Cancer Mortality Following<i>In Utero</i>Exposure Among Offspring of Female Mayak Worker Cohort Members

Schonfeld, Sara J.; Tsareva, Yulia; Preston, Dale L.; Okatenko, P.V.; Gilbert, Ethel S.; Ron, Elaine; Sokolnikov, Mikhail; Koshurnikova, N.A.

doi:10.1667/rr2848.1

Cited by 28 publications

(22 citation statements)

References 21 publications

(35 reference statements)

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“…In-utero exposure was shown to increase the risk of all types of childhood cancer in the Oxford Study of Childhood Cancers (largest case-control study) (Bithell and Stewart, 1975). However, several cohort studies have found no clear evidence of an increase in radiation-induced childhood cancer (Boice and Miller, 1999;Schulze-Rath et al, 2008;Schonfeld et al, 2012). A recent report of atomic bomb survivors suggested that adult-onset cancer risk from in-utero exposure is lower than cancer risk following exposure in early childhood (Preston et al, 2008).…”

Section: Effects On Embryos Fetuses and Childrenmentioning

confidence: 99%

Cellular mechanisms underlying failed beta cell regeneration in offspring of protein-restricted pregnant mice

Cox

Beamish

Carter

et al. 2013

Exp Biol Med (Maywood)

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Low birth weight and poor foetal growth following low protein (LP) exposure are associated with altered islet development and glucose intolerance in adulthood. Additionally, LP-fed offspring fail to regenerate their β-cells following depletion with streptozotocin (STZ) in contrast to control-fed offspring that restore β-cell mass. Our objective was to identify signalling pathways and cellular functions that may be critically altered in LP offspring rendering them susceptible to developing long-term glucose intolerance and decreased β-cell plasticity. Pregnant Balb/c mice were fed a control (C; 20% protein) or an isocaloric LP (8% protein) diet throughout gestation and C diet thereafter. Female offspring were injected intraperitoneally with 35 mg/kg STZ or vehicle on days 1 to 5 for each dietary treatment. At 30 days of age, total RNA was extracted from pancreatic tissue for microarray analysis using the Affymetrix GeneChip Mouse Genome 430 2.0. Gene and protein expression were quantified from isolated islets. Finally, β-cell proliferation was determined in vitro following REG1α treatment. The microarray data and GO enrichment analysis indicated that foetal protein restriction alters the early expression of genes necessary for many cell functions, such as oxidative phosphorylation and free radical scavenging. Expression of Reg1 was upregulated following STZ, whereas protein content was decreased in LP + STZ islets. Furthermore, REG1α failed to stimulate β-cell proliferation in vitro in LP + STZ islets. Therefore, early nutritional insults may programme the Reg1 pathway resulting in a limited ability to increase β-cell mass during metabolic stress. In conclusion, this study implicates the Reg1 pathway in β-cell regeneration and describes altered programming of gene expression in LP offspring, which underlies later development of cell dysfunction and glucose intolerance in adulthood.

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Section: Effects On Embryos Fetuses and Childrenmentioning

confidence: 99%

Cellular mechanisms underlying failed beta cell regeneration in offspring of protein-restricted pregnant mice

Cox

Beamish

Carter

et al. 2013

Exp Biol Med (Maywood)

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“…For MWOC members, fetal exposure to external radiation was estimated using the Mayak Worker Dosimetry System 2008 that incorporates estimates of each mother's annual uterine dose of γ- radiation based on film badge records and work history (Schonfeld et al , 2012). Pregnancies were assumed to have begun 280 days before childbirth.…”

Section: Methodsmentioning

confidence: 99%

“…Pregnancies were assumed to have begun 280 days before childbirth. The period of no occupational exposure (because of maternity leave, other leave days, and the practice of transferring pregnant workers to worksites with no ionising radiation exposure) was assumed to be a total of 175 days for women who gave birth before 1960, and 265 days thereafter, as described elsewhere (Schonfeld et al , 2012). Dose rates were adjusted as appropriate for pregnancies that occurred very close together.…”

Section: Methodsmentioning

confidence: 99%

In utero exposure to radiation and haematological malignancies: pooled analysis of Southern Urals cohorts

et al. 2016

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Background:It is scientifically uncertain whether in utero exposure to low-dose ionising radiation increases the lifetime risk of haematological malignancies.Methods:We pooled two cohorts from the Southern Urals comprising offspring of female workers of a large nuclear facility (the Mayak Production Association) and of women living in areas along the Techa River contaminated by nuclear accidents/waste from the same facility, with detailed dosimetry.Results:The combined cohort totalled 19 536 subjects with 700 504 person-years at risk over the period of incidence follow-up, and slightly more over the period of mortality follow-up, yielding 58 incident cases and 36 deaths up to age 61 years. Risk was increased in subjects who received in utero doses of ⩾80 mGy (excess relative risk (ERR): 1.27; 95% confidence interval (CI): −0.20 to 4.71), and the risk increased consistently per 100 mGy of continuous exposure in utero (ERR: 0.77; CI: 0.02 to 2.56). No association was apparent in mortality-based analyses. Results for leukaemia and lymphoma were similar. A very weak positive association was observed between incidence and postnatal exposure.Conclusions:In summary, the results suggest a positive association between in utero exposure to ionising radiation and risk of haematological malignancies, but the small number of outcomes and inconsistent incidence and mortality findings preclude firm conclusions.

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“…2,3 Risk models for stochastic cancer risk are typically derived from radiation epidemiology studies of cohort members either exposed to external radiation fields (e.g., atomic bomb survivors) [4][5][6] or internalized radioactivity (e.g., workers at the Mayak Pu production facility and surrounding Southern Urals villages). [7][8][9] In each of these scenarios, estimates of radiation dose to active marrow would ideally be derived using customized computational models of bone marrow irradiation (e.g., individual patients or discrete cohort members). Unfortunately, the geometric complexity of the skeletal tissuesat both its macroscopic and microscopic levelpresently precludes such an approach.…”

Section: Introductionmentioning

confidence: 99%

Quantitative impact of changes in marrow cellularity, skeletal size, and bone mineral density on active marrow dosimetry based upon a reference model

et al. 2017

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Purpose: The hematopoietically active tissues of skeletal bone marrow are a prime target for computational dosimetry given potential risks of leukemia and, at higher dose levels, acute marrow toxicity. The complex three-dimensional geometry of trabecular spongiosa, however, complicates schema for dose assessment in such a way that only a few reference skeletal models have been developed to date, and which are based upon microimaging of a limited number of cadaveric bone spongiosa cores. The question then arises as to what degree of accuracy is achievable from reference skeletal dose models when applied to individual patients or specific exposed populations? Methods: Patient variability in marrow dosimetry were quantified for three skeletal sites -the ribs, lumbar vertebrae, and cranium -for the beta-emitters 45 Ca, 153 Sm, and 90 Y, and the alpha-particle emitters 223 Ra, 219 Rn, and 215 Po, the latter two being the immediate progeny of the former. For each radionuclide and bone site, three patient parameters were altered from their values in the reference model: (1) bone size as a surrogate for patient stature, (2) marrow cellularity as a surrogate for ageor disease-related changes in marrow adiposity, and (3) the trabecular bone volume fraction as a surrogate for bone mineral density. Marrow dose variability is expressed as percent differences in the radionuclide S value given by the reference model and the patient-parameterized model. The impact of radionuclide biokinetics on marrow dosimetry was not considered. Results: Variations in overall bone size play a very minor role in active marrow dose variability. Marrow cellularity is a significant factor in dose variability for active marrow self-irradiation, but it plays no role for radionuclides localized to the trabecular bone matrix. Variations in trabecular bone volume fractions impact the active marrow dose variability for short-range particle emitters 45 Ca, 223 Ra, 219 Rn, and 215 Po in the vertebrae and ribs, skeletal sites with small spongiosa proportions of trabecular bone. In the cranium, with its relative high proportion of trabecular bone, significant differences in marrow dosimetry from the reference model were noted for all radionuclides. Conclusions: Skeletal models of active marrow dosimetry should be more fully parameterized to permit closer matching to patient bone density and marrow cellularity, particularly when considering short-range particle emitters localized to either the bone trabeculae or active marrow, respectively.

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Cancer Mortality FollowingIn UteroExposure Among Offspring of Female Mayak Worker Cohort Members

Cited by 28 publications

References 21 publications

Cellular mechanisms underlying failed beta cell regeneration in offspring of protein-restricted pregnant mice

Cellular mechanisms underlying failed beta cell regeneration in offspring of protein-restricted pregnant mice

In utero exposure to radiation and haematological malignancies: pooled analysis of Southern Urals cohorts

Quantitative impact of changes in marrow cellularity, skeletal size, and bone mineral density on active marrow dosimetry based upon a reference model

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