Detection of Agonistic Activities Against Five Human Nuclear Receptors in River Environments of Japan Using a Yeast Two-Hybrid Assay

Inoue, Daisuke; Nakama, Koki; Matsui, Hisaji; Sei, Kazunari; Ike, Michihiko

doi:10.1007/s00128-008-9616-1

Cited by 24 publications

(22 citation statements)

References 13 publications

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“…However, the causative contaminants, which were named environmental retinoids, were not identified (Gardiner et al, 2003). Very recently, RAR agonistic activity was detected in wastewater treatment plants (WWTPs) and their receiving rivers in Beijing, China (Zhen et al, 2009) and several rivers in the Kinki region of Japan (Inoue et al, 2009). The results of these studies confirmed that RAR agonist contamination exists in the aquatic environment.…”

Section: Introductionmentioning

confidence: 99%

Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan

et al. 2010

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RARa agonistic activityRiver Surface water Yeast two-hybrid assay a b s t r a c t This study was conducted to investigate the agonistic activity against human retinoic acid receptor (RAR) a in the Lake Biwa-Yodo River and the Ina River in the Kinki region of Japan.To accomplish this, a yeast two-hybrid assay was used to elucidate the spatial and temporal variations and potential sources of RARa agonist contamination in the river basins. RARa agonistic activity was commonly detected in the surface water samples collected along two rivers at different periods, with maximum all-trans retinoic acid (atRA) equivalents of 47.6 ng-atRA/L and 23.5 ng-atRA/L being observed in Lake Biwa-Yodo River and Ina River, respectively. The results indicated that RARa agonists are always present and widespread in the rivers. Comparative investigation of RARa and estrogen receptor a agonistic activities at 20 stations along each river revealed that the spatial variation pattern of RARa agonist contamination was entirely different from that of the estrogenic compound contamination.This suggests that the effluent from municipal wastewater treatment plants, a primary source of estrogenic compounds, seemed not to be the cause of RARa agonist contamination in the rivers. Fractionation using high performance liquid chromatography (HPLC) directed by the bioassay found two bioactive fractions from river water samples, suggesting the presence of at least two RARa agonists in the rivers. Although a trial conducted to identify RARa agonists in the major bioactive fraction was not completed as part of this study, comparison of retention times in HPLC analysis and quantification with liquid chromatography-mass spectrometry analysis revealed that the major causative contaminants responsible for the RARa agonistic activity were not RAs (natural RAR ligands) and 4-oxoRAs, while 4-oxo-RAs were identified as the major RAR agonists in sewage in Beijing, China.These findings suggest that there are unknown RARa agonists with high activity in the rivers. A v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / w a t r e s w a t e r r e s e a r c h 4 4 ( 2 0 1 0 ) 2 4 0 9 -2 4 1 80043-1354/$ -see front matter ª

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Section: Introductionmentioning

confidence: 99%

Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan

et al. 2010

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“…Our recent studies in 4 rivers in the Kinki region and in several WWTPs in Osaka and Toyama Prefectures detected statistically significant RARα agonistic activity commonly in surface waters in all of the investigated rivers 56,57) and influents and effluents from the WWTPs. 58,59) River water pollution by RAR agonists occurs irrespective of the pollution level of the rivers, and surprisingly even in the upstream suburban areas with little human activity.…”

Section: Environmental Pollution By Rar Agonists In Japanmentioning

confidence: 76%

“…58,59) River water pollution by RAR agonists occurs irrespective of the pollution level of the rivers, and surprisingly even in the upstream suburban areas with little human activity. 56,57) In addition, strong RARα agonistic activity unaccountable by the activity of WWTP effluents was detected in river water samples. 56,57,59) Therefore, WWTPs do not seem to be the major source of RAR agonists in our study areas in Japan, which is different from the RAR agonist pollution found in Beijing, China as described above.…”

Section: Environmental Pollution By Rar Agonists In Japanmentioning

confidence: 99%

“…56,57) In addition, strong RARα agonistic activity unaccountable by the activity of WWTP effluents was detected in river water samples. 56,57,59) Therefore, WWTPs do not seem to be the major source of RAR agonists in our study areas in Japan, which is different from the RAR agonist pollution found in Beijing, China as described above. Also, simultaneous investigation of the agonistic activities at RARα and estrogen receptor α suggests that the variation along the watercourse of RAR agonist pollution in Japanese rivers is completely dissimilar to that of the estrogenic contamination, a widely known EDCs problem.…”

Section: Environmental Pollution By Rar Agonists In Japanmentioning

confidence: 99%

“…Also, simultaneous investigation of the agonistic activities at RARα and estrogen receptor α suggests that the variation along the watercourse of RAR agonist pollution in Japanese rivers is completely dissimilar to that of the estrogenic contamination, a widely known EDCs problem. 56,57) Although the RAR agonists present in aquatic samples in Japan are not yet identified (Table 3), the river pollution level in the Kinki region of Japan appears to be greater than that in Beijing, China. 40,57) However, the maximal atRA-EQ in river water was estimated to be 47.6 ng/l, 57) which was more than 10-fold lower than the atRA level leading to the abnormal morphological developments in vertebrates (Table 1).…”

Section: Environmental Pollution By Rar Agonists In Japanmentioning

confidence: 99%

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Disruption of Retinoic Acid Receptor Signaling by Environmental Pollutants

Inoue

Sei

Ike

2010

JOURNAL OF HEALTH SCIENCE

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Retinoic acid (RA) receptors (RARs) are nuclear receptors that play a critical role in regulating cellular proliferation, development and differentiation in vertebrates in response to endogenous RAs, i.e., all-trans RA and 9-cis RA. On the other hand, it has been well-known that both a deficiency and an excess of RA and related retinoids can cause a variety of teratogenic effects on developing embryos of vertebrates, which has been proven to be an RAR-mediated process. Therefore, the occurrence of xenobiotic environmental pollutants that interfere with RARs and disrupt the RAR signaling (i.e., show RAR agonistic or antagonistic effects) may pose a threat to the health of wild animals and humans. This review mainly focuses on RAR agonists. We summarize the RAR agonistic activity of natural and xenobiotic compounds determined using in vitro bioassay systems and present recent field research showing the occurrence of RAR agonist contamination in the aquatic environment in North America, China and Japan. Environmental pollution by RAR agonists is a new endocrine disruption issue discovered very recently, and relevant knowledge is very limited. Further research will be required to obtain accurate information to assess the possible risks of RAR agonists in the environment.

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Determination and occurrence of retinoic acids and their 4‐oxo metabolites in Liaodong Bay, China, and its adjacent rivers

Jia

et al. 2010

Enviro Toxic and Chemistry

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Retinoic acids (RAs) and their metabolites play an important role in abnormal morphological development and are speculated to be a possible cause for the increased rates of deformities in wild frog populations. In the current study, a method using ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry was developed for simultaneously analyzing all-trans-RA (at-RA), 13-cis-RA (13c-RA), 9-cis-RA (9c-RA), and their 4-oxo metabolites, all-trans-4-oxo-RA (at-4-oxo-RA), 13-cis-4-oxo-RA (13c-4-oxo-RA), and 9-cis-4-oxo-RA (9c-4-oxo-RA) in wastewaters and surface waters. Method detection limits were matrix dependent, ranging from 0.02 to 0.37 ng/L. The method was used to investigate the occurrence of RAs and 4-oxo-RAs in Liaodong Bay and its adjacent rivers. Of these six retinoids, at-RA, 13c-RA, at-4-oxo-RA, and 13c-4-oxo-RA were detected in river waters at detection frequencies of 100%, 92%, 48.6%, and 21.6%, and concentrations of 0.05 to 1.23 ng/L, less than 0.03 to 0.41 ng/L, less than 0.02 to 1.00 ng/L, and less than 0.06 to 0.81 ng/L, respectively. Retinoic acids were detected for the first time in the aquatic environment and were found to be more persistent than 4-oxo-RAs. The hazard quotient for mortality of frog embryos caused by induction by retinoids detected in the current study was then estimated, and the value was calculated to be 0.09. No retinoid was detected in seawaters.

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Detection of Agonistic Activities Against Five Human Nuclear Receptors in River Environments of Japan Using a Yeast Two-Hybrid Assay

Cited by 24 publications

References 13 publications

Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan

Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan

Disruption of Retinoic Acid Receptor Signaling by Environmental Pollutants

Determination and occurrence of retinoic acids and their 4‐oxo metabolites in Liaodong Bay, China, and its adjacent rivers

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