Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident. Meredith Yeager et al. Science Apr 22 2021:eabg2365. DOI: 10.1126/science.abg2365
Abstract: Effects of radiation exposure from the Chernobyl nuclear accident remain a topic of interest. We investigated whether children born to parents employed as cleanup workers or exposed to occupational and environmental ionizing radiation post-accident were born with more germline de novo mutations (DNMs). Whole-genome sequencing of 130 children (born 1987-2002) and their parents did not reveal an increase in the rates, distributions, or types of DNMs versus previous studies. We find no elevation in total DNMs regardless of cumulative preconception gonadal paternal (mean = 365 mGy, range = 0-4,080 mGy) or maternal (mean = 19 mGy, range = 0-550 mGy) exposure to ionizing radiation and conclude over this exposure range, evidence is lacking for a substantial effect on germline DNMs in humans, suggesting minimal impact on health of subsequent generations.
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There was no evidence for a relationship between the total number of DNMs and preconception ionizing radiation dose (cumulative estimated gonadal dose at 38 weeks before birth) for maternal (−0.02 DNM per mGy, 95% CI: −0.04-0.007, p = 0.17) or paternal (−0.0007 DNM per mGy, 95% CI: −0.003-0.002, p = 0.56) exposures (Table 2 and fig. S2). In an analysis restricted to DNMs with known parent-of-origin (42%; Table 1), no effect of radiation was observed (table S4) whereas the effect of parental age remained robust; the parent-of-origin point estimates for paternal and maternal age effects were 0.71 and 0.28, respectively. Further investigation did not reveal evidence for an effect of preconception dose for any individual class of DNMs evaluated (table S5). Sensitivity analysis conducted with doses truncated at 1000 mGy or log transformed (ln(1+dose(mGy))) did not reveal an impact of maternal and paternal dose modeling on association with DNMs (Table 3). We further investigated categorical dose levels and found no increase in DNMs for any dose category, even 1000+mGy paternal dose (table S6). No effect of time since exposure was observed between parental preconception ionizing radiation exposure and DNM count for children born in the years immediately following the Chernobyl accident (Fig. 1). Moreover, when restricting to SNVs, there was no difference in the distribution of nucleotide substitutions based on quartile of maternal and paternal dose (fig. S3). Furthermore, the rates and types (molecular spectra) of DNMs observed in the current study were similar to those observed in prior studies conducted in general populations (Fig. 2 and fig. S4) (2–4, 6, 8).
Since lifestyle exposures such as smoking have been associated with alterations of DNA (for example, mosaic loss of Y chromosome (32)), we also investigated possible effects of prenatal parental alcohol consumption and smoking on DNMs. We observed no association between the number of DNMs and either paternal tobacco smoking at conception (6.78, 95% CI = −16.62-14.87, p = 0.13, Table 2 and Fig. 1) or maternal tobacco smoking at conception (23.38, 95% CI = −2.00-48.77, p = 0.07, Table 2 and Fig. 1). Similarly, no effect was observed for increasing levels of paternal (p = 0.12) or maternal (p = 0.12) preconception alcohol consumption. In addition, sequencing batch had no impact on the number of DNMs (4.45, 95% CI = −5.07-13.97, p = 0.34).
Relative telomere length was measured by qPCR (33) in participants to investigate the potential transgenerational impact of parental ionizing radiation on leukocyte telomere length in children. As expected, an overall relationship was observed between increasing age at blood draw and shorter relative telomere length due to age-related telomere length attrition (p = 4.49×10−19, fig. S5). We did not observe an effect of paternal or maternal age at conception on relative telomere length in adult children (p = 0.95 and 0.06, respectively; table S7). While our analysis did not find evidence for an effect of total paternal preconception ionizing radiation exposure on relative leukocyte telomere length (p = 0.88), we did observe a possible effect of total maternal preconception exposure that requires confirmation (−2.75×10−4, 95% CI = −5.20×10−4 - −2.90×10−5, p = 0.03; table S7). There was no evidence for a transgenerational effect of paternal or maternal smoking on child’s telomere length (p = 0.91 and 0.22, respectively, table S7).
Although it is reassuring that no transgenerational effects of ionizing radiation were observed in adult children of Chernobyl cleanup workers and evacuees in the current study, additional investigation is needed to address the effects of acute high-dose parental gonadal exposure closer to conception. The upper 95% confidence bound suggests the largest effect consistent with our data is <1 DNM per 100 mGy from paternal or maternal exposure (Table 3 and tables S8 and S9). Previously, Dubrova et al. (22, 29) reported a two-fold increase in mini-satellite mutations in children born to parents living in a highly exposed region of Belarus. Weinberg et al. (34) reported an increase in the mutation rate at microsatellite loci among children born to cleanup workers. Subsequent small studies have not reported an increased mini-satellite or microsatellite mutation rate in children of cleanup workers, including those with low doses (0.09-0.23 Gy) (21, 30, 35) or in children of the atomic-bomb survivors of Hiroshima or Nagasaki (31).
Our study evaluated peripheral blood from adult children conceived months or years after the Chernobyl accident, which limited the ability to assess exposure closer to conception; however, there was no evidence of notable differences in DNMs in children born the following year (1987). Since these families were recruited several decades after the accident, we acknowledge potential survivor bias among sampled children, although this is unlikely since there is no consistent demonstration in humans of sustained clinical effects of preconception ionizing radiation exposure (36). The number of parental gonadal radiation-induced double strand breaks could be fewer than anticipated based on animal data, which often assesses acute exposure (as a single burst) at higher doses (2-4 Gy; (13, 37)). Doses to the Chernobyl liquidators were mostly lower and exposure was fractionated over an extended period of time, which could have decreased the probability of gonadal DNM events. Moreover, it is plausible that the balance between radiation-induced mutations and accurate repair over time favored the latter. Additionally, there could have been a loss of power due to dose errors. Further human studies are needed to investigate the frequency of radiation-induced mutations and the subsequent response to address both the accuracy and efficiency of DNA repair. In a genomic landscape analysis of 440 cases of papillary thyroid cancer following the Chernobyl accident, increased radiation exposure was associated with a shift in tumor drivers from point mutations to small indels and non-homologous end joining events underlying fusions and other structural variants (38). Notably, there was no evidence of a radiation-specific single base substitution signature, gene expression pattern or methylation profile in cases of thyroid cancer with comparable radiation exposure history; instead, these were strongly associated with the tumor driver.
The rate, class distribution, and SNV type distribution of DNMs in adult children born to parents exposed to ionizing radiation, specifically of the type and amount relevant to Chernobyl cleanup workers and evacuees, are comparable to those reported in the general population. No effect of radiation on the specific classes of DNMs (SNVs, indels, complex variants, or clusters) was observed (table S5). Paternal age remains the strongest contributor to DNMs, although with maternal age DNMs also increase albeit with lower magnitude (Table 2 and table S4; (12)). Our study sample did not include mothers with high exposure (>1 Gy), but lower maternal dose was not associated with elevated DNMs, consistent with animal studies (13). Furthermore, our analysis of 130 adult children from 105 couples using 80X coverage of short-read technology suggests that if such effects on human germline DNA occur, they are uncommon or of small magnitude. This is one of the first studies to systematically evaluate alterations in human mutation rates in response to a man-made disaster, such as accidental radiation exposure. Investigation of trios drawn from survivors of the Hiroshima atomic bomb could shed further light on this public health question. In conclusion, children of individuals exposed to either occupational or environmental radiation do not appear to experience elevated rates of DNMs from their parents’ exposure. Thus, our study does not provide support for a transgenerational effect of ionizing radiation on germline DNA in humans.
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