-Leemhuis AG et al. Consensus bases definition of growth restriction in the newborn. J Pediatr 2018; 196: 71–76. Google Scholar


Finken MJJ, van der Steen M, Smeets CCJ, Walenkamp MJE, de Bruin C, Hokken-Koelega ACS et al. Children born small for gestational age: Differential diagnosis, molecular genetic evaluation, and implications. Endocr Rev 2018; 39: 851–894. Google Scholar


Malhotra A, Allison BJ, Castillo-Melendez M, Jenkin G, Polglase GR, Miller SL. Neonatal Morbidities of Fetal Growth Restriction: Pathophysiology and Impact. Front Endocrinol (Lausanne) 2019; 10: 55. Google Scholar


Ross MG, Mansano RZ. (2020 Sep 15). Fetal Growth Restriction. Medscape. (Date accessed: 2022 July 6.) ( Scholar


Huxley RR, Shiell AW, Law CM. The role of size at birth and postnatal catch-up growth in determining systolic blood pressure: a systematic review of the literature. J Hypertens 2000;18: 815–31. Google Scholar


Whincup PH, Kaye SJ, Owen CG, Huxley R, Cook DG, Anazawa S, et al. Birth weight and risk of type 2 diabetes: a systematic review. JAMA 2008; 300: 2886–97. Google Scholar


Risnes KR, Vatten LJ, Baker JL, Jameson K, Sovio U, Kajantie E, et al. Birthweight and mortality in adulthood: a systematic review and meta-analysis. Int J Epidemiol 2011; 40: 647–61. Google Scholar


Leunissen RW, Kerkhof GF, Stijnen T, Hokken-Koelega A. Timing and tempo of first-year rapid growth in relation to cardiovascular and metabolic risk profile in early adulthood. JAMA 2009; 301: 2234–42. Google Scholar


Singhal A, Fewtrell M, Cole TJ, Lucas A. Low nutrient intake and early growth for later insulin resistance in adolescents born preterm. Lancet 2003; 361: 1089–97. Google Scholar


Teh WT, Stern C, Chander S, Hickey M. The impact of uterine radiation on subsequent fertility and pregnancy outcomes. Biomed Res Int 2014; 2014: 482968. Google Scholar


Signorello LB, Cohen SS, Bosetti C, Stovall M, Kasper CE, Weathers RE, et al. Female survivors of childhood cancer: preterm birth and low birth weight among their children. J Natl Cancer Inst 2006; 98:1453–61. Google Scholar


Signorello LB, Mulvihill JJ, Green DM, Munro HM, Stovall M, Weathers RE, et al. Stillbirth and neonatal death in relation to radiation exposure before conception: a retrospective cohort study. Lancet 2010; 376(9741): 624–30. Google Scholar


Mushannen T, Cortez P, Stanford FC, Singhal V. Obesity and hypogonadism-a narrative review highlighting the need for high-quality data in adolescents. Children (Basel). 2019; 6: 63. Google Scholar


Freeman EW, Sammel MD, Lin H, Gracia CR. Obesity and reproductive hormone levels in the transition to menopause. Menopause 2010; 17: 718–26. Google Scholar


Bale TL. Sex differences in prenatal epigenetic programming of stress pathways. Stress 2011; 14: 348–56. Google Scholar


Eichenlaub-Ritter U, Adler ID, Carere A, Pacchierotti F. Gender differences in germ-cell mutagenesis and genetic risk. Environ Res 2007; 104: 22–36. Google Scholar


Nakamura S, Tanaka IB 3rd , Tanaka S, Nakaya K, Sakata N, Oghiso Y. Adiposity in female B6C3F1 mice continuously irradiated with low-dose-rate gamma rays. Radiat Res 2010; 173: 333–41. Google Scholar


Sasaki S, Kasuga T, Sato F, Kawashima N. Induction of hepatocellular tumor by x-ray irradiation at perinatal stage of mice. Gan 1978; 69: 451–2. Google Scholar


Nitta Y, Kamiya K, Yokoro K. Carcinogenic effect of in utero 252Cf and 60Co irradiation in C57BL/6N × C3H/He F1 (B6C3F1) mice. J Radiat Res 1992; 33: 319–33. Google Scholar


Stewart A, Webb J, Giles D, Hewitt D. Malignant disease in childhood and diagnostic irradiation in utero. Lancet 1956; 27:447. Google Scholar


Kato H, Yoshimoto Y, Schull WJ. Risk of cancer among children exposed to atomic bomb radiation in utero: a review. IARC Sci Publ. 1989; (96): 365–74. Google Scholar


55. Valentin J, editor. Annals of the International Commission on Radiological Protection. Publication 90. Biological Effects after Prenatal Irradiation (Embryo and Fetus). London: Elsevier Science Ltd; 2003. Google Scholar


National Council on Radiation Protection and Measurements. Ionizing radiation exposure of the population of the United States. Bethesda, MD: NCRP Report No. 160; 2009. Google Scholar


Minamisawa T, Hirokaga K, Sasaki S, Noda Y. Effects of fetal exposure to gamma rays on aggressive behavior in adult male mice. J Radiat Res 1992; 33: 243–9. Scholar


Minamisawa T, Hirokaga K. Long-term effects of prenatal exposure to low levels of gamma rays on open-field activity in male mice. Radiat Res 1995; 144: 237–40. Google Scholar


Hicks SP, D'Amato CJ. Low dose radiation of the developing brain. Science 1963; 141: 903–905. Google Scholar


Jensh RP, Brent RL, Vogel WH. Studies of the effect of 0.4-Gy and 0.6-Gy prenatal X-irradiation on postnatal adult behavior in the Wistar rat. Teratology 1987; 35: 53–61. Google Scholar


Kimler BF, Norton S. Behavioral changes and structural defects in rats irradiated in utero. Int J Radiat Oncol Biol Phys 1988; 15: 1171–7. Google Scholar


Mavragani IV, Laskaratou DA, Frey B, Candéias SM, Gaipl US, Lumniczky K, et al. Key mechanisms involved in ionizing radiation-induced systemic effects. A current review. Toxicol Res (Camb) 2016; 5: 12–33. Google Scholar


Belli M, Indovina L. The Response of Living Organisms to Low Radiation Environment and Its Implications in Radiation Protection. Front Public Health 2020; 8: 601711. Google Scholar


Rothkamm K, Löbrich M. Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses. Proc Natl Acad Sci U S A 2003; 100: 5057–62 Google Scholar


Grudzenski S, Raths A, Conrad S, Rübe CE, Löbrich M. Inducible response required for repair of low-dose radiation damage in human fibroblasts. Proc Natl Acad Sci U S A 2010; 107: 14205–10. Google Scholar


Borrás C. Radiation effects on the embryo and fetus. Phys Med 2018; 52 (Suppl. 1): 26–27. ( Scholar


United Nations Scientific Committee on the Effects of Atomic Radiation. Sources and Effects of Ionizing Radiation, Vol II. Effects. Report to the General Assembly, with Scientific Annexes. United Nations, New York, 2000. Google Scholar
©2022 by Radiation Research Society. All rights of reproduction in any form reserved.
Ignacia B. Tanaka III, Rei Nakahira, Jun-ichiro Komura, and Satoshi Tanaka "Life Span, Cause of Death and Neoplasia in B6C3F1 Mice Exposed In Utero to Low- and Medium-Dose-Rate Gamma Rays," Radiation Research 198(6), 553-572, (7 October 2022).
Received: 21 July 2022; Accepted: 22 September 2022; Published: 7 October 2022
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