https://www.frontiersin.org/articles/10 ... 15096/full
"Our data suggest that legacy and new generation PFAS can differentially influence TSH dependent signaling pathways through the direct interaction with TSH-R."
Du Y, Chen C, Zhou G, Cai Z, Man Q, Liu B, Wang WC - "Perfluorooctanoic acid disrupts thyroid-specific genes expression and regulation via the TSH-TSHR signaling pathway in thyroid cells" Environ Res 239(Pt 1):117372 (2023). doi: 10.1016/j.envres.2023.117372
https://pubmed.ncbi.nlm.nih.gov/37827365/
"Based on these findings, it can be inferred that PFOA disrupts the TSH-activated cAMP signaling pathway by inhibiting TSHR expression and its N-glycosylation. We propose that this mechanism may contribute to the decrease in thyroid hormone levels caused by PFOA."
Elumalai S, Karunakaran U, Won KC, Chung SM, Moon JS - "Perfluorooctane sulfonate-induced oxidative stress contributes to pancreatic β-cell apoptosis by inhibiting cyclic adenosine monophosphate pathway: Prevention by pentoxifylline" Environ Pollut 320:120959 (2023) doi: 10.1016/j.envpol.2022.120959
https://www.sciencedirect.com/science/a ... 9122021741
Guan R, Luan F, Li N, Qiu Z, Liu W, Cui Z, Zhao C, Li X - "Identification of molecular initiating events and key events leading to endocrine disrupting effects of PFOA: Integrated molecular dynamic, transcriptomic, and proteomic analyses" Chemosphere 307(Pt 2):135881 (2022) doi: 10.1016/j.chemosphere.2022.135881
https://www.sciencedirect.com/science/a ... 3522023748
"MD modeling and fluorescence analysis proved that, on binding to the G protein-coupled estrogen receptor-1 (GPER), PFOA could induce a conformational change in the receptor, turning it into an active state. The results also indicated that the binding to GPER was the MIE [molecular initiating event] that led to the adverse outcome (AO) of PFOA."
Guruge KS, Yeung LW, Yamanaka N, Miyazaki S, Lam PK, Giesy JP, Jones PD, Yamashita N - "Gene expression profiles in rat liver treated with perfluorooctanoic acid (PFOA)" Toxicol Sci 89(1):93-107 (2006) doi: 10.1093/toxsci/kfj011
https://academic.oup.com/toxsci/article/89/1/93/1663593
"G-protein coupled receptor protein signaling pathways were significantly suppressed...PFOA both up- and down-regulated
gene expression that are related to signal transduction and G-protein coupled receptors."
Kim J, Lee G, Lee YM, Zoh KD, Choi K - "Thyroid disrupting effects of perfluoroundecanoic acid and perfluorotridecanoic acid in zebrafish (Danio rerio) and rat pituitary (GH3) cell line" Chemosphere 262:128012 (2021) doi: 10.1016/j.chemosphere.2020.128012
https://www.sciencedirect.com/science/a ... 3520322074
"In GH3 cells, exposure to PFUnDA and PFTrDA upregulated Tshβ gene, suggesting that these PFCAs increase thyroid hormone synthesis through stimulation by Tsh."
Kim S, Stroski KM, Killeen G, Smitherman C, Simcik MF, Brooks BW - "8:8 Perfluoroalkyl phosphinic acid affects neurobehavioral development, thyroid disruption, and DNA methylation in developing zebrafish" Sci Total Environ 736:139600 (2020) doi: 10.1016/j.scitotenv.2020.139600
https://www.sciencedirect.com/science/a ... 972033120X
"At 144 h, several genes related to thyroid hormones that are essential for neurodevelopment, including corticotropin releasing hormone b (crhb), iodothyronine deiodinase 3a (dio3a), thyroid-stimulating hormone receptor (tshr) and nkx2 homeobox1 (nkx 2.1), were up-regulated by 8:8 PFPiA at 5.79 μM."
Li X, Chen L, Zhou H, Wang J, Zhao C, Pang X - "PFOA regulate adenosine receptors and downstream concentration-response cAMP-PKA pathway revealed by integrated omics and molecular dynamics analyses" Sci Total Environ 803:149910 (2022). doi: 10.1016/j.scitotenv.2021.149910
https://www.sciencedirect.com/science/a ... 9721049858
" In the cAMP signaling pathway, the adenosine A1 receptor (ADORA1) recognized the low concentration of PFOA and induced pathway 'Gi-cAMP-PKA' to decrease the concentration of cAMP. This indicated that the low concentration of PFOA may promote breast hyperplasia and inhibit lactation. While adenosine A2A receptor (ADORA2A) recognized the high concentration of PFOA and induced pathway 'GS-AC-cAMP-RKA' to increase the concentration of cAMP, induce cell damage and may lead to the deterioration of breast cancer... Furthermore, considering the strong binding ability of PFOA with ADORA1, PFOA tends to bind to ADORA1 at a low concentration. On the other side, PFOA at high concentration will continue to bind to another receptor protein, ADORA2A, and activate subsequent signaling pathways. Combined analyses of transcriptomic and proteomic revealed that different concentrations of PFOA regulate cellular calcium-related pathways. The cAMP pathway showed a concentration-response effect of PFOA."
Liu Q, Liu Y, Li X, Wang D, Zhang A, Pang J, He J, Chen X, Tang NJ - "Perfluoroalkyl substances promote breast cancer progression via ERα and GPER mediated PI3K/Akt and MAPK/Erk signaling pathways" Ecotoxicol Environ Saf 258:114980 (2023) . doi: 10.1016/j.ecoenv.2023.114980
https://www.sciencedirect.com/science/a ... 1323004840
"Two estrogen receptors (ER), ERα and G protein-coupled estrogen receptor (GPER), mediated the promoting effects of PFOA by activating MAPK/Erk and PI3K/Akt signaling pathways. These pathways were regulated by ERα and GPER in MCF-7 cells or independently by GPER in MDA-MB-231 cells. Overall, our study provides a better overview of the mechanisms associated with PFASs-induced breast cancer development and progression."
Qin WP, Cao LY, Li CH, Guo LH, Colbourne J, Ren XM - "Perfluoroalkyl Substances Stimulate Insulin Secretion by Islet β Cells via G Protein-Coupled Receptor 40" Environ Sci Technol 54(6):3428-3436 (2020) doi: 10.1021/acs.est.9b07295
https://pubs.acs.org/doi/10.1021/acs.est.9b07295
"...we demonstrated clearly that 1 h exposure of perfluorooctanesulfonate (PFOS) stimulated insulin secretion and intracellular calcium level by activating G protein-coupled receptor 40 (GPR40), a vital free fatty acid regulated membrane receptor on islet β cells. We further showed that the observed effects of PFASs on the mouse model may also exist in humans by investigating the molecular binding interaction of PFASs with human GPR40. We thus provided evidence for a novel mechanism for how insulin-secretion is disrupted by PFASs in humans."
Shan L, Chai Y, Gao T, Li K, Yu J, Liang F, Ni Y, Sun P - "Perfluorooctane sulfonate and perfluorooctanoic acid inhibit progesterone-responsive capacitation through cAMP/PKA signaling pathway and induce DNA damage in human sperm" Environ Toxicol Pharmacol 100:104165 (2023) doi: 10.1016/j.etap.2023.104165
https://www.sciencedirect.com/science/a ... 8923001072
Szilagyi JT, Freedman AN, Kepper SL, Keshava AM, Bangma JT, Fry RC - "Per- and Polyfluoroalkyl Substances Differentially Inhibit Placental Trophoblast Migration and Invasion In Vitro" Toxicol Sci 175(2):210-219 (2020) doi: 10.1093/toxsci/kfaa043
https://pubmed.ncbi.nlm.nih.gov/32219433/
Inhibition of chemokine receptors with pertussis toxin (10 ng/ml), a G-protein inhibitor, inhibited trophoblast migration similar to the PFAS.
Yong L, Huang M, Wei Y, Xu J, Yi Z - "Investigating the interaction between three perfluorinated carboxylic acids and the G protein-coupled estrogen receptor: spectroscopic analyses and computational simulations" Anal Methods 12(31):3944-3953 (2020) doi: 10.1039/d0ay01052a
https://pubs.rsc.org/en/content/article ... D0AY01052A
Zhang L, Duan X, Sun W, Sun H - "Perfluorooctane sulfonate acute exposure stimulates insulin secretion via GPR40 pathway" Sci Total Environ 726:138498 (2020). doi: 10.1016/j.scitotenv.2020.138498
https://pubmed.ncbi.nlm.nih.gov/32305757/
"By using specific inhibitors, we found that the GPR40 downstream pathways, phospholipase C (PLC) and L-type Ca2+ channels (LTCC) were involved in PFOS-stimulated [Ca2+]i elevation and insulin secretion."
see also:
Conley JM, Lambright CS, Evans N, Strynar MJ, McCord J, McIntyre BS, Travlos GS, Cardon MC, Medlock-Kakaley E, Hartig PC, Wilson VS, Gray LE Jr. - "Adverse Maternal, Fetal, and Postnatal Effects of Hexafluoropropylene Oxide Dimer Acid (GenX) from Oral Gestational Exposure in Sprague-Dawley Rats" Environ Health Perspect 127(3):37008 (2019) doi: 10.1289/EHP4372
https://ehp.niehs.nih.gov/doi/10.1289/EHP4372
Reo NV, Narayanan L, Kling KB, Adinehzadeh M - "Perfluorodecanoic acid, a peroxisome proliferator, activates phospholipase C, inhibits CTP:phosphocholine cytidylyltransferase, and elevates diacylglycerol in rat liver" Toxicol Lett 86(1):1-11 (1996) doi: 10.1016/0378-4274(96)03653-3.
"Perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) are peroxisome proliferators that cause hepatotoxicity in rodents...PFDA also caused a threefold increase in liver diacylglycerol (DAG) concentration." NOTE: DAG is activated through Gq/11
Roth K, Petriello MC - "Exposure to per- and polyfluoroalkyl substances (PFAS) and type 2 diabetes risk" Front Endocrinol (Lausanne) 13:965384. doi: 10.3389/fendo.2022.965384
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9388934/
Chen JJ, Gong YH, He L - "Role of GPR40 in pathogenesis and treatment of Alzheimer's disease and type 2 diabetic dementia" J Drug Target 27(4):347-354 (2019) doi: 10.1080/1061186X.2018.1491979
https://www.tandfonline.com/doi/abs/10. ... 18.1491979
"In the presence of glucose, GPR40 was primarily activated by the Gq/11-phospholipase C (PLC) pathway."
Birru RL, Liang HW, Farooq F, Bedi M, Feghali M, Haggerty CL, Mendez DD, Catov JM, Ng CA, Adibi JJ - "A pathway level analysis of PFAS exposure and risk of gestational diabetes mellitus" Environ Health 20(1):63 (2021) doi: 10.1186/s12940-021-00740-z
https://ehjournal.biomedcentral.com/art ... 21-00740-z
"Epidemiological studies demonstrate a clear association of biomarkers of thyroid hormones and glucose metabolism with GDM development. We report biologic plausibility and epidemiologic evidence that PFAS dysregulation of maternal thyroid hormones and thyrotropin (TSH) may disrupt glucose homeostasis, increasing the risk of GDM. Overall, epidemiological studies demonstrate that PFAS were positively associated with TSH and negatively with triiodothyronine (T3) and thyroxine (T4). PFAS were generally positively associated with glucose and insulin levels in pregnancy. We propose dysregulation of thyroid function and glucose metabolism may be a critical and missing component in the accurate estimation of PFAS on the risk of GDM."
Zang L, Liu X, Xie X, Zhou X, Pan Y, Dai J - "Exposure to per- and polyfluoroalkyl substances in early pregnancy, risk of gestational diabetes mellitus, potential pathways, and influencing factors in pregnant women: A nested case-control study" Environ Pollut 326:121504 (2023) doi: 10.1016/j.envpol.2023.121504
https://www.sciencedirect.com/science/a ... 9123005067
"The PFAS-associated disruption of maternal thyroid function may alter glucose homeostasis."
GPER & PPARα --> PPAR & PFAS viewtopic.php?p=6826#p6826
Jafarynezhad F, Shahbazian M, Farhadi Z, Yadeghari M, Rezvani ME, Safari F, Azizian H - "The G-Protein-Coupled Estrogen Receptor Agonist Prevents Cardiac Lipid Accumulation by Stimulating Cardiac Peroxisome Proliferator-Activated Receptor α: A Preclinical Study in Ovariectomized-Diabetic Rat Model" Int J Endocrinol Metab 20(3):e123560 (2022) doi: 10.5812/ijem-123560
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9661540/
- G1: mER; CEPR; GPER; DRY12; FEG-1; GPR30; LERGU; LyGPR; CMKRL2; LERGU2; GPCR-Br
Summary
This gene encodes a multi-pass membrane protein that localizes to the endoplasmic reticulum and a member of the G-protein coupled receptor 1 family. This receptor binds estrogen and activates multiple downstream signaling pathways, leading to stimulation of adenylate cyclase and an increase in cyclic AMP levels, while also promoting intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus. This protein therefore plays a role in the rapid nongenomic signaling events widely observed following stimulation of cells and tissues with estrogen. This receptor has been shown to play a role in diverse biological processes, including bone and nervous system development, metabolism, cognition, male fertility and uterine function. [provided by RefSeq, Aug 2017]
https://www.ncbi.nlm.nih.gov/gene/2852# ... 20Activity.