Identification of receptors for eight endocrine disrupting chemicals and their underlying mechanisms using zebrafish as a model organism

Abstract

Herein, eight common endocrine disrupting chemicals (EDCs) were exposed to zebrafish (Danio rerio) to investigate the relationship between different EDCs and their activated estrogen receptors. Under acute exposure, we identified five major malformation types whose incidence and deformity modes differed among EDCs. Luciferase analysis divided the EDC receptors into four categories: (i) triclosan (TCS), 17ß-estradiol (E2) and estriol (E3) mainly activated GPER expression; (ii) bisphenol A (BPA), p-(tert-octyl) phenol (POP), 17α-ethynylestradiol (EE2), E2 and E3 activated ERβ expression; (iii) E2 and E3 acted on both GPER and ERβ; and (iv) estrone (E1) and 9,9-bis(4-hydroxyphenyl)fluorene (BHPF) had little effect on the two receptors. In vivo immunofluorescence experiments on 96-hpf larvae provided evidence that TCS and POP acted on GPER and ERβ, respectively, while E2 acted on the two receptors simultaneously. Luciferase activities in the promoter regions of gper (À 986 to À 488) and erβ (À 1998 to À 1496) were higher than those in other regions, identifying these key regions as targets for transcription activity. TCS promoted GPER expression by acting on the JUND transcription factor, while POP promoted ERβ expression by activating the Foxl1 transcription factor. In contrast, E2 mainly regulated transcription of GPER and ERβ by Arid3a. These findings provide compelling evidence that different EDCs possess varying estrogen receptors, leading to differential regulatory pathways and abnormality symptoms. These results offer an experimental strategy and fundamental information to assess the molecular mechanisms of EDC-induced estrogen effects.

Triclosan regulates the Nrf2/HO‐1 pathway through the PI3K/Akt/JNK signaling cascade to induce oxidative damage in neurons

“…In recent years, research on TCS and its metabolite triclocarban (TCC) has mainly focused on the ecological environment and aquatic organisms 2,36,37 . Many studies have also confirmed a range of potential hazards of TCS, such as genetic toxicity, endocrine disruption, cardiac toxicity, neurotoxicity, and adverse pregnancy outcome 38–42 . In particular, the neurotoxicity induced by TCS has gradually become the focus of research due to its unclear mechanism of toxicity.…”

Triclosan targets miR-144 abnormal expression to induce neurodevelopmental toxicity mediated by activating PKC/MAPK signaling pathway

“…(Li et al, 2020;Zhu et al, 2020). Thus, we posit that TCS targets GPER for activation of the PKC/MAPK signaling pathway, in which PKC is phosphorylated to become dissociated from the PKC-Keap1 compound and thereby becomes activated (Huang et al, 2020). MAPK is mainly composed of four sub-families, which are extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 5 (ERK5) (Dou et al, 2021).…”

“…In recent years, TCS was documented to have an estrogenic effect through targeting a new type of G-protein coupled estrogen membrane receptor (GPER) (Wang et al, 2021). Previous research by our group documented that TCS exposure activated GPER to trigger an estrogen effect (Huang et al, 2020). GPER is a non-classical estrogen receptor binding to the plasma membrane through seven transmembrane domains, it is widely distributed in the brain functional area related to emotion control, serving an important role in regulation of the HPA axis and mood (Zheng et al, 2020).…”

“…Although miR-144 was predicted to be highly enriched in the brain (Zhou et al, 2019), the mechanism by which TCS induces estrogen effects has not been addressed from the perspective of miR-144 regulation. Based on our previous research, GPER was activated in zebrafish following TCS exposure (Huang et al, 2020;Wang et al, 2020) Bioinformatics analysis and a series of experiments verified that the abnormal expression of miR-144 could cause neurotoxicity to zebrafish larvae, and the underlying upstream pathways triggering miR-144 abnormal expression were further examined after GPER was activated by TCS. Collectively, the results of previous studies inferred that the PKC/MAPK signaling pathway was involved in the process of TCS-induced neurotoxicity.…”

Identification of Potential Bisphenol A (BPA) Exposure Biomarkers in Ovarian Cancer

“…GPR30 plays a key role in the physiology of the reproductive system [ 16 , 17 ] and metabolism [ 18 ]. In the case of BPA, it has been shown to bind to multiple ERs including ERα, ERβ (cytoplasmic and membrane-bound), GPR30 and human nuclear receptor estrogen-related receptor gamma (ERRγ) [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ].…”