愛媛大学化学汚染・沿岸環境研究拠点

共同研究報告書 研究内容

Effects of 1,3,7-tribromodibenzo-p-dioxin, a natural dioxin on chicken embryos:
comparison with effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin
Jae-Gon Park, Eun-Young Kim
Department of Biology and Department of Life and Nanopharmaceutical Science,
Kyung Hee University
Aim and procedure
1,3,7-Tribromodibenzo-p-dioxin (1,3,7-TriBDD) is a dominant congener among
naturally occurring PBDDs throughout the marine food web. Concentrations of 1,3,7TriBDD ranging from 0.002 pg/g to 160 ng/g were detected in marine algae, sponges,
shellfish, and fish. Mussels accumulate 1,3,7-TriBDD by ingesting various algal species
and are prey resources for marine birds. Thus, naturally occurring 1,3,7-TriBDD may
potentially affect higher trophic animals, including different avian species that prey onmussels exposed to 1,3,7-TriBDD. In addition, a previous study pointed out thepossibility of increasing concentrations of 1,3,7-TriBDD in the marine environment, asclimate change may increase the populations of algal species producing 1,3,7-TriBDD.
Despite the potentially growing risk of 1,3,7-TriBDD to the marine ecosystem, the effects
of 1,3,7-TriBDD on animals, including avian species, have not fully been investigated.
Therefore, this study aimed to investigate the effects of 1,3,7-TriBDD exposure on
chicken embryos, which is a sensitive avian model to dioxin exposure. A transcriptomic
analysis of the liver of chicken embryos treated with 1,3,7-TriBDD was performed.
Moreover, a bioinformatic analysis of differentially expressed genes (DEGs) induced or
repressed by 1,3,7-TriBDD exposure was performed to provide insights into the effectsof this congener on DEG-enriched pathways. A similar experiment was performed with2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a representative and the most toxic
compound among dioxins, and the results were compared with those of 1,3,7-TriBDD.
Results
Transcriptome analysis revealed that genes with expression levels altered by exposure
to 1,3,7-TriBDD were primarily categorized in cancer- and metabolism-related pathways.
These results suggest that 1,3,7-TriBDD possibly induces cancer and metabolicalterations. The transcriptome analysis of the chicken embryos treated with 2.5 μM TCDD

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(T2.5/Control) identified similar representative pathways as 1,3,7-TriBDD administration.
Within the cancer-related pathways, the overall transcriptomes of the groups treatedwith 1,3,7-TriBDD and TCDD tended to be upregulated. Pathways in the KEGG databasemost relevant to hepatocellular carcinoma included the MAPK signaling pathway,
oxidative stress, TGFβ signaling pathway, and Pi3-Akt signaling pathway. The activationof these pathways desensitizes tumor cells to antigrowth signals by preventing exclusion
and apoptosis, and dysregulating cell proliferation. Furthermore, 1,3,7-TriBDD-induced
the mRNA and protein expression of ckPcna, which is an indicator of excessive cellproliferation and early cancer development, thereby supporting the possibility that 1,3,7TriBDD exposure can induce a precancerous state. Considering that TCDD is recognized
as a class 1 carcinogen and tumor promotion by dioxin exposure is related to uncontrolledcell proliferation, the transcriptome results suggest that 1,3,7-TriBDD administration
might also lead to excessive cell proliferation that can induce a precancerous state.
The comparisons of pathways between the 1,3,7-TriBDD- and TCDD-treated groups
showed that the two compounds had impacted four pathways in the opposite direction.
These pathways, which are related to breast cancer, hepatitis C, insulin signaling, andperoxisome, were mostly activated by 1,3,7-TriBDD exposure, but were suppressed by
TCDD exposure. These distinct responses may have caused different phenotypic effects
between the 1,3,7-TriBDD- and TCDD-treated embryos. In this study, TCDD-treatedchicken embryos had shorter body and head lengths compared with the control embryos,
whereas no morphological effects were observed in the 1,3,7-TriBDD-treated embryos.
The mortality of chicken embryos was also higher in those treated with TCDD than inthose treated with 1,3,7-TriBDD. Thus, the suppression of insulin signaling in the TCDDtreated group is possibly responsible for the increased developmental failure andmorphological effects of chicken embryos.
Publication/conference presentation
1. Kanda, K., Ito, S., Koh, D.H., Kim, E.Y., Iwata, H. (2021): Effects of tris(2chloroethyl) phosphate exposure on chicken embryos in a shell-less incubation system,
Ecotoxicology
andEnvironmental
Safety,207,111263,
doi.org/10.1016/j.ecoenv.2020.111263
2. Hoa, T.N., Li, L., Eguchi, A., Kannan, K., Kim, E.Y., Iwata, H. (2021): Effects on theliver lipidome of rat offspring prenatally exposed to bisphenol A, Science of the Total
Environment, 759, 143466, doi.org/10.1016/j.scitotenv.2020.143466
3. Cho, M.K., Park, J.G., Iwata, H., Kim, E.Y. (2021): 2,3,7,8-Tetrachlorodibenzo-pdioxin prompted differentiation to CD4+CD8-CD25+ and CD4+CD8+CD25+ Tregs

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and altered expression of immune-related genes in the thymus of chicken embryos,
Ecotoxicology
andEnvironmental
Safety,211,111947,
doi.org/10.1016/j.ecoenv.2021.111947
4. Dau, P.T., Ishibashi, H., Tuyen, L.H., Sakai, H., Hirano, M., Kim, E.Y., Iwata, H.
(2021): Assessment of binding potencies of polychlorinated biphenyls andpolybrominated diphenyl ethers with Baikal seal and mouse constitutive androstane
receptors: Comparisons across species and congeners, Science of the Total
Environment, 150631, doi.org/10.1016/j.scitotenv.2021.150631
Perspectives in future
The exposure of avian species to 1,3,7-TriBDD, a naturally occurring dioxin, may
induce changes to genes involved in metabolic alterations and the precancerous state,similar to the effects of TCDD. The common effects may be triggered by AHR activation,
as suggested by the induction of ckCyp1a4 and 1a5. Although recent studies have focusedon the effects of PBDD congeners on various organisms, the target congeners were mostly
2,3,7,8-substitutions, whereas 1,3,7-TriBDD received much less attention. The results ofthis study also revealed that the transcriptomic effects of 1,3,7-TriBDD are at least
partially distinct from those of TCDD. This slight difference may lead to minor effects by
1,3,7-TriBDD exposure and fatal effects by TCDD exposure. Given that the risk of 1,3,7TriBDD may be of increasing concern, further studies are necessary to understand thecomprehensive effects of 1,3,7-TriBDD on various animals that inhabit coastal
ecosystems.

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