New Approach Methodologies (NAMs) to assess killer whale (Orcinus orca) estrogen receptor alpha (ERα) transactivation potencies by DDTs and their risks
Killer whales (Orcinus orca), as apex predators, accumulate high levels of persistent organic pollutants (POPs) such as dichlorodiphenyltrichloroethane and its analogs (DDTs) and face their risks at the population level. The assessment of the function of estrogen receptor alpha (ERα) is crucial for...
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Elsevier
2025-02-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325000971 |
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| author | Dave Arthur R. Robledo Takahito Kumagawa Mari Ochiai Hisato Iwata |
| author_facet | Dave Arthur R. Robledo Takahito Kumagawa Mari Ochiai Hisato Iwata |
| author_sort | Dave Arthur R. Robledo |
| collection | DOAJ |
| description | Killer whales (Orcinus orca), as apex predators, accumulate high levels of persistent organic pollutants (POPs) such as dichlorodiphenyltrichloroethane and its analogs (DDTs) and face their risks at the population level. The assessment of the function of estrogen receptor alpha (ERα) is crucial for evaluating impact of DDTs on killer whale endocrine and reproductive health. However, due to ethical constraints, little is known about the effects of DDTs on the function of killer whale ERα (kwERα). This study aimed to assess kwERα transactivation potencies in response to various DDTs (p,p′-DDT, o,p′-DDT, p,p′-DDD, o,p′-DDD, p,p′-DDE, o,p′-DDE, and p,p′-DDOH) by New Approach Methodologies (NAMs). We constructed an in vitro kwERα-expressed reporter gene assay and measured transactivation potencies of DDTs as the 10 % effective concentration (REC10) relative to the maximum response to 17β-estradiol exposure. We also employed in silico approaches such as molecular docking and protein-ligand network analysis (PLNA) to elucidate the interaction of kwERα protein and DDTs. The in vitro results revealed an estrogenic potency in the order of 17β-estradiol > o,p’-DDT > o,p’-DDE > o,p’-DDD > p,p’-DDD > p,p’-DDOH > p,p’-DDT > p,p’-DDE (no activity). Strong positive correlations were found between in vitro REC10 values and in silico docking scores, suggesting the structure-activity relationship of the estrogenic potencies of DDTs to kwERɑ. PLNA highlighted contribution of Glu353 and Phe404 in kwERα as essential residues to the interaction with DDTs. Risk assessments indicated that the o,p’-DDT-estrogenic equivalency quantities of DDTs in the blubber of both Irish and Canadian Arctic killer whales exceeded the in vitro REC10 of o,p’-DDT, suggesting a significant risk of kwERα-mediated endocrine disruption in these populations. These findings underscore the importance of NAMs including in vitro and in silico approaches for assessing the endocrine and reproductive risk in killer whales. |
| format | Article |
| id | doaj-art-c113aa87b2484dffb09de9db8b54d667 |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-02-01 |
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| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-c113aa87b2484dffb09de9db8b54d6672025-02-02T05:26:38ZengElsevierEcotoxicology and Environmental Safety0147-65132025-02-01291117761New Approach Methodologies (NAMs) to assess killer whale (Orcinus orca) estrogen receptor alpha (ERα) transactivation potencies by DDTs and their risksDave Arthur R. Robledo0Takahito Kumagawa1Mari Ochiai2Hisato Iwata3Center for Marine Environmental Studies (CMES), Ehime University, Matsuyama, JapanCenter for Marine Environmental Studies (CMES), Ehime University, Matsuyama, JapanCenter for Marine Environmental Studies (CMES), Ehime University, Matsuyama, JapanCorresponding author.; Center for Marine Environmental Studies (CMES), Ehime University, Matsuyama, JapanKiller whales (Orcinus orca), as apex predators, accumulate high levels of persistent organic pollutants (POPs) such as dichlorodiphenyltrichloroethane and its analogs (DDTs) and face their risks at the population level. The assessment of the function of estrogen receptor alpha (ERα) is crucial for evaluating impact of DDTs on killer whale endocrine and reproductive health. However, due to ethical constraints, little is known about the effects of DDTs on the function of killer whale ERα (kwERα). This study aimed to assess kwERα transactivation potencies in response to various DDTs (p,p′-DDT, o,p′-DDT, p,p′-DDD, o,p′-DDD, p,p′-DDE, o,p′-DDE, and p,p′-DDOH) by New Approach Methodologies (NAMs). We constructed an in vitro kwERα-expressed reporter gene assay and measured transactivation potencies of DDTs as the 10 % effective concentration (REC10) relative to the maximum response to 17β-estradiol exposure. We also employed in silico approaches such as molecular docking and protein-ligand network analysis (PLNA) to elucidate the interaction of kwERα protein and DDTs. The in vitro results revealed an estrogenic potency in the order of 17β-estradiol > o,p’-DDT > o,p’-DDE > o,p’-DDD > p,p’-DDD > p,p’-DDOH > p,p’-DDT > p,p’-DDE (no activity). Strong positive correlations were found between in vitro REC10 values and in silico docking scores, suggesting the structure-activity relationship of the estrogenic potencies of DDTs to kwERɑ. PLNA highlighted contribution of Glu353 and Phe404 in kwERα as essential residues to the interaction with DDTs. Risk assessments indicated that the o,p’-DDT-estrogenic equivalency quantities of DDTs in the blubber of both Irish and Canadian Arctic killer whales exceeded the in vitro REC10 of o,p’-DDT, suggesting a significant risk of kwERα-mediated endocrine disruption in these populations. These findings underscore the importance of NAMs including in vitro and in silico approaches for assessing the endocrine and reproductive risk in killer whales.http://www.sciencedirect.com/science/article/pii/S0147651325000971Killer whalesDDTsEstrogen receptor α (ERα)Endocrine disruptionNew Approach Methodologies (NAMs)Risk assessment |
| spellingShingle | Dave Arthur R. Robledo Takahito Kumagawa Mari Ochiai Hisato Iwata New Approach Methodologies (NAMs) to assess killer whale (Orcinus orca) estrogen receptor alpha (ERα) transactivation potencies by DDTs and their risks Ecotoxicology and Environmental Safety Killer whales DDTs Estrogen receptor α (ERα) Endocrine disruption New Approach Methodologies (NAMs) Risk assessment |
| title | New Approach Methodologies (NAMs) to assess killer whale (Orcinus orca) estrogen receptor alpha (ERα) transactivation potencies by DDTs and their risks |
| title_full | New Approach Methodologies (NAMs) to assess killer whale (Orcinus orca) estrogen receptor alpha (ERα) transactivation potencies by DDTs and their risks |
| title_fullStr | New Approach Methodologies (NAMs) to assess killer whale (Orcinus orca) estrogen receptor alpha (ERα) transactivation potencies by DDTs and their risks |
| title_full_unstemmed | New Approach Methodologies (NAMs) to assess killer whale (Orcinus orca) estrogen receptor alpha (ERα) transactivation potencies by DDTs and their risks |
| title_short | New Approach Methodologies (NAMs) to assess killer whale (Orcinus orca) estrogen receptor alpha (ERα) transactivation potencies by DDTs and their risks |
| title_sort | new approach methodologies nams to assess killer whale orcinus orca estrogen receptor alpha erα transactivation potencies by ddts and their risks |
| topic | Killer whales DDTs Estrogen receptor α (ERα) Endocrine disruption New Approach Methodologies (NAMs) Risk assessment |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325000971 |
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