The p-Phthalates Terephthalic Acid and Dimethyl Terephthalate Used in the Manufacture of PET Induce In Vitro Adipocytes Dysfunction by Altering Adipogenesis and Thermogenesis Mechanisms
Abstract
:1. Introduction
2. Results
2.1. p-Phthalates In Vitro Toxicity and In Silico ADME
2.2. Effects of p-Phthalates on Adipogenesis Markers
2.3. p-Phthalates-Induced PPAR-γ Expression Is Dependent on Estrogen Receptor (ER)
2.4. p-Phthalates Reduce the Thermogenic Pathway
2.5. p-Phthalates Induce the NF-κB Proinflammatory Pathway
3. Discussion
4. Materials and Methods
4.1. In Silico ADME Screening of Tested Compounds
4.2. Reagents
4.3. Cell Culture and Treatments
4.4. Sulforhodamine B Assay
4.5. Cell Lysates Preparation
4.6. Immunoblotting
4.7. Real-Time PCR
4.8. Oil Red O Staining
4.9. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Welle, F. Food Law Compliance of Poly(ethylene Terephthalate) (PET) Food Packaging Materials. In Food Additives and Packaging; American Chemical Society: Washington, DC, USA, 2014; Volume 1162, pp. 167–195. [Google Scholar]
- Kim, D.-J.; Lee, K.-T. Determination of monomers and oligomers in polyethylene terephthalate trays and bottles for food use by using high performance liquid chromatography-electrospray ionization-mass spectrometry. Polym. Test. 2012, 31, 490–499. [Google Scholar] [CrossRef]
- Khaneghah, A.M.; Limbo, S.; Shoeibi, S.; Mazinani, S. HPLC study of migration of terephthalic acid and isophthalic acid from PET bottles into edible oils. J. Sci. Food Agric. 2014, 94, 2205–2209. [Google Scholar] [CrossRef] [PubMed]
- European Commission. Commission Regulation (EU) No 10/2011 of 14 January 2011 on plastic materials and articles intended to come into contact with food. Off. J. Eur. Union 2011, 12, L12/1–L12/89. [Google Scholar]
- Wang, Y.; Qian, H. Phthalates and Their Impacts on Human Health. Healthcare 2021, 9, 603. [Google Scholar] [CrossRef] [PubMed]
- Giuliani, A.; Zuccarini, M.; Cichelli, A.; Khan, H.; Reale, M. Critical Review on the Presence of Phthalates in Food and Evidence of Their Biological Impact. Int. J. Environ. Res. Public Health 2020, 17, 5655. [Google Scholar] [CrossRef] [PubMed]
- Net, S.; Sempéré, R.; Delmont, A.; Paluselli, A.; Ouddane, B. Occurrence, fate, behavior and ecotoxicological state of phthalates in different environmental matrices. Environ. Sci. Technol. 2015, 49, 4019–4035. [Google Scholar] [CrossRef]
- Casajuana, N.; Lacorte, S. Presence and release of phthalic esters and other endocrine disrupting compounds in drinking water. Chromatographia 2003, 57, 649–655. [Google Scholar] [CrossRef]
- Mihucz, V.G.; Záray, G. Occurrence of antimony and phthalate esters in polyethylene terephthalate bottled drinking water. Appl. Spectrosc. Rev. 2016, 51, 183–209. [Google Scholar] [CrossRef]
- Street, M.E.; Angelini, S.; Bernasconi, S.; Burgio, E.; Cassio, A.; Catellani, C.; Cirillo, F.; Deodati, A.; Fabbrizi, E.; Fanos, V.; et al. Current Knowledge on Endocrine Disrupting Chemicals (EDCs) from Animal Biology to Humans, from Pregnancy to Adulthood: Highlights from a National Italian Meeting. Int. J. Mol. Sci. 2018, 19, 1647. [Google Scholar] [CrossRef] [Green Version]
- Zhang, Y.; Meng, X.; Chen, L.; Li, D.; Zhao, L.; Zhao, Y.; Li, L.; Shi, H. Age and sex-specific relationships between phthalate exposures and obesity in Chinese children at puberty. PLoS ONE 2014, 9, e104852. [Google Scholar] [CrossRef]
- Buser, M.C.; Murray, H.E.; Scinicariello, F. Age and sex differences in childhood and adulthood obesity association with phthalates: Analyses of NHANES 2007-2010. Int. J. Hyg. Environ. Health 2014, 217, 687–694. [Google Scholar] [CrossRef]
- Wang, H.; Zhou, Y.; Tang, C.; He, Y.; Wu, J.; Chen, Y.; Jiang, Q. Urinary phthalate metabolites are associated with body mass index and waist circumference in Chinese school children. PLoS ONE 2013, 8, e56800. [Google Scholar] [CrossRef] [Green Version]
- Corton, J.C.; Lapinskas, P.J. Peroxisome proliferator-activated receptors: Mediators of phthalate ester-induced effects in the male reproductive tract? Toxicol. Sci. 2005, 83, 4–17. [Google Scholar] [CrossRef] [Green Version]
- Hurst, C.H.; Waxman, D.J. Activation of PPARalpha and PPARgamma by environmental phthalate monoesters. Toxicol. Sci. 2003, 74, 297–308. [Google Scholar] [CrossRef] [Green Version]
- Ge, R.S.; Chen, G.R.; Dong, Q.; Akingbemi, B.; Sottas, C.M.; Santos, M.; Sealfon, S.C.; Bernard, D.J.; Hardy, M.P. Biphasic effects of postnatal exposure to diethylhexylphthalate on the timing of puberty in male rats. J. Androl. 2007, 28, 513–520. [Google Scholar] [CrossRef] [Green Version]
- Evans, R.M.; Barish, G.D.; Wang, Y.X. PPARs and the complex journey to obesity. Nat. Med. 2004, 10, 355–361. [Google Scholar] [CrossRef]
- Grün, F.; Blumberg, B. Minireview: The case for obesogens. Mol. Endocrinol. 2009, 23, 1127–1134. [Google Scholar] [CrossRef] [Green Version]
- Maradonna, F.; Carnevali, O. Lipid Metabolism Alteration by Endocrine Disruptors in Animal Models: An Overview. Front. Endocrinol. 2018, 9, 654. [Google Scholar] [CrossRef] [Green Version]
- Lee, M.K.; Blumberg, B. Transgenerational effects of obesogens. Basic Clin. Pharmacol. Toxicol. 2019, 125 (Suppl. 3), 44–57. [Google Scholar] [CrossRef]
- Kambia, N.; Séverin, I.; Farce, A.; Dahbi, L.; Dine, T.; Moreau, E.; Sautou, V.; Chagnon, M.C. Comparative Effects of Di-(2-ethylhexyl)phthalate and Di-(2-ethylhexyl)terephthalate Metabolites on Thyroid Receptors: In Vitro and In Silico Studies. Metabolites 2021, 11, 94. [Google Scholar] [CrossRef]
- Kambia, N.K.; Séverin, I.; Farce, A.; Moreau, E.; Dahbi, L.; Duval, C.; Dine, T.; Sautou, V.; Chagnon, M.C. In vitro and in silico hormonal activity studies of di-(2-ethylhexyl)terephthalate, a di-(2-ethylhexyl)phthalate substitute used in medical devices, and its metabolites. J. Appl. Toxicol. 2019, 39, 1043–1056. [Google Scholar] [CrossRef] [PubMed]
- Birnbaum, L.S.; Schug, T.T. Phthalates in our food. Endocr. Disruptors 2013, 1, e25078. [Google Scholar] [CrossRef]
- Dhaka, V.; Singh, S.; Anil, A.G.; Sunil Kumar Naik, T.S.; Garg, S.; Samuel, J.; Kumar, M.; Ramamurthy, P.C.; Singh, J. Occurrence, toxicity and remediation of polyethylene terephthalate plastics. A review. Environ. Chem. Lett. 2022, 20, 1777–1800. [Google Scholar] [CrossRef] [PubMed]
- Yang, J.; Wang, H.; Du, H.; Xu, L.; Liu, S.; Yi, J.; Chen, Y.; Jiang, Q.; He, G. Serum Bisphenol A, glucose homeostasis, and gestational diabetes mellitus in Chinese pregnant women: A prospective study. Environ. Sci. Pollut. Res. Int. 2021, 28, 12546–12554. [Google Scholar] [CrossRef] [PubMed]
- Specht, I.O.; Toft, G.; Hougaard, K.S.; Lindh, C.H.; Lenters, V.; Jönsson, B.A.; Heederik, D.; Giwercman, A.; Bonde, J.P. Associations between serum phthalates and biomarkers of reproductive function in 589 adult men. Environ. Int. 2014, 66, 146–156. [Google Scholar] [CrossRef]
- Bølling, A.K.; Sripada, K.; Becher, R.; Bekö, G. Phthalate exposure and allergic diseases: Review of epidemiological and experimental evidence. Environ. Int. 2020, 139, 105706. [Google Scholar] [CrossRef]
- Yang, C.; Harris, S.A.; Jantunen, L.M.; Kvasnicka, J.; Nguyen, L.V.; Diamond, M.L. Phthalates: Relationships between Air, Dust, Electronic Devices, and Hands with Implications for Exposure. Environ. Sci. Technol. 2020, 54, 8186–8197. [Google Scholar] [CrossRef]
- Ambele, M.A.; Dhanraj, P.; Giles, R.; Pepper, M.S. Adipogenesis: A Complex Interplay of Multiple Molecular Determinants and Pathways. Int. J. Mol. Sci. 2020, 21, 4283. [Google Scholar] [CrossRef]
- Moreno-Indias, I.; Tinahones, F.J. Impaired adipose tissue expandability and lipogenic capacities as ones of the main causes of metabolic disorders. J. Diabetes Res. 2015, 2015, 970375. [Google Scholar] [CrossRef] [Green Version]
- Feige, J.N.; Gelman, L.; Rossi, D.; Zoete, V.; Métivier, R.; Tudor, C.; Anghel, S.I.; Grosdidier, A.; Lathion, C.; Engelborghs, Y.; et al. The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis. J. Biol. Chem. 2007, 282, 19152–19166. [Google Scholar] [CrossRef] [Green Version]
- Sargis, R.M.; Johnson, D.N.; Choudhury, R.A.; Brady, M.J. Environmental endocrine disruptors promote adipogenesis in the 3T3-L1 cell line through glucocorticoid receptor activation. Obesity 2010, 18, 1283–1288. [Google Scholar] [CrossRef]
- Grün, F.; Blumberg, B. Environmental obesogens: Organotins and endocrine disruption via nuclear receptor signaling. Endocrinology 2006, 147, S50–S55. [Google Scholar] [CrossRef] [Green Version]
- Guo, L.; Li, X.; Tang, Q.Q. Transcriptional regulation of adipocyte differentiation: A central role for CCAAT/enhancer-binding protein (C/EBP) β. J. Biol. Chem. 2015, 290, 755–761. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ertunc, M.E.; Hotamisligil, G.S. Lipid signaling and lipotoxicity in metaflammation: Indications for metabolic disease pathogenesis and treatment. J. Lipid Res. 2016, 57, 2099–2114. [Google Scholar] [CrossRef] [Green Version]
- Prentice, K.J.; Saksi, J.; Hotamisligil, G.S. Adipokine FABP4 integrates energy stores and counterregulatory metabolic responses. J. Lipid Res. 2019, 60, 734–740. [Google Scholar] [CrossRef] [Green Version]
- Wu, L.; Zhang, L.; Li, B.; Jiang, H.; Duan, Y.; Xie, Z.; Shuai, L.; Li, J.; Li, J. AMP-Activated Protein Kinase (AMPK) Regulates Energy Metabolism through Modulating Thermogenesis in Adipose Tissue. Front. Physiol. 2018, 9, 122. [Google Scholar] [CrossRef] [Green Version]
- Chondronikola, M.; Volpi, E.; Børsheim, E.; Porter, C.; Annamalai, P.; Enerbäck, S.; Lidell, M.E.; Saraf, M.K.; Labbe, S.M.; Hurren, N.M.; et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes 2014, 63, 4089–4099. [Google Scholar] [CrossRef] [Green Version]
- Jäger, S.; Handschin, C.; St-Pierre, J.; Spiegelman, B.M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc. Natl. Acad. Sci. USA 2007, 104, 12017–12022. [Google Scholar] [CrossRef] [Green Version]
- Jun, H.J.; Joshi, Y.; Patil, Y.; Noland, R.C.; Chang, J.S. NT-PGC-1α activation attenuates high-fat diet-induced obesity by enhancing brown fat thermogenesis and adipose tissue oxidative metabolism. Diabetes 2014, 63, 3615–3625. [Google Scholar] [CrossRef] [Green Version]
- Wellen, K.E.; Hotamisligil, G.S. Obesity-induced inflammatory changes in adipose tissue. J. Clin. Investig. 2003, 112, 1785–1788. [Google Scholar] [CrossRef]
- Hayden, M.S.; Ghosh, S. Regulation of NF-kappaB by TNF family cytokines. Semin. Immunol. 2014, 26, 253–266. [Google Scholar] [CrossRef] [PubMed]
- Kern, L.; Mittenbühler, M.J.; Vesting, A.J.; Ostermann, A.L.; Wunderlich, C.M.; Wunderlich, F.T. Obesity-Induced TNFα and IL-6 Signaling: The Missing Link between Obesity and Inflammation-Driven Liver and Colorectal Cancers. Cancers 2018, 11, 24. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Keresztes, S.; Tatár, E.; Czégény, Z.; Záray, G.; Mihucz, V.G. Study on the leaching of phthalates from polyethylene terephthalate bottles into mineral water. Sci. Total Environ. 2013, 458–460, 451–458. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pomatto, V.; Cottone, E.; Cocci, P.; Mozzicafreddo, M.; Mosconi, G.; Nelson, E.R.; Palermo, F.A.; Bovolin, P. Plasticizers used in food-contact materials affect adipogenesis in 3T3-L1 cells. J. Steroid Biochem. Mol. Biol. 2018, 178, 322–332. [Google Scholar] [CrossRef] [PubMed]
- Osimitz, T.G.; Eldridge, M.L.; Sloter, E.; Welsh, W.; Ai, N.; Sayler, G.S.; Menn, F.; Toole, C. Lack of androgenicity and estrogenicity of the three monomers used in Eastman’s Tritan™ copolyesters. Food Chem. Toxicol. 2012, 50, 2196–2205. [Google Scholar] [CrossRef]
- Ball, G.L.; McLellan, C.J.; Bhat, V.S. Toxicological review and oral risk assessment of terephthalic acid (TPA) and its esters: A category approach. Crit. Rev. Toxicol. 2012, 42, 28–67. [Google Scholar] [CrossRef]
- Luciani-Torres, M.G.; Moore, D.H.; Goodson, W.H., 3rd; Dairkee, S.H. Exposure to the polyester PET precursor--terephthalic acid induces and perpetuates DNA damage-harboring non-malignant human breast cells. Carcinogenesis 2015, 36, 168–176. [Google Scholar] [CrossRef] [Green Version]
- Jang, J.W.; Lee, J.W.; Yoon, Y.D.; Kang, J.S.; Moon, E.Y. Bisphenol A and its substitutes regulate human B cell survival via Nrf2 expression. Environ. Pollut. 2020, 259, 113907. [Google Scholar] [CrossRef]
- Schaffert, A.; Karkossa, I.; Ueberham, E.; Schlichting, R.; Walter, K.; Arnold, J.; Blüher, M.; Heiker, J.T.; Lehmann, J.; Wabitsch, M.; et al. Di-(2-ethylhexyl) phthalate substitutes accelerate human adipogenesis through PPARγ activation and cause oxidative stress and impaired metabolic homeostasis in mature adipocytes. Environ. Int. 2022, 164, 107279. [Google Scholar] [CrossRef]
- Schaffert, A.; Krieg, L.; Weiner, J.; Schlichting, R.; Ueberham, E.; Karkossa, I.; Bauer, M.; Landgraf, K.; Junge, K.M.; Wabitsch, M.; et al. Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ. Int. 2021, 156, 106730. [Google Scholar] [CrossRef]
- Loftus, T.M.; Jaworsky, D.E.; Frehywot, G.L.; Townsend, C.A.; Ronnett, G.V.; Lane, M.D.; Kuhajda, F.P. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 2000, 288, 2379–2381. [Google Scholar] [CrossRef]
- Zhou, L.; Chen, H.; Xu, Q.; Han, X.; Zhao, Y.; Song, X.; Zhao, T.; Ye, L. The effect of di-2-ethylhexyl phthalate on inflammation and lipid metabolic disorder in rats. Ecotoxicol. Environ. Saf. 2019, 170, 391–398. [Google Scholar] [CrossRef]
- Soto, A.M.; Sonnenschein, C.; Chung, K.L.; Fernandez, M.F.; Olea, N.; Serrano, F.O. The E-SCREEN assay as a tool to identify estrogens: An update on estrogenic environmental pollutants. Environ. Health Perspect. 1995, 103 (Suppl. 7), 113–122. [Google Scholar] [CrossRef] [Green Version]
- Harris, C.A.; Henttu, P.; Parker, M.G.; Sumpter, J.P. The estrogenic activity of phthalate esters in vitro. Environ. Health Perspect. 1997, 105, 802–811. [Google Scholar] [CrossRef]
- Takeuchi, S.; Iida, M.; Kobayashi, S.; Jin, K.; Matsuda, T.; Kojima, H. Differential effects of phthalate esters on transcriptional activities via human estrogen receptors alpha and beta, and androgen receptor. Toxicology 2005, 210, 223–233. [Google Scholar] [CrossRef]
- Boucher, J.G.; Boudreau, A.; Atlas, E. Bisphenol A induces differentiation of human preadipocytes in the absence of glucocorticoid and is inhibited by an estrogen-receptor antagonist. Nutr. Diabetes 2014, 4, e102. [Google Scholar] [CrossRef] [Green Version]
- Sonavane, M. Chapter 1 Classical and Non-classical Estrogen Receptor Effects of Bisphenol A. In Bisphenol A: A Multi-Modal Endocrine Disruptor; The Royal Society of Chemistry: London, UK, 2022; pp. 1–25. [Google Scholar] [CrossRef]
- Zhang, W.; Li, J.Y.; Wei, X.C.; Wang, Q.; Yang, J.Y.; Hou, H.; Du, Z.W.; Wu, X.A. Effects of dibutyl phthalate on lipid metabolism in liver and hepatocytes based on PPARα/SREBP-1c/FAS/GPAT/AMPK signal pathway. Food Chem. Toxicol. 2021, 149, 112029. [Google Scholar] [CrossRef]
- Schaedlich, K.; Gebauer, S.; Hunger, L.; Beier, L.S.; Koch, H.M.; Wabitsch, M.; Fischer, B.; Ernst, J. DEHP deregulates adipokine levels and impairs fatty acid storage in human SGBS-adipocytes. Sci. Rep. 2018, 8, 3447. [Google Scholar] [CrossRef] [Green Version]
- Lee, J.-H.; Cho, B.-Y.; Choi, S.-H.; Jung, T.-D.; Choi, S.-I.; Lim, J.-H.; Lee, O.-H. Sulforaphane attenuates bisphenol A-induced 3T3-L1 adipocyte differentiation through cell cycle arrest. J. Funct. Foods 2018, 44, 17–23. [Google Scholar] [CrossRef]
- Omran, F.; Christian, M. Inflammatory Signaling and Brown Fat Activity. Front. Endocrinol. 2020, 11, 156. [Google Scholar] [CrossRef]
- Manteiga, S.; Lee, K. Monoethylhexyl Phthalate Elicits an Inflammatory Response in Adipocytes Characterized by Alterations in Lipid and Cytokine Pathways. Environ. Health Perspect. 2017, 125, 615–622. [Google Scholar] [CrossRef] [PubMed]
- Campioli, E.; Martinez-Arguelles, D.B.; Papadopoulos, V. In utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate promotes local adipose and systemic inflammation in adult male offspring. Nutr. Diabetes 2014, 4, e115. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pires, D.E.; Blundell, T.L.; Ascher, D.B. pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. J. Med. Chem. 2015, 58, 4066–4072. [Google Scholar] [CrossRef] [PubMed]
- Giofrè, S.V.; Napoli, E.; Iraci, N.; Speciale, A.; Cimino, F.; Muscarà, C.; Molonia, M.S.; Ruberto, G.; Saija, A. Interaction of selected terpenoids with two SARS-CoV-2 key therapeutic targets: An in silico study through molecular docking and dynamics simulations. Comput. Biol. Med. 2021, 134, 104538. [Google Scholar] [CrossRef] [PubMed]
- Kujawski, J.; Popielarska, H.; Myka, A.; Drabińska, B.; Bernard, M.K. The log P Parameter as a Molecular Descriptor in the Computer—Aided Drug Design—An Overview. Comput. Methods Sci. Technol. 2012, 18, 81–88. [Google Scholar] [CrossRef]
- Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 2001, 46, 3–26. [Google Scholar] [CrossRef]
- Anwar, S.; Fratantonio, D.; Ferrari, D.; Saija, A.; Cimino, F.; Speciale, A. Berry anthocyanins reduce proliferation of human colorectal carcinoma cells by inducing caspase-3 activation and p21 upregulation. Mol. Med. Rep. 2016, 14, 1397–1403. [Google Scholar] [CrossRef] [Green Version]
- Molonia, M.S.; Quesada-Lopez, T.; Speciale, A.; Muscarà, C.; Saija, A.; Villarroya, F.; Cimino, F. In Vitro Effects of Cyanidin-3-O-Glucoside on Inflammatory and Insulin-Sensitizing Genes in Human Adipocytes Exposed to Palmitic Acid. Chem. Biodivers. 2021, 18, e2100607. [Google Scholar] [CrossRef]
- Bradford, M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 1976, 72, 248–254. [Google Scholar] [CrossRef]
- Muscarà, C.; Molonia, M.S.; Speciale, A.; Bashllari, R.; Cimino, F.; Occhiuto, C.; Saija, A.; Cristani, M. Anthocyanins ameliorate palmitate-induced inflammation and insulin resistance in 3T3-L1 adipocytes. Phytother. Res. 2019, 33, 1888–1897. [Google Scholar] [CrossRef]
- Molonia, M.S.; Occhiuto, C.; Muscarà, C.; Speciale, A.; Bashllari, R.; Villarroya, F.; Saija, A.; Cimino, F.; Cristani, M. Cyanidin-3-O-glucoside restores insulin signaling and reduces inflammation in hypertrophic adipocytes. Arch. Biochem. Biophys. 2020, 691, 108488. [Google Scholar] [CrossRef]
- Zhang, Y.; Yu, H.; Gao, P.; Chen, J.; Yu, C.; Zong, C.; Lu, S.; Li, X.; Ma, X.; Liu, Y.; et al. The Effect of Growth Hormone on Lipid Accumulation or Maturation in Adipocytes. Cell. Physiol. Biochem. 2016, 39, 2135–2148. [Google Scholar] [CrossRef]
- Asano, H.; Kanamori, Y.; Higurashi, S.; Nara, T.; Kato, K.; Matsui, T.; Funaba, M. Induction of beige-like adipocytes in 3T3-L1 cells. J. Vet. Med. Sci. 2014, 76, 57–64. [Google Scholar] [CrossRef] [Green Version]
- Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001, 25, 402–408. [Google Scholar] [CrossRef]
- Molonia, M.S.; Occhiuto, C.; Muscarà, C.; Speciale, A.; Ruberto, G.; Siracusa, L.; Cristani, M.; Saija, A.; Cimino, F. Effects of a pinitol-rich Glycyrrhiza glabra L. leaf extract on insulin and inflammatory signaling pathways in palmitate-induced hypertrophic adipocytes. Nat. Prod. Res. 2021, 36, 4768–4775. [Google Scholar] [CrossRef]
- Mehlem, A.; Hagberg, C.E.; Muhl, L.; Eriksson, U.; Falkevall, A. Imaging of neutral lipids by oil red O for analyzing the metabolic status in health and disease. Nat. Protoc. 2013, 8, 1149–1154. [Google Scholar] [CrossRef]
TPA | DMT | ||
---|---|---|---|
Parameter | |||
Molecular Weight | 166.132 | 194.186 | |
miLopP | 1.76 | 2.28 | |
TPSA | 74.60 | 52.61 | |
#Rotatable Bonds | 2 | 2 | |
#Acceptors | 2 | 4 | |
#Donors | 2 | 0 | |
Surface Area | 68.073 | 81.441 | |
Water solubility | Numeric (log mol/L) | −2.602 | −1.827 |
Caco-2 permeability | Numeric (log Papp in 10−6 cm/s) | 0.716 | 1.256 |
Intestinal absorption (human) | Numeric (% absorbed) | 76.537 | 89.396 |
Skin Permeability | Numeric (log Kp) | −2.735 | −2.512 |
P-glycoprotein substrate | Categorical (Yes/No) | No | No |
P-glycoprotein I inhibitor | Categorical (Yes/No) | No | No |
P-glycoprotein II inhibitor | Categorical (Yes/No) | No | No |
VDss (human) | Numeric (log L/kg) | −2.006 | −0.432 |
Fraction unbound (human) | Numeric (Fu) | 0.556 | 0.368 |
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Molonia, M.S.; Muscarà, C.; Speciale, A.; Salamone, F.L.; Toscano, G.; Saija, A.; Cimino, F. The p-Phthalates Terephthalic Acid and Dimethyl Terephthalate Used in the Manufacture of PET Induce In Vitro Adipocytes Dysfunction by Altering Adipogenesis and Thermogenesis Mechanisms. Molecules 2022, 27, 7645. https://doi.org/10.3390/molecules27217645
Molonia MS, Muscarà C, Speciale A, Salamone FL, Toscano G, Saija A, Cimino F. The p-Phthalates Terephthalic Acid and Dimethyl Terephthalate Used in the Manufacture of PET Induce In Vitro Adipocytes Dysfunction by Altering Adipogenesis and Thermogenesis Mechanisms. Molecules. 2022; 27(21):7645. https://doi.org/10.3390/molecules27217645
Chicago/Turabian StyleMolonia, Maria Sofia, Claudia Muscarà, Antonio Speciale, Federica Lina Salamone, Giovanni Toscano, Antonella Saija, and Francesco Cimino. 2022. "The p-Phthalates Terephthalic Acid and Dimethyl Terephthalate Used in the Manufacture of PET Induce In Vitro Adipocytes Dysfunction by Altering Adipogenesis and Thermogenesis Mechanisms" Molecules 27, no. 21: 7645. https://doi.org/10.3390/molecules27217645