Perinatal triphenyl phosphate exposure induces metabolic dysfunctions through the EGFR/ERK/AKT signaling pathway: Mechanistic in vitro and in vivo studies
Triphenyl phosphate (TPhP), a widely used organophosphate-flame retardant, is ubiquitously found in household environments and may adversely affect human health. Evidence indicates that TPhP exposure causes metabolic dysfunctions in vivo; however, the underlying mechanism of such adverse effects has...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651323012605 |
| _version_ | 1797401813789442048 |
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| author | Phum Tachachartvanich Xylina Rusit Jason Tong Chanapa Mann Michele A. La Merrill |
| author_facet | Phum Tachachartvanich Xylina Rusit Jason Tong Chanapa Mann Michele A. La Merrill |
| author_sort | Phum Tachachartvanich |
| collection | DOAJ |
| description | Triphenyl phosphate (TPhP), a widely used organophosphate-flame retardant, is ubiquitously found in household environments and may adversely affect human health. Evidence indicates that TPhP exposure causes metabolic dysfunctions in vivo; however, the underlying mechanism of such adverse effects has not been comprehensively investigated. Herein, we utilized two in vitro models including mouse and human preadipocytes to delineate adipogenic mechanisms of TPhP. The results revealed that both mouse and human preadipocytes exposed to TPhP concentration-dependently accumulated more fat through a significant upregulation of epidermal growth factor receptor (EGFR). We demonstrated that TPhP significantly promoted adipogenesis through the activation of EGFR/ERK/AKT signaling pathway as evident by a drastic reduction in adipogenesis of preadipocytes cotreated with inhibitors of EGFR and its major effectors. Furthermore, we confirmed the mechanism of TPhP-induced metabolic dysfunctions in vivo. We observed that male mice perinatally exposed to TPhP had a significant increase in adiposity, hepatic triglycerides, insulin resistance, plasma insulin levels, hypotension, and phosphorylated EGFR in gonadal fat. Interestingly, an administration of a potent and selective EGFR inhibitor significantly ameliorated the adverse metabolic effects caused by TPhP. Our findings uncovered a potential mechanism of TPhP-induced metabolic dysfunctions and provided implications on toxic metabolic effects posed by environmental chemicals. |
| first_indexed | 2024-03-09T02:15:43Z |
| format | Article |
| id | doaj.art-46465d227f264879a89db701ec1d8e21 |
| institution | Directory Open Access Journal |
| issn | 0147-6513 |
| language | English |
| last_indexed | 2024-03-09T02:15:43Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj.art-46465d227f264879a89db701ec1d8e212023-12-07T05:27:27ZengElsevierEcotoxicology and Environmental Safety0147-65132024-01-01269115756Perinatal triphenyl phosphate exposure induces metabolic dysfunctions through the EGFR/ERK/AKT signaling pathway: Mechanistic in vitro and in vivo studiesPhum Tachachartvanich0Xylina Rusit1Jason Tong2Chanapa Mann3Michele A. La Merrill4Department of Environmental Toxicology, University of California, Davis 95616, CA, USA; Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210, ThailandDepartment of Environmental Toxicology, University of California, Davis 95616, CA, USADepartment of Environmental Toxicology, University of California, Davis 95616, CA, USADepartment of Environmental Toxicology, University of California, Davis 95616, CA, USADepartment of Environmental Toxicology, University of California, Davis 95616, CA, USA; Corresponding author.Triphenyl phosphate (TPhP), a widely used organophosphate-flame retardant, is ubiquitously found in household environments and may adversely affect human health. Evidence indicates that TPhP exposure causes metabolic dysfunctions in vivo; however, the underlying mechanism of such adverse effects has not been comprehensively investigated. Herein, we utilized two in vitro models including mouse and human preadipocytes to delineate adipogenic mechanisms of TPhP. The results revealed that both mouse and human preadipocytes exposed to TPhP concentration-dependently accumulated more fat through a significant upregulation of epidermal growth factor receptor (EGFR). We demonstrated that TPhP significantly promoted adipogenesis through the activation of EGFR/ERK/AKT signaling pathway as evident by a drastic reduction in adipogenesis of preadipocytes cotreated with inhibitors of EGFR and its major effectors. Furthermore, we confirmed the mechanism of TPhP-induced metabolic dysfunctions in vivo. We observed that male mice perinatally exposed to TPhP had a significant increase in adiposity, hepatic triglycerides, insulin resistance, plasma insulin levels, hypotension, and phosphorylated EGFR in gonadal fat. Interestingly, an administration of a potent and selective EGFR inhibitor significantly ameliorated the adverse metabolic effects caused by TPhP. Our findings uncovered a potential mechanism of TPhP-induced metabolic dysfunctions and provided implications on toxic metabolic effects posed by environmental chemicals.http://www.sciencedirect.com/science/article/pii/S0147651323012605Triphenyl phosphateInsulin resistanceMetabolic healthEpidermal growth factor receptorAdipogenesis |
| spellingShingle | Phum Tachachartvanich Xylina Rusit Jason Tong Chanapa Mann Michele A. La Merrill Perinatal triphenyl phosphate exposure induces metabolic dysfunctions through the EGFR/ERK/AKT signaling pathway: Mechanistic in vitro and in vivo studies Ecotoxicology and Environmental Safety Triphenyl phosphate Insulin resistance Metabolic health Epidermal growth factor receptor Adipogenesis |
| title | Perinatal triphenyl phosphate exposure induces metabolic dysfunctions through the EGFR/ERK/AKT signaling pathway: Mechanistic in vitro and in vivo studies |
| title_full | Perinatal triphenyl phosphate exposure induces metabolic dysfunctions through the EGFR/ERK/AKT signaling pathway: Mechanistic in vitro and in vivo studies |
| title_fullStr | Perinatal triphenyl phosphate exposure induces metabolic dysfunctions through the EGFR/ERK/AKT signaling pathway: Mechanistic in vitro and in vivo studies |
| title_full_unstemmed | Perinatal triphenyl phosphate exposure induces metabolic dysfunctions through the EGFR/ERK/AKT signaling pathway: Mechanistic in vitro and in vivo studies |
| title_short | Perinatal triphenyl phosphate exposure induces metabolic dysfunctions through the EGFR/ERK/AKT signaling pathway: Mechanistic in vitro and in vivo studies |
| title_sort | perinatal triphenyl phosphate exposure induces metabolic dysfunctions through the egfr erk akt signaling pathway mechanistic in vitro and in vivo studies |
| topic | Triphenyl phosphate Insulin resistance Metabolic health Epidermal growth factor receptor Adipogenesis |
| url | http://www.sciencedirect.com/science/article/pii/S0147651323012605 |
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