Prenatal exposure of mice to the human liver carcinogen aflatoxin B
It has become axiomatic that critical windows of susceptibility to genotoxins exist and that genetic damage in utero may be a trigger for later life cancers. Data supporting this critical window hypothesis are remarkably few. This study provides a quantitative bridge between DNA damage by the liver...
| Main Authors: | , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Wiley Blackwell
2017
|
| Online Access: | http://hdl.handle.net/1721.1/106632 https://orcid.org/0000-0003-0176-1920 https://orcid.org/0000-0003-0771-9889 https://orcid.org/0000-0002-2196-5691 |
| _version_ | 1826188840803500032 |
|---|---|
| author | Thiantanawat, Apinya Egner, Patricia A. Groopman, John D. Chawanthayatham, Supawadee Wogan, Gerald N Croy, Robert G Essigmann, John M |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Thiantanawat, Apinya Egner, Patricia A. Groopman, John D. Chawanthayatham, Supawadee Wogan, Gerald N Croy, Robert G Essigmann, John M |
| author_sort | Thiantanawat, Apinya |
| collection | MIT |
| description | It has become axiomatic that critical windows of susceptibility to genotoxins exist and that genetic damage in utero may be a trigger for later life cancers. Data supporting this critical window hypothesis are remarkably few. This study provides a quantitative bridge between DNA damage by the liver carcinogen aflatoxin B[subscript 1] (AFB[subscript 1]) during prenatal development and the risk of later life genetic disease. AFB[subscript 1] was given to pregnant C57BL/6J mice, carrying F[subscript 1] gestation day 14 (GD14) embryos of the B6C3F1 genotype. Ultra-high performance liquid chromatography and mass spectrometry (UPLC-MS) using aflatoxin-[superscript 15]N[subscript 5]-guanine adduct standards afforded measurement of the AFB[subscript 1]-N[superscript 7]-Gua and AFB[subscript 1]-FAPY adducts 6-hr post dosing in liver DNA of mothers and embryos. A parallel cohort gave birth and the livers of the F[subscript 1] were analyzed for mutations in the gpt gene at 3 and 10 weeks of age. The data revealed mutational spectra dominated by G:C to T:A mutations in both the mother and offspring that are characteristic of AFB[subscript 1] and distinct from background. It was shown that adducts in GD14 embryos were 20-fold more potent inducers of mutagenesis than adducts in parallel-dosed adults. This sensitivity enhancement correlated with Ki67 staining of the liver, reflecting the proliferative potential of the tissue. Taken together, these data provide insight into the relative genetic risks of prenatal and adult exposures to AFB[subscript 1]. Early life exposure, especially during the embryonic period, is strikingly more mutagenic than treatment later in life. Moreover the data provide a baseline against which risk prevention strategies can be evaluated. |
| first_indexed | 2024-09-23T08:05:32Z |
| format | Article |
| id | mit-1721.1/106632 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:05:32Z |
| publishDate | 2017 |
| publisher | Wiley Blackwell |
| record_format | dspace |
| spelling | mit-1721.1/1066322022-09-30T07:28:38Z Prenatal exposure of mice to the human liver carcinogen aflatoxin B Thiantanawat, Apinya Egner, Patricia A. Groopman, John D. Chawanthayatham, Supawadee Wogan, Gerald N Croy, Robert G Essigmann, John M Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Chemistry Chawanthayatham, Supawadee Wogan, Gerald N Croy, Robert G Essigmann, John M It has become axiomatic that critical windows of susceptibility to genotoxins exist and that genetic damage in utero may be a trigger for later life cancers. Data supporting this critical window hypothesis are remarkably few. This study provides a quantitative bridge between DNA damage by the liver carcinogen aflatoxin B[subscript 1] (AFB[subscript 1]) during prenatal development and the risk of later life genetic disease. AFB[subscript 1] was given to pregnant C57BL/6J mice, carrying F[subscript 1] gestation day 14 (GD14) embryos of the B6C3F1 genotype. Ultra-high performance liquid chromatography and mass spectrometry (UPLC-MS) using aflatoxin-[superscript 15]N[subscript 5]-guanine adduct standards afforded measurement of the AFB[subscript 1]-N[superscript 7]-Gua and AFB[subscript 1]-FAPY adducts 6-hr post dosing in liver DNA of mothers and embryos. A parallel cohort gave birth and the livers of the F[subscript 1] were analyzed for mutations in the gpt gene at 3 and 10 weeks of age. The data revealed mutational spectra dominated by G:C to T:A mutations in both the mother and offspring that are characteristic of AFB[subscript 1] and distinct from background. It was shown that adducts in GD14 embryos were 20-fold more potent inducers of mutagenesis than adducts in parallel-dosed adults. This sensitivity enhancement correlated with Ki67 staining of the liver, reflecting the proliferative potential of the tissue. Taken together, these data provide insight into the relative genetic risks of prenatal and adult exposures to AFB[subscript 1]. Early life exposure, especially during the embryonic period, is strikingly more mutagenic than treatment later in life. Moreover the data provide a baseline against which risk prevention strategies can be evaluated. National Institutes of Health (U.S.) (Grants ES016313, P30-ES002109, P01 ES006052, P30 ES003819, and P30 CA006973) Center of Excellence on Environmental Health, Toxicology and Management of Chemicals, Thailand Schlumberger Foundation. Faculty for the Future 2017-01-26T15:15:53Z 2017-01-26T15:15:53Z 2014-08 2014-05 Article http://purl.org/eprint/type/JournalArticle 0020-7136 1811-9735 http://hdl.handle.net/1721.1/106632 Chawanthayatham, Supawadee et al. “Prenatal Exposure of Mice to the Human Liver Carcinogen Aflatoxin B 1 Reveals a Critical Window of Susceptibility to Genetic Change: Genetic Effects of Aflatoxin B 1.” International Journal of Cancer 136.6 (2015): 1254–1262. https://orcid.org/0000-0003-0176-1920 https://orcid.org/0000-0003-0771-9889 https://orcid.org/0000-0002-2196-5691 en_US http://dx.doi.org/10.1002/ijc.29102 International Journal of Cancer Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Wiley Blackwell PMC |
| spellingShingle | Thiantanawat, Apinya Egner, Patricia A. Groopman, John D. Chawanthayatham, Supawadee Wogan, Gerald N Croy, Robert G Essigmann, John M Prenatal exposure of mice to the human liver carcinogen aflatoxin B |
| title | Prenatal exposure of mice to the human liver carcinogen aflatoxin B |
| title_full | Prenatal exposure of mice to the human liver carcinogen aflatoxin B |
| title_fullStr | Prenatal exposure of mice to the human liver carcinogen aflatoxin B |
| title_full_unstemmed | Prenatal exposure of mice to the human liver carcinogen aflatoxin B |
| title_short | Prenatal exposure of mice to the human liver carcinogen aflatoxin B |
| title_sort | prenatal exposure of mice to the human liver carcinogen aflatoxin b |
| url | http://hdl.handle.net/1721.1/106632 https://orcid.org/0000-0003-0176-1920 https://orcid.org/0000-0003-0771-9889 https://orcid.org/0000-0002-2196-5691 |
| work_keys_str_mv | AT thiantanawatapinya prenatalexposureofmicetothehumanlivercarcinogenaflatoxinb AT egnerpatriciaa prenatalexposureofmicetothehumanlivercarcinogenaflatoxinb AT groopmanjohnd prenatalexposureofmicetothehumanlivercarcinogenaflatoxinb AT chawanthayathamsupawadee prenatalexposureofmicetothehumanlivercarcinogenaflatoxinb AT wogangeraldn prenatalexposureofmicetothehumanlivercarcinogenaflatoxinb AT croyrobertg prenatalexposureofmicetothehumanlivercarcinogenaflatoxinb AT essigmannjohnm prenatalexposureofmicetothehumanlivercarcinogenaflatoxinb |