Identification of Retinoic Acid Receptor Agonists in Sewage Treatment Plants

Zhen, Huajun; Wu, Xiaodan; Hu, Jianying; Xiao, Yang; Yang, Min; Hirotsuji, Junji; Nishikawa, J; Nakanishi, Takashi; Ike, Michihiko

doi:10.1021/es9000328

Cited by 44 publications

(45 citation statements)

References 37 publications

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“…S2), which was greater than those (0.7 ± 0.8 ng/L) reported previously in a river basin, Liaodong Bay, China, where untreated wastewaters are discharged directly into the rivers (29). The greatest total concentration of RAs and 4-oxoRAs in water from Taihu Lake was 2.0 × 10 ng/L, which was comparable to concentrations in raw influents of sewage treatment plants (28). Taihu Lake is an important drinking water source for local residents, and domestic wastewaters without treatment are not directly discharged into the lake.…”

Section: Resultsmentioning

confidence: 53%

“…RAs and their metabolites can enter into the aquatic environments through discharge of domestic sewage. Concentrations of RAs and their bioactive metabolites 4-oxo-RAs in treated wastewater have generally been found to be less than 1.0 ng/L (28,29). Recently, anomalous concentrations of RAs and 4-oxoRAs (up to 20 ng/L) were measured in some protected drinking water sources (30), which suggested that there might be unidentified sources of RAs in aquatic systems.…”

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confidence: 99%

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Cyanobacteria blooms produce teratogenic retinoic acids

Jiang

Wan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Deformed amphibians have been observed in eutrophic habitats, and some clues point to the retinoic acids (RAs) or RA mimics. However, RAs are generally thought of as vertebrate-specific hormones, and there was no evidence that RAs exist in cyanobacteria or algae blooms. By analyzing RAs and their analogs 4-oxo-RAs in natural cyanobacteria blooms and cultures of cyanobacteria and algae, we showed that cyanobacteria blooms could produce RAs, which were powerful animal teratogens. Intracellular RAs and 4-oxo-RAs with concentrations between 0.4 and 4.2 × 10 2 ng/L were detected in all bloom materials, and extracellular concentrations measured in water from Taihu Lake, China, were as great as 2.0 × 10 ng/L, which might pose a risk to wildlife through chronic exposure. Further examination of 39 cyanobacteria and algae species revealed that 32 species could produce RAs and 4-oxo-RAs (1.6-1.4 × 10 3 ng/g dry weight), and the dominant cyanobacteria species in Taihu Lake, Microcystis flos-aquae and Microcystis aeruginosa, produced high amounts of RAs and 4-oxo-RAs with concentrations of 1.4 × 10 3 and 3.7 × 10 2 ng/g dry weight, respectively. Most genera of cyanobacteria that could produce RAs and 4-oxo-RAs, such as Microcystis, Anabaena, and Aphanizomenon, often occur dominantly in blooms. Production of RAs and 4-oxo-RAs by cyanobacteria was associated with species, origin location, and growth stage. These results represent a conclusive demonstration of endogenous production of RAs in freshwater cyanobacteria blooms. The observation of teratogenic RAs in cyanobacteria is evolutionarily and ecologically significant because RAs are vertebrate-specific hormones, and cyanobacteria form extensive and highly visible blooms in many aquatic ecosystems.eutrophication | phytoplankton | deformities | Asia

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Section: Resultsmentioning

confidence: 53%

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confidence: 99%

Cyanobacteria blooms produce teratogenic retinoic acids

Jiang

Wan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…We investigated the RARα agonistic activity in seven WWTPs and their receiving rivers (Tonghui River and Qing River) and detected a significant activity mainly in the ethyl acetate fraction (medium polar fraction) of the wastewater and water samples. 40) The maximal atRA equivalents (atRA-EQ) in the fraction estimated based on the results of yeast two-hybrid assay were 13.4, 3.2 and 10.0 ng/l in WWTP influent, WWTP effluent and river water, respectively, which were much lower than the atRA concentration exhibiting teratogenic effects in animals ( Table 1). Most of the RARα agonistic activity detected in river water seemed to be explained by WWTP effluents and untreated wastewater discharged from several wastewater discharging pipes.…”

Section: Findings Of Rar Agonist Contamination In the Aquatic Environmentioning

confidence: 98%

“…Oxidative metabolites of RA in humans and animals such as 4-oxo-RA, 4-hydroxy-RA, 18-hydroxy-RA and 5,6-epoxy-RA can bind to RARs and activate the RAR-mediated transcription via an RA response element. 28,[38][39][40] In particular, 4-oxo-RAs such as 4-oxo-atRA and 4-oxo-13-cis RA (4-oxo-13cRA) have been proven to have RAR agonistic activity equivalent to atRA using different in vitro bioassay systems. 28,38,40) Furthermore, numerous studies have demonstrated that these RA metabolites exhibit RAR-mediated biological activity just as RA does.…”

Section: Natural and Xenobiotic Compounds That Act As Rar Agonistsmentioning

confidence: 99%

“…28,[38][39][40] In particular, 4-oxo-RAs such as 4-oxo-atRA and 4-oxo-13-cis RA (4-oxo-13cRA) have been proven to have RAR agonistic activity equivalent to atRA using different in vitro bioassay systems. 28,38,40) Furthermore, numerous studies have demonstrated that these RA metabolites exhibit RAR-mediated biological activity just as RA does. 28,[41][42][43][44][45] Recent studies have also revealed that xenobiotic environmental pollutants can elicit the binding affinity to and the agonistic activity on RARs.…”

Section: Natural and Xenobiotic Compounds That Act As Rar Agonistsmentioning

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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Deriving bio‐equivalents from in vitro bioassays: Assessment of existing uncertainties and strategies to improve accuracy and reporting

Wagner

Vermeirssen

Buchinger

et al. 2013

Enviro Toxic and Chemistry

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Bio-equivalents (e.g., 17β-estradiol or dioxin equivalents) are commonly employed to quantify the in vitro effects of complex human or environmental samples. However, there is no generally accepted data analysis strategy for estimating and reporting bio-equivalents. Therefore, the aims of the present study are to 1) identify common mathematical models for the derivation of bio-equivalents from the literature, 2) assess the ability of those models to correctly predict bio-equivalents, and 3) propose measures to reduce uncertainty in their calculation and reporting. We compiled a database of 234 publications that report bio-equivalents. From the database, we extracted 3 data analysis strategies commonly used to estimate bio-equivalents. These models are based on linear or nonlinear interpolation, and the comparison of effect concentrations (ECX ). To assess their accuracy, we employed simulated data sets in different scenarios. The results indicate that all models lead to a considerable misestimation of bio-equivalents if certain mathematical assumptions (e.g., goodness of fit, parallelism of dose-response curves) are violated. However, nonlinear interpolation is most suitable to predict bio-equivalents from single-point estimates. Regardless of the model, subsequent linear extrapolation of bio-equivalents generates additional inaccuracy if the prerequisite of parallel dose-response curves is not met. When all these factors are taken into consideration, it becomes clear that data analysis introduces considerable uncertainty in the derived bio-equivalents. To improve accuracy and transparency of bio-equivalents, we propose a novel data analysis strategy and a checklist for reporting Minimum Information about Bio-equivalent ESTimates (MIBEST).

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Identification of Retinoic Acid Receptor Agonists in Sewage Treatment Plants

Cited by 44 publications

References 37 publications

Cyanobacteria blooms produce teratogenic retinoic acids

Cyanobacteria blooms produce teratogenic retinoic acids

Disruption of Retinoic Acid Receptor Signaling by Environmental Pollutants

Deriving bio‐equivalents from in vitro bioassays: Assessment of existing uncertainties and strategies to improve accuracy and reporting

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