A Comparative Study of Human and Zebrafish Pregnane X Receptor Activities of Pesticides and Steroids Using In Vitro Reporter Gene Assays

Creusot, Nicolas; Garoche, Clémentine; Grimaldi, Marina; Boulahtouf, Abdelhay; Chiavarina, Barbara; Bourguet, William; Balaguer, Patrick

doi:10.3389/fendo.2021.665521

Cited by 10 publications

(4 citation statements)

References 31 publications

(65 reference statements)

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“…The tentative identification of PCL oligomers in the methanolic extracts supports this idea. Because ligands for human and zebrafish PXR are not wholly identical, the activation of zebrafish PXR by PCL and its degradation products will require further investigation. Nonetheless, PXR activity in rats and zebrafish has been reported upon nanoparticle exposure. − Whether PXR activation is part of the mechanism of toxicity from exposure to PCL pellets is unknown.…”

Section: Discussionmentioning

confidence: 99%

Moldable Plastics (Polycaprolactone) can be Acutely Toxic to Developing Zebrafish and Activate Nuclear Receptors in Mammalian Cells

James,

Medvedev,

Makarov

et al. 2024

ACS Biomater. Sci. Eng.

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Popularized on social media, hand-moldable plastics are formed by consumers into tools, trinkets, and dental prosthetics. Despite the anticipated dermal and oral contact, manufacturers share little information with consumers about these materials, which are typically sold as microplastic-sized resin pellets. Inherent to their function, moldable plastics pose a risk of dermal and oral exposure to unknown leachable substances. We analyzed 12 moldable plastics advertised for modeling and dental applications and determined them to be polycaprolactone (PCL) or thermoplastic polyurethane (TPU). The bioactivities of the most popular brands advertised for modeling applications of each type of polymer were evaluated using a zebrafish embryo bioassay. While water-borne exposure to the TPU pellets did not affect the targeted developmental end points at any concentration tested, the PCL pellets were acutely toxic above 1 pellet/mL. The aqueous leachates of the PCL pellets demonstrated similar toxicity. Methanolic extracts from the PCL pellets were assayed for their bioactivity using the Attagene FACTORIAL platform. Of the 69 measured end points, the extracts activated nuclear receptors and transcription factors for xenobiotic metabolism (pregnane X receptor, PXR), lipid metabolism (peroxisome proliferator-activated receptor γ, PPARγ), and oxidative stress (nuclear factor erythroid 2-related factor 2, NRF2). By nontargeted high-resolution comprehensive two-dimensional gas chromatography (GC × GC-HRT), we tentatively identified several compounds in the methanolic extracts, including PCL oligomers, a phenolic antioxidant, and residues of suspected antihydrolysis and cross-linking additives. In a follow-up zebrafish embryo bioassay, because of its stated high purity, biomedical grade PCL was tested to mitigate any confounding effects due to chemical additives in the PCL pellets; it elicited comparable acute toxicity. From these orthogonal and complementary experiments, we suggest that the toxicity was due to oligomers and nanoplastics released from the PCL rather than chemical additives. These results challenge the perceived and assumed inertness of plastics and highlight their multiple sources of toxicity.

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Section: Discussionmentioning

confidence: 99%

Moldable Plastics (Polycaprolactone) can be Acutely Toxic to Developing Zebrafish and Activate Nuclear Receptors in Mammalian Cells

James,

Medvedev,

Makarov

et al. 2024

ACS Biomater. Sci. Eng.

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show abstract

“…The tentative identification of PCL oligomers in the methanolic extracts supports this idea. Because ligands for human and zebrafish PXR are not wholly identical, 95 the activation of zebrafish PXR by PCL and its degradation products will require further investigation.…”

Section: Nanoplastics and Oligomersmentioning

confidence: 99%

Moldable plastics (polycaprolactone) can be acutely toxic to developing zebrafish and activate nuclear receptors in mammalian cells

James,

Medvedev,

Makarov

et al. 2024

Preprint

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Popularized on social media, hand-moldable plastics are formed by consumers into tools, trinkets, and dental prosthetics. Despite the anticipated dermal and oral contact, manufacturers share little information with consumers about these materials. Inherent to their function, moldable plastics pose a risk of dermal and oral exposure to unknown leachable substances. We analyzed 12 moldable plastics advertised for modeling and dental applications and determined them to be polycaprolactone (PCL) or thermoplastic polyurethane (TPU). The bioactivities of the most popular brands advertised for modeling applications of each type of polymer were evaluated using a zebrafish embryo bioassay. Both products were sold as microplastic-sized resin pellets. While water-borne exposure to the TPU pellets did not affect the targeted developmental endpoints at any concentration tested, the PCL pellets were acutely toxic above 1 pellet/mL. Aqueous leachates of the PCL pellets demonstrated similar toxicity. Methanolic extracts from the PCL pellets were assayed for their bioactivity using the Attagene FACTORIAL platform. Of the 69 measured endpoints, the extracts activated nuclear receptors and transcription factors for xenobiotic metabolism (pregnane X receptor, PXR), lipid metabolism (peroxisome proliferator-activated receptor gamma, PPARg), and oxidative stress (nuclear factor erythroid 2-related factor 2, NRF2). By non-targeted high-resolution comprehensive two-dimensional gas chromatography (GC×GC-HRT), we tentatively identified several compounds in the methanolic extracts, including PCL oligomers, a phenolic antioxidant, and residues of suspected anti-hydrolysis and crosslinking additives. In a follow-up zebrafish embryo bioassay, because of its stated high purity, biomedical grade PCL was tested to mitigate any confounding effects due to chemical additives in the PCL pellets; it elicited comparable acute toxicity. From these orthogonal and complementary experiments, we suggest that the toxicity was due to oligomers and nanoplastics released from the PCL rather than chemical additives. These results challenge the perceived and assumed inertness of plastics and highlight their multiple sources of toxicity.

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“…Previous studies have reported that chemicals have different binding potencies to human and fish receptors. − For example, steroids are generally stronger activators of the zebrafish pregnane X receptor, while pesticides are more potent on the human pregnane X receptor . Progestins activate the human progesterone receptor, whereas they act as zebrafish progesterone receptor antagonists .…”

Section: Introductionmentioning

confidence: 99%

Biological-Activity-Based Prioritization of Antidepressants in Wastewater in England and Japan

Zhang

Kato

Ihara

et al. 2023

Environ. Sci. Technol.

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Antidepressants are one of the most commonly prescribed pharmaceuticals. Although they have been frequently detected in aquatic environments around the globe, little is known regarding their adverse effects on humans and aquatic organisms. Recently, an in vitro monoamine transporter inhibition assay was developed to detect transporter-inhibitory activities of antidepressants in wastewater in Japan. However, it was unclear which antidepressants were responsible for transporter-inhibitory activities in wastewater. Herein, the per capita consumption of 32 antidepressants, their excretion of unchanged parent compounds, per capita water consumption, removal rate during wastewater treatment processes, and potency values from the monoamine transporter inhibition assay were used to prioritize antidepressants of concern in effluent wastewater in England and Japan. In both countries, sertraline and O-desmethylvenlafaxine had the highest contribution to inhibitory activities against the human serotonin transporter (hSERT) and zebrafish SERT (zSERT), respectively. It was found that the antidepressants inhibited the zSERT more strongly than the hSERT. The inhibitory activities found against the zSERT in wastewater in England and Japan were higher than thresholds for abnormal behavior in fish. The antidepressants prioritized in this study provide insight into launching environmental monitoring and ecotoxicological studies of antidepressants.

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A Comparative Study of Human and Zebrafish Pregnane X Receptor Activities of Pesticides and Steroids Using In Vitro Reporter Gene Assays

Cited by 10 publications

References 31 publications

Moldable Plastics (Polycaprolactone) can be Acutely Toxic to Developing Zebrafish and Activate Nuclear Receptors in Mammalian Cells

Moldable Plastics (Polycaprolactone) can be Acutely Toxic to Developing Zebrafish and Activate Nuclear Receptors in Mammalian Cells

Moldable plastics (polycaprolactone) can be acutely toxic to developing zebrafish and activate nuclear receptors in mammalian cells

Biological-Activity-Based Prioritization of Antidepressants in Wastewater in England and Japan

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