Abstract
The wide use of phthalates, as phthalates are used in the manufacturing of not only plastics but also many others goods, has become a main concern in the current century because of their potency to induce deleterious effects on organism health. The toxic effects of phthalates such as reproductive toxicity, cardiotoxicity, hepatotoxicity, nephrotoxicity, teratogenicity, and tumor development have been widely indicated by previous experimental studies. Some of the important mechanisms of toxicity by phthalates are the induction and promotion of inflammation, oxidative stress, and apoptosis. Awareness of the involved molecular pathways of these mechanisms will permit the detection of exact molecular targets of phthalates to protect or treat their toxicity. Up to now, various transcription factors and signaling pathways have been associated with phthalate-induced toxicity which by influencing on nuclear surface and the expression of different genes can alter cell hemostasis. In different studies, the role of nuclear factor erythroid 2–related factor 2 (Nrf2), nuclear factor-κB (NF-κB), and phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathways in processes of oxidative stress, inflammation, apoptosis, and cancer has been shown following exposure to phthalates. In the present review, we aim to survey experimental studies (in vitro and in vivo) in order to show firstly the most involved receptors and also the importance and the role of the mentioned signaling pathways in phthalate-induced toxicity, and with considering this point, the future studies can focus on these molecular targets as a strategic method to reduce environmental chemicals-induced toxicity especially phthalates toxic effects.
Similar content being viewed by others
References
Abbott BD (2009) Review of the expression of peroxisome proliferator-activated receptors alpha (PPARα), beta (PPARβ), and gamma (PPARγ) in rodent and human development. Reprod Toxicol 27:246–257
Alam MS, Ohsako S, Matsuwaki T, Zhu XB, Tsunekawa N, Kanai Y, Sone H, Tohyama C, Kurohmaru M (2010) Induction of spermatogenic cell apoptosis in prepubertal rat testes irrespective of testicular steroidogenesis: a possible estrogenic effect of di (n-butyl) phthalate. Reproduction 139(427):437
Amara I, Timoumi R, Graiet I, Ben Salem I, Adelou K, Abid-Essefi S (2019) Di (2-ethylhexyl) phthalate induces cytotoxicity in Hek-293 cell line, implication of the Nrf-2/Ho-1 antioxidant pathway. Environ Toxicol 34:1034–1042
Amara I, Salah A, Timoumi R, Annabi E, Scuto M, Trovato A, Neffati F, Calabrese V, Abid-Essefi S (2020a) Effect of di (2-ethylhexyl) phthalate on Nrf2-regulated glutathione homeostasis in mouse kidney. Cell Stress Chaperones 25:919–928
Amara I, Scuto M, Zappalà A, Ontario ML, Petralia A, Abid-Essefi S, Maiolino L, Signorile A, Trovato Salinaro A, Calabrese V (2020b) Hericium erinaceus prevents Dehp-induced mitochondrial dysfunction and apoptosis in Pc12 cells. Int J Mol Sci 21:2138
Ashari S, Karami M, Shokrzadeh M, Ghandadi M, Ghassemi-Barghi N, Dashti A, Ranaee M, Mohammadi H (2020) The implication of mitochondrial dysfunction and mitochondrial oxidative damage in di (2-ethylhexyl) phthalate induced nephrotoxicity in both in vivo and in vitro models. Toxicol Mech Methods 30:427–437
Barakat R, Lin P-C, Park CJ, Best-Popescu C, Bakry HH, Abosalem ME, Abdelaleem NM, Flaws JA, Ko C (2018) Prenatal exposure to Dehp induces neuronal degeneration and neurobehavioral abnormalities in adult male mice. Toxicol Sci 164:439–452
Berger K, Coker E, Rauch S, Eskenazi B, Balmes J, Kogut K, Holland N, Calafat AM, Harley K (2020) Prenatal phthalate, paraben, and phenol exposure and childhood allergic and respiratory outcomes: evaluating exposure to chemical mixtures. Sci Total Environ 138418
Bernard L, Décaudin B, Lecoeur M, Richard D, Bourdeaux D, Cueff R, Sautou V, Group, A. S (2014) Analytical methods for the determination of Dehp plasticizer alternatives present in medical devices: a review. Talanta 129:39–54
Bhatia H, Kumar A, Ogino Y, Gregg A, Chapman J, Mclaughlin MJ, Iguchi T (2014) Di-n-butyl phthalate causes estrogenic effects in adult male Murray rainbowfish (Melanotaenia fluviatilis). Aquat Toxicol 149:103–115
Bhatt D, Ghosh S (2014) Regulation of the Nf-κB-mediated transcription of inflammatory genes. Front Immunol 5:71
Birrell SN, Butler LM, Harris JM, Buchanan G, Tilley WD (2007) Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer. FASEB J 21:2285–2293
Bissegger S, Castro MAP, Yargeau V, Langlois VS (2018) Phthalates modulate steroid 5-reductase transcripts in the western clawed frog embryo. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology 213:39–46
Bølling AK, Ovrevik J, Samuelsen JT, Holme JA, Rakkestad KE, Mathisen GH, Paulsen RE, Korsnes MS, Becher R (2012) Mono-2-ethylhexylphthalate (Mehp) induces Tnf-α release and macrophage differentiation through different signalling pathways in Raw264. 7 cells. Toxicol Lett 209:43–50
Buerger AN, Schmidt J, Chase A, Paixao C, Patel TN, Brumback BA, Kane AS, Martyniuk CJ, Bisesi JH Jr (2019) Examining the responses of the zebrafish (Danio rerio) gastrointestinal system to the suspected obesogen diethylhexyl phthalate. Environ Pollut 245:1086–1094
Campioli E, Batarseh A, Li J, Papadopoulos V (2011) The endocrine disruptor mono-(2-ethylhexyl) phthalate affects the differentiation of human liposarcoma cells (Sw 872). PLoS One 6:e28750
Chebbi, M., Beltifa, A., Alibi, S., Di Bella, G., Loturco, V., Sire, O., Ben Mansour, H. & Le Tilly, V. (2020) Estrogenic hazards of short chain phthalates and bisphenols found in cosmetic products. International Journal of Environmental Health Research 1-12
Chen F-P, Chien M-H (2014) Lower concentrations of phthalates induce proliferation in human breast cancer cells. Climacteric 17:377–384
Chen H-S, Chiang P-H, Wang Y-C, Kao M-C, Shieh T-H, Tsai C-F, Tsai E-M (2012) Benzyl butyl phthalate induces necrosis by AhR mediation of Cyp1B1 expression in human granulosa cells. Reprod Toxicol 33:67–75
Chen S, Dong Y, Xu C, Jiang L, Chen Y, Jiang C, Hou W, Li W (2013a) Involvement of a chromatin modifier in response to mono-(2-ethylhexyl) phthalate (Mehp)-induced Sertoli cell injury: probably an indirect action via the regulation of NfκB/FasL circuitry. Biochem Biophys Res Commun 440:749–755
Chen X, Qin Q, Zhang W, Zhang Y, Zheng H, Liu C, Yang Y, Xiong W, Yuan J (2013b) Activation of the Pi3K–Akt–mtor signaling pathway promotes Dehp-induced Hep3B cell proliferation. Food Chem Toxicol 59:325–333
Chen J, Zhang Z, Cai L (2014) Diabetic cardiomyopathy and its prevention by nrf2: current status. Diabetes Metab J 38(337):345
Chen L, Chen J, Xie CM, Zhao Y, Wang X, Zhang YH (2015) Maternal disononyl phthalate exposure activates allergic airway inflammation via stimulating the phosphoinositide 3-kinase/Akt pathway in rat pups. Biomed Environ Sci 28:190–198
Chen F-P, Chien M-H, Chern IY-Y (2016) Impact of low concentrations of phthalates on the effects of 17β-estradiol in Mcf-7 breast cancer cells. Taiwanese Journal of Obstetrics and Gynecology 55:826–834
Chen F-P, Chien M-H, Chen H-Y, Ng Y-T (2018) Effects of phthalates on normal human breast cells co-cultured with different fibroblasts. PLoS One 13:e0199596
Chen J, Zhou X, Zhang H, Liu Y, Cao C, Dong R, Yuan Y, Wang M, Lu Y, Wu M (2019a) Association between urinary concentration of phthalate metabolites and impaired renal function in Shanghai adults. Environ Pollut 245:149–162
Chen Y, Li C, Song P, Yan B, Yang X, Wu Y, Ma P (2019b) Hepatic and renal tissue damage in Balb/c mice exposed to diisodecyl phthalate: the role of oxidative stress pathways. Food Chem Toxicol 132:110600
Chiang HC, Wang C-H, Yeh S-C, Lin Y-H, Kuo Y-T, Liao C-W, Tsai F-Y, Lin W-Y, Chuang W-H, Tsou T-C (2017) Comparative microarray analyses of mono (2-ethylhexyl) phthalate impacts on fat cell bioenergetics and adipokine network. Cell Biol Toxicol 33:511–526
Chiu CY, Sun SC, Chiang CK, Wang CC, Chan DC, Chen HJ, Liu SH, Yang RS (2018) Plasticizer di (2-ethylhexyl) phthalate interferes with osteoblastogenesis and adipogenesis in a mouse model. J Orthop Res 36:1124–1134
Cho YJ, Park SB, Han M (2015) Di-(2-ethylhexyl)-phthalate induces oxidative stress in human endometrial stromal cells in vitro. Mol Cell Endocrinol 407:9–17
Chou C, Huang HW, Yang CF, Dahms HU, Liang SS, Wang TN, Kuo PL, Hsi E, Tsai EM, Chiu CC (2019) Reduced camptothecin sensitivity of estrogen receptor-positive human breast cancer cells following exposure to di (2-ethylhexyl) phthalate (Dehp) is associated with Dna methylation changes. Environ Toxicol 34:401–414
Christen V, Crettaz P, Oberli-Schrämmli A, Fent K (2012) Antiandrogenic activity of phthalate mixtures: validity of concentration addition. Toxicol Appl Pharmacol 259:169–176
Christiansen S, Boberg J, Axelstad M, Dalgaard M, Vinggaard AM, Metzdorff SB, Hass U (2010) Low-dose perinatal exposure to di (2-ethylhexyl) phthalate induces anti-androgenic effects in male rats. Reprod Toxicol 30:313–321
Cocci P, Mosconi G, Arukwe A, Mozzicafreddo M, Angeletti M, Aretusi G, Palermo FA (2015) Effects of diisodecyl phthalate on Ppar: Rxr-dependent gene expression pathways in sea bream hepatocytes. Chem Res Toxicol 28:935–947
Crobeddu B, Ferraris E, Kolasa E, Plante I (2019) Di (2-ethylhexyl) phthalate (Dehp) increases proliferation of epithelial breast cancer cells through progesterone receptor dysregulation. Environ Res 173:165–173
Dai Y, Yang Y, Xu X, Hu Y (2015) Effects of uterine and lactational exposure to di-(2-ethylhexyl) phthalate on spatial memory and Nmda receptor of hippocampus in mice. Horm Behav 71:41–48
De Mello Santos T, Ltr DS, Jc R, Scarano W, Rf D (2017) Alterations in prostate morphogenesis in male rat offspring after maternal exposure to Di-n-butyl-phthalate (Dbp). Reprod Toxicol 69:254–264
Dekeyser JG, Stagliano MC, Auerbach SS, Prabhu KS, Jones AD, Omiecinski CJ (2009) Di (2-ethylhexyl) phthalate is a highly potent agonist for the human constitutive androstane receptor splice variant Car2. Mol Pharmacol 75:1005–1013
Dekeyser JG, Laurenzana EM, Peterson EC, Chen T, Omiecinski CJ (2011) Selective phthalate activation of naturally occurring human constitutive androstane receptor splice variants and the pregnane X receptor. Toxicol Sci 120:381–391
Deng J, Miller SA, Wang HY, Xia W, Wen Y, Zhou BP, Li Y, Lin SY, Hung MC (2002) β-catenin interacts with and inhibits Nf-κB in human colon and breast cancer. Cancer Cell 2:323–334
Deng T, Zhang Y, Wu Y, Ma P, Duan J, Qin W, Yang X, Chen M (2018) Dibutyl phthalate exposure aggravates type 2 diabetes by disrupting the insulin-mediated Pi3K/Akt signaling pathway. Toxicol Lett 290:1–9
Di Lorenzo M, Forte M, Valiante S, Laforgia V, De Falco M (2018) Interference of dibutylphthalate on human prostate cell viability. Ecotoxicol Environ Saf 147:565–573
Di Masi A, De Marinis E, Ascenzi P, Marino M (2009) Nuclear receptors Car and Pxr: molecular, functional, and biomedical aspects. Mol Asp Med 30:297–343
Ding Y, Liu Y, Fei F, Yang L, Mao G, Zhao T, Zhang Z, Yan M, Feng W, Wu X (2019) Study on the metabolism toxicity, susceptibility and mechanism of di-(2-ethylhexyl) phthalate on rat liver Brl cells with insulin resistance in vitro. Toxicology 422:102–120
Djavaheri-Mergny M, Maiuri M, Kroemer G (2010) Cross talk between apoptosis and autophagy by caspase-mediated cleavage of Beclin 1. Oncogene 29(1717):1719
Dombert C, Capela D, Poissenot K, Parmentier C, Bergsten E, Pionneau C, Chardonnet S, Hardin-Pouzet H, Grange-Messent V, Keller M (2017) Neural mechanisms underlying the disruption of male courtship behavior by adult exposure to di (2-ethylhexyl) phthalate in mice. Environ Health Perspect 125:097001
Du Z, Xia J, Xc S, Xn L, Zhang C, Hs Z, Zhu S, Jl L (2017) A novel nuclear xenobiotic receptors (AhR/Pxr/Car)-mediated mechanism of Dehp-induced cerebellar toxicity in quails (Coturnix japonica) via disrupting Cyp enzyme system homeostasis. Environ Pollut 226:435–443
Duan J, Kang J, Qin W, Deng T, Liu H, Li B, Yu W, Gong S, Yang X, Chen M (2018) Exposure to formaldehyde and diisononyl phthalate exacerbate neuroinflammation through Nf-κB activation in a mouse asthma model. Ecotoxicol Environ Saf 163:356–364
Efsa Panel on Food Contact Materials E Aids, Psilano V, Baviera B, Bolognesi JM, Chesson C, Cocconcelli A, Gott PCR, Dm Grob K, Lampi E (2019) Update of the risk assessment of di-butylphthalate (Dbp), butyl-benzyl-phthalate (Bbp), bis (2-ethylhexyl) phthalate (Dehp), di-isononylphthalate (Dinp) and di-isodecylphthalate (Didp) for use in food contact materials. EFSA J 17:e05838
El-Fattah AAA, Fahim AT, Nah S, Bm A (2016) Resveratrol and curcumin ameliorate di-(2-ethylhexyl) phthalate induced testicular injury in rats. Gen Comp Endocrinol 225:45–54
Engel A, Buhrke T, Imber F, Jessel S, Seidel A, VÖlkel W, Lampen A (2017) Agonistic and antagonistic effects of phthalates and their urinary metabolites on the steroid hormone receptors Erα, Erβ, and Ar. Toxicol Lett 277:54–63
Erkekoglu P, Giray BK, Kızilgün M, Rachidi W, Hininger-Favier I, Roussel A-M, Favier A, Hincal F (2012) Di (2-ethylhexyl) phthalate-induced renal oxidative stress in rats and protective effect of selenium. Toxicol Mech Methods 22:415–423
Ernst J, Jann J-C, Biemann R, Koch HM, Fischer B (2014) Effects of the environmental contaminants Dehp and Tcdd on estradiol synthesis and aryl hydrocarbon receptor and peroxisome proliferator-activated receptor signalling in the human granulosa cell line Kgn. Mol Hum Reprod 20:919–928
Eveillard A, Lasserre F, De Tayrac M, Polizzi A, Claus S, Canlet C, Mselli-Lakhal L, Gotardi G, Paris A, Guillou H (2009a) Identification of potential mechanisms of toxicity after di-(2-ethylhexyl)-phthalate (Dehp) adult exposure in the liver using a systems biology approach. Toxicol Appl Pharmacol 236:282–292
Eveillard A, Mselli-Lakhal L, Mogha A, Lasserre F, Polizzi A, Pascussi J-M, Guillou H, Martin PG, Pineau T (2009b) Di-(2-ethylhexyl)-phthalate (Dehp) activates the constitutive androstane receptor (Car): a novel signalling pathway sensitive to phthalates. Biochem Pharmacol 77:1735–1746
Fan P, Li Z, Zuo C, Fang M (2020) Promotion effects of mono-2-ethyhexyl phthalate (Mehp) on migration and invasion of human melanoma cells via activation of Tgf-β signals. Cell Biochem Funct 38:38–46
Fang H, Fang W, Cao H, Luo S, Cong J, Liu S, Pan F, Jia X (2019) Di-(2-ethylhexyl)-phthalate induces apoptosis via the Pparγ/Pten/Akt pathway in differentiated human embryonic stem cells. Food Chem Toxicol 131:110552
Feige J, Gerber A, Casals-Casas C, Yang Q, Winkler C, Bedu E, Bueno M, Gelman L, Auwerx J, Gonzalez FJ (2010) The pollutant diethylhexyl phthalate regulates hepatic energy metabolism via species-specific Pparα-dependent mechanisms. Environ Health Perspect 118:234–241
Feng W, Liu Y, Ding Y, Mao G, Zhao T, Chen K, Qiu X, Xu T, Zhao X, Wu X, Yang L (2020) Typical neurobehavioral methods and transcriptome analysis reveal the neurotoxicity and mechanisms of di(2-ethylhexyl) phthalate on pubertal male Icr mice with type 2 diabetes mellitus. Arch Toxicol 94:1279–1302
Franken C, Lambrechts N, Govarts E, Koppen G, Den Hond E, Ooms D, Voorspoels S, Bruckers L, Loots I, Nelen V (2017) Phthalate-induced oxidative stress and association with asthma-related airway inflammation in adolescents. Int J Hyg Environ Health 220:468–477
Fu G, Dai J, Zhang D, Zhu L, Tang X, Zhang L, Zhou T, Duan P, Quan C, Zhang Z (2017) Di (2-ethylhexyl) phthalate induces apoptosis through mitochondrial pathway in Gc-2spd cells. Environ Toxicol 32:1055–1064
Fu Y, Dong J, Wang J, You M, Wei L, Fu H, Wang Y, Chen J (2018) Developmental exposure to di-(2-ethylhexyl) phthalate induces cerebellar granule cell apoptosis via the Pi3K/Akt signaling pathway. Experimental neurobiology 27:472
Fu G, Dai J, Li Z, Chen F, Liu L, Yi L, Teng Z, Quan C, Zhang L, Zhou T (2020) The role of Stat3/p53 and Pi3K-Akt-mtor signaling pathway on Dehp-induced reproductive toxicity in pubertal male rat. Toxicol Appl Pharmacol 404:115151
Gao F, Hu W, Li Y, Shen H, Hu J (2017) Mono-2-ethylhexyl phthalate inhibits human extravillous trophoblast invasion via the Pparγ pathway. Toxicol Appl Pharmacol 327:23–29
Ghosh J, Das J, Manna P, Sil PC (2010) Hepatotoxicity of di-(2-ethylhexyl) phthalate is attributed to calcium aggravation, Ros-mediated mitochondrial depolarization, and Erk/Nf-κB pathway activation. Free Radic Biol Med 49:1779–1791
Golshan M, Hatef A, Socha M, Milla S, Butts IA, Carnevali O, Rodina M, SokoŁowska-MikoŁajczyk M, Fontaine P, Linhart O (2015) Di-(2-ethylhexyl)-phthalate disrupts pituitary and testicular hormonal functions to reduce sperm quality in mature goldfish. Aquat Toxicol 163:16–26
Grytting VS, Olderbø BP, Holme JA, Samuelsen JT, Solhaug A, Becher R, BØlling AK (2019) Di-n-butyl phthalate modifies Pma-induced macrophage differentiation of Thp-1 monocytes via Pparγ. Toxicol in Vitro 54:168–177
Gulliver LS (2017) Xenobiotics and the glucocorticoid receptor. Toxicol Appl Pharmacol 319:69–79
Hannon PR, Peretz J, Flaws JA (2014) Daily exposure to Di (2-ethylhexyl) phthalate alters estrous cyclicity and accelerates primordial follicle recruitment potentially via dysregulation of the phosphatidylinositol 3-kinase signaling pathway in adult mice. Biol Reprod 90(136):1–11
Hayashi Y, Ito Y, Yamagishi N, Yanagiba Y, Tamada H, Wang D, Ramdhan DH, Naito H, Harada Y, Kamijima M (2011) Hepatic peroxisome proliferator-activated receptor α may have an important role in the toxic effects of di (2-ethylhexyl) phthalate on offspring of mice. Toxicology 289:1–10
Hayashi Y, Ito Y, Naito H, Tamada H, Yamagishi N, Kondo T, Ishikawa T, Gonzalez FJ, Nakajima T (2019) In utero exposure to di (2-ethylhexyl) phthalate suppresses blood glucose and leptin levels in the offspring of wild-type mice. Toxicology 415:49–55
Hayden MS, Ghosh S (2004) Signaling to Nf-kappaB. Genes Dev 18:2195–2224
Hayden MS, Ghosh S (2008) Shared principles in Nf-κB signaling. Cell 132:344–362
Herrero Ó, Planelló R, Morcillo G (2015) The plasticizer benzyl butyl phthalate (Bbp) alters the ecdysone hormone pathway, the cellular response to stress, the energy metabolism, and several detoxication mechanisms in Chironomus riparius larvae. Chemosphere 128:266–277
Heudorf U, Mersch-Sundermann V, Angerer J (2007) Phthalates: toxicology and exposure. Int J Hyg Environ Health 210:623–634
Hsieh T, Tsai CF, Hsu CY, Kuo PL, Lee JN, Chai CY, Wang SC, Tsai EM (2012) Phthalates induce proliferation and invasiveness of estrogen receptor-negative breast cancer through the AhR/Hdac6/c-Myc signaling pathway. FASEB J 26:778–787
Hsu JW, Yeh S-C, Tsai F-Y, Chen H-W, Tsou T-C (2019) Fibroblast growth factor 21 secretion enhances glucose uptake in mono (2-ethylhexyl) phthalate-treated adipocytes. Toxicol in Vitro 59:246–254
Huang Q, Zhang H, Chen Y-J, Chi Y-L, Dong S (2016) The inflammation response to Dehp through Pparγ in endometrial cells. Int J Environ Res Public Health 13:318
Huang X, Liu G, Guo J, Su Z (2018) The Pi3K/Akt pathway in obesity and type 2 diabetes. Int J Biol Sci 14(1483):1496
Ito T, Inoue KI, Nishimura N, Takano H (2012a) Phthalate esters modulate the differentiation and maturation of mouse peripheral blood mononuclear cell-derived dendritic cells. J Appl Toxicol 32:142–148
Ito Y, Nakamura, T., Yanagiba, Y., Ramdhan, D. H., Yamagishi, N., Naito, H., Kamijima, M., Gonzalez, F. J. & Nakajima, T. 2012b Plasticizers may activate human hepatic peroxisome proliferator-activated receptor α less than that of a mouse but may activate constitutive androstane receptor in liver. Ppar research
Jaimes Iii R, Swiercz A, Sherman M, Muselimyan N, Marvar PJ, Posnack NG (2017) Plastics and cardiovascular health: phthalates may disrupt heart rate variability and cardiovascular reactivity. Am J Phys Heart Circ Phys 313:H1044–H1053
Jiang J-T, Sun W-L, Jing Y-F, Liu S-B, Ma Z, Hong Y, Ma L, Qin C, Liu Q, Stratton HJ (2011) Prenatal exposure to di-n-butyl phthalate induces anorectal malformations in male rat offspring. Toxicology 290:322–326
Jiang J-T, Xu H-L, Zhu Y-P, Wood K, Li E-H, Sun W-L, Yuan Q, Xu D-L, Liu Z-H, Zhao W (2015) Reduced Fgf10/Fgfr2 and androgen receptor (Ar) in anorectal malformations male rats induced by di-n-butyl phthalate (Dbp): a study on the local and systemic toxicology of Dbp. Toxicology 338:77–85
Jiang J-T, Zhong C, Zhu Y-P, Xu D-L, Wood K, Sun W-L, Li E-H, Liu Z-H, Zhao W, Ruan Y (2016) Prenatal exposure to di-n-butyl phthalate (Dbp) differentially alters androgen cascade in undeformed versus hypospadiac male rat offspring. Reprod Toxicol 61:75–81
Jiang XP, Tang JY, Xu Z, Han P, Qin ZQ, Yang CD, Wang SQ, Tang M, Wang W, Qin C (2017) Sulforaphane attenuates di-N-butylphthalate-induced reproductive damage in pubertal mice: involvement of the Nrf2-antioxidant system. Environ Toxicol 32:1908–1917
Kang J, Song J, Shen S, Li B, Yang X, Chen M (2016) Diisononyl phthalate aggravates allergic dermatitis by activation of Nf-kB. Oncotarget 7(85472):85482
Kang J, Ding Y, Li B, Liu H, Yang X, Chen M (2017) Trpa1 mediated aggravation of allergic contact dermatitis induced by Dinp and regulated by Nf-κB activation. Sci Rep 7:43586
Kang J, Duan J, Song J, Luo C, Liu H, Li B, Yang X, Yu W, Chen M (2018) Exposure to a combination of formaldehyde and Dinp aggravated asthma-like pathology through oxidative stress and Nf-κB activation. Toxicology 404:49–58
Kawano M, Qin X-Y, Yoshida M, Fukuda T, Nansai H, Hayashi Y, Nakajima T, Sone H (2014) Peroxisome proliferator-activated receptor α mediates di-(2-ethylhexyl) phthalate transgenerational repression of ovarian Esr1 expression in female mice. Toxicol Lett 228:235–240
Kim JH (2019) Di (2-ethylhexyl) phthalate promotes lung cancer cell line A549 progression via Wnt/β-catenin signaling. J Toxicol Sci 44:237–244
Kim TS, Jung KK, Kim SS, Kang IH, Baek JH, Nam H-S, Hong S-K, Lee BM, Hong JT, Oh KW (2010) Effects of in utero exposure to Di (n-Butyl) phthalate on development of male reproductive tracts in Sprague-Dawley rats. J Toxic Environ Health A 73:1544–1559
Kim Y-J, Kim E-Y, Ryu J-C (2011) Identification of estrogenic genes responding to phthalate esters treatment in human Mcf-7 cells. Molecular & Cellular Toxicology 7:163–170
KlopČIČ I, KolŠek K, Dolenc MS (2015) Glucocorticoid-like activity of propylparaben, butylparaben, diethylhexyl phthalate and tetramethrin mixtures studied in the Mda-kb2 cell line. Toxicol Lett 232:376–383
Kocbach BØlling A, Holme JA, Bornehag CG, Nygaard UC, Bertelsen RJ, NÅnberg E, Bodin J, Sakhi AK, Thomsen C, Becher R (2013) Pulmonary phthalate exposure and asthma - is Ppar a plausible mechanistic link? EXCLI J 12:733–759
Kuo CH, Hsieh CC, Kuo HF, Huang MY, Yang SN, Chen LC, Huang SK, Hung CH (2013) Phthalates suppress type I interferon in human plasmacytoid dendritic cells via epigenetic regulation. Allergy 68:870–879
Lake AD, Wood CE, Bhat VS, Chorley BN, Carswell GK, Sey YM, Kenyon EM, Padnos B, Moore TM, Tennant AH (2015) Dose and effect thresholds for early key events in a Pparα-mediated mode of action. Toxicol Sci 149:312–325
Lassot I, Robbins I, Kristiansen M, Rahmeh R, Jaudon F, Magiera MM, Mora S, Vanhille L, Lipkin A, Pettmann B (2010) Trim17, a novel E3 ubiquitin-ligase, initiates neuronal apoptosis. Cell Death Differ 17(1928):1941
Laurenzana EM, Coslo DM, Vigilar MV, Roman AM, Omiecinski CJ (2016) Activation of the constitutive androstane receptor by monophthalates. Chem Res Toxicol 29:1651–1661
Lee H-R, Hwang K-A, Choi K-C (2014) The estrogen receptor signaling pathway activated by phthalates is linked with transforming growth factor-β in the progression of LncaP prostate cancer models. Int J Oncol 45:595–602
Lehraiki A, Racine C, Krust A, Habert R, Levacher C (2009) Phthalates impair germ cell number in the mouse fetal testis by an androgen-and estrogen-independent mechanism. Toxicol Sci 111:372–382
Lenters V, Portengen L, Rignell-Hydbom A, JÖnsson BA, Lindh CH, Piersma AH, Toft G, Bonde JP, Heederik D, Rylander L (2016) Prenatal phthalate, perfluoroalkyl acid, and organochlorine exposures and term birth weight in three birth cohorts: multi-pollutant models based on elastic net regression. Environ Health Perspect 124:365–372
Li H, Wu S, Ma Q, Shi N (2011) The pesticide deltamethrin increases free radical production and promotes nuclear translocation of the stress response transcription factor Nrf2 in rat brain. Toxicol Ind Health 27:579–590
Li R, Yu C, Gao R, Liu X, Lu J, Zhao L, Chen X, Ding Y, Wang Y, He J (2012) Effects of Dehp on endometrial receptivity and embryo implantation in pregnant mice. J Hazard Mater 241:231–240
Li X, Jiang L, Cheng L, Chen H (2014) Dibutyl phthalate-induced neurotoxicity in the brain of immature and mature rat offspring. Brain Dev 36:653–660
Li Y, Hu Y, Dong C, Lu H, Zhang C, Hu Q, Li S, Qin H, Li Z, Wang Y (2016) Vimentin-mediated steroidogenesis induced by phthalate esters: involvement of Dna demethylation and nuclear factor κB. PLoS One 11:e0146138
Li X, Li J, Zhang Y, Zhou Y (2017) Di-n-butyl phthalate induced hypospadias relates to autophagy in genital tubercle via the Pi3K/Akt/mtor pathway. J Occup Health 59:8–16
Li N, Liu T, Guo K, Zhu J, Yu G, Wang S, Ye L (2018) Effect of mono-(2-ethylhexyl) phthalate (Mehp) on proliferation of and steroid hormone synthesis in rat ovarian granulosa cells in vitro. J Cell Physiol 233:3629–3637
Li R, Xing Q-W, Wu X-L, Zhang L, Tang M, Tang J-Y, Wang J-Z, Han P, Wang S-Q, Wang W (2019) Di-n-butyl phthalate epigenetically induces reproductive toxicity via the Pten/Akt pathway. Cell Death Dis 10:1–16
Lien EC, Dibble CC, Toker A (2017) Pi3K signaling in cancer: beyond Akt. Curr Opin Cell Biol 45:62–71
Lin C-H, Chen T-J, Chen S-S, Hsiao P-C, Yang R-C (2011) Activation of Trim17 by Pparγ is involved in di (2-ethylhexyl) phthalate (Dehp)-induced apoptosis on Neuro-2a cells. Toxicol Lett 206:245–251
Lin Y-C, Kuo K-K, Wuputra K, Lin S-H, Ku C-C, Yang Y-H, Wang S-W, Wang S-W, Wu D-C, Wu C-C (2014) Bovine induced pluripotent stem cells are more resistant to apoptosis than testicular cells in response to mono-(2-ethylhexyl) phthalate. Int J Mol Sci 15:5011–5031
Liu S-B, Ma Z, Sun W-L, Sun X-W, Hong Y, Ma L, Qin C, Stratton HJ, Liu Q, Jiang J-T (2012) The role of androgen-induced growth factor (Fgf8) on genital tubercle development in a hypospadiac male rat model of prenatal exposure to di-n-butyl phthalate. Toxicology 293:53–58
Liu C, Qian P, Yang L, Zhang L, Chen C, He M, Lu Y, Feng W, Li M, Zhang Y (2016a) Pubertal exposure to di-(2-ethylhexyl)-phthalate inhibits G9a-mediated histone methylation during spermatogenesis in mice. Arch Toxicol 90:955–969
Liu ZH, Li EH, Xu DL, Sun WL, Hong Y, Zhao W, Xia SJ, Jiang JT (2016b) Genetic research and structural dysplasia assessment of anorectal malformations in neonatal male rats induced by di (n-butyl) phthalate. Environ Toxicol 31:261–268
Lonard DM, O’malley BW (2012) Nuclear receptor coregulators: modulators of pathology and therapeutic targets. Nat Rev Endocrinol 8:598
Luo Y, Li X-N, Zhao Y, Du Z-H, Li J-L (2019) Dehp triggers cerebral mitochondrial dysfunction and oxidative stress in quail (Coturnix japonica) via modulating mitochondrial dynamics and biogenesis and activating Nrf2-mediated defense response. Chemosphere 224:626–633
Ma T, Zhou Y, Xia Y, Meng X, Jin H, Wang B, Chen Y, Qiu J, Wu J, Ding J (2020) Maternal exposure to di-n-butyl phthalate promotes the formation of testicular tight junctions through downregulation of Nf-κB/Cox-2/Pge2/Mmp-2 in mouse offspring. Environ Sci Technol 54:8245–8258
Manikkam, M., Tracey, R., Guerrero-Bosagna, C. & Skinner, M. K. 2013. Plastics derived endocrine disruptors (Bpa, Dehp and Dbp) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. PloS one, 8.
Mankidy R, Wiseman S, Ma H, Giesy JP (2013) Biological impact of phthalates. Toxicol Lett 217:50–58
Manteiga S, Lee K (2017) Monoethylhexyl phthalate elicits an inflammatory response in adipocytes characterized by alterations in lipid and cytokine pathways. Environ Health Perspect 125:615–622
Maradonna F, Evangelisti M, Gioacchini G, Migliarini B, Olivotto I, Carnevali O (2013) Assay of vtg, Ers and Ppars as endpoint for the rapid in vitro screening of the harmful effect of Di-(2-ethylhexyl)-phthalate (Dehp) and phthalic acid (Pa) in zebrafish primary hepatocyte cultures. Toxicol in Vitro 27:84–91
Martinez-Arguelles D, Culty M, Zirkin BR, Papadopoulos V (2009) In utero exposure to di-(2-ethylhexyl) phthalate decreases mineralocorticoid receptor expression in the adult testis. Endocrinology 150:5575–5585
Martinez-Arguelles DB, Guichard T, Culty M, Zirkin BR, Papadopoulos V (2011) In utero exposure to the antiandrogen di-(2-ethylhexyl) phthalate decreases adrenal aldosterone production in the adult rat. Biol Reprod 85:51–61
Martinez-Arguelles D, Campioli E, Lienhart C, Fan J, Culty M, Zirkin BR, Papadopoulos V (2014) In utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate induces long-term changes in gene expression in the adult male adrenal gland. Endocrinology 155:1667–1678
Mohammadi H, Ghassemi-Barghi N, Malakshah O, Ashari S (2019) Pyrethroid exposure and neurotoxicity: a mechanistic approach. Arh Hig Rada Toksikol 70:74–89
Mu X, Liao X, Chen X, Li Y, Wang M, Shen C, Zhang X, Wang Y, Liu X, He J (2015) Dehp exposure impairs mouse oocyte cyst breakdown and primordial follicle assembly through estrogen receptor-dependent and independent mechanisms. J Hazard Mater 298:232–240
Nakashima R, Hayashi Y, Md K, Jia X, Wang D, Naito H, Ito Y, Kamijima M, Gonzalez FJ, Nakajima T (2013) Exposure to Dehp decreased four fatty acid levels in plasma of prepartum mice. Toxicology 309:52–60
Nguyen PM, Park MS, Chow M, Chang JH, Wrischnik L, Chan WK (2010) Benzo [a] pyrene increases the Nrf2 content by downregulating the Keap1 message. Toxicol Sci 116:549–561
Nishioka J, Iwahara C, Kawasaki M, Yoshizaki F, Nakayama H, Takamori K, Ogawa H, Iwabuchi K (2012) Di-(2-ethylhexyl) phthalate induces production of inflammatory molecules in human macrophages. Inflamm Res 61:69–78
Oh PS, Lim K, Lim KT (2010) Phytoglycoprotein (75 kDa) inhibits expression of interleukin-1β stimulated by Dehp in human mast cells. Cell Biochem Funct 28:352–359
Parillo F, Maranesi M, Brecchia G, Gobbetti A, Boiti C, Zerani M (2014) In vivo chronic and in vitro acute effects of di (2-ethylhexyl) phthalate on pseudopregnant rabbit corpora lutea: possible involvement of peroxisome proliferator-activated receptor gamma. Biol Reprod 90(41):1–14
Peixoto AR, Santos TM, Brandt JZ, Delella FK, Gonçalves BF, Campos SG, Taboga SR, Favaro WJ, Domeniconi RF, Scarano WR (2016) Gestational and lactational exposition to Di-N-butyl-phthalate (Dbp) increases inflammation and preneoplastic lesions in prostate of Wistar rats after carcinogenic N-methyl-N-nitrosourea (Mnu) plus testosterone protocol. Environ Toxicol 31:1185–1195
Peng C, Ouyang Y, Lu N, Li N (2020) The Nf-κB signaling pathway, the microbiota, and gastrointestinal tumorigenesis: recent advances. Front Immunol 11
PÉrez PA, Toledo J, Del Valle Sosa L, Peinetti N, Torres AI, De Paul AL, Gutiérrez S (2020) The phthalate Dehp modulates the estrogen receptors α and β increasing lactotroph cell population in female pituitary glands. Chemosphere 127304
Petit J, Wakx A, Gil S, Fournier T, Auzeil N, Rat P, Laprévote O (2018) Lipidome-wide disturbances of human placental Jeg-3 cells by the presence of Mehp. Biochimie 149:1–8
Pomatto V, Cottone E, Cocci P, Mozzicafreddo M, Mosconi G, Nelson ER, Palermo FA, Bovolin P (2018) Plasticizers used in food-contact materials affect adipogenesis in 3T3-L1 cells. J Steroid Biochem Mol Biol 178:322–332
Posnack NG, Swift LM, Kay MW, Lee NH, Sarvazyan N (2012) Phthalate exposure changes the metabolic profile of cardiac muscle cells. Environ Health Perspect 120:1243–1251
Qin Z, Tang J, Han P, Jiang X, Yang C, Li R, Tang M, Shen B, Wang W, Qin C (2017) Protective effects of sulforaphane on di-n-butylphthalate-induced testicular oxidative stress injury in male mice offsprings via activating Nrf2/Are pathway. Oncotarget 8(82956):82967
Qin W, Duan J, Xie X, Kang J, Deng T, Chen M (2020) Exposure to diisononyl phthalate promotes atopic march by activating of Nf-κB and p38 Mapk. Toxicol Appl Pharmacol 395:114981
Rai SN, Dilnashin H, Birla H, Singh SS, Zahra W, Rathore AS, Singh BK, Singh SP (2019) The role of Pi3K/Akt and Erk in neurodegenerative disorders. Neurotox Res 35:775–795
Rashad MM, Galal MK, Abou-El-Sherbini KS, El-Behairy AM, Gouda EM, Moussa SZ (2018) Nano-sized selenium attenuates the developmental testicular toxicity induced by di-n-butyl phthalate in pre-pubertal male rats. Biomed Pharmacother 107:1754–1762
Rasoulpour RJ, Boekelheide K (2005) Nf-κB is activated in the rat testis following exposure to mono-(2-ethylhexyl) phthalate. Biol Reprod 72:479–486
Rubio V, Valverde M, Rojas E (2010) Effects of atmospheric pollutants on the Nrf2 survival pathway. Environ Sci Pollut Res 17:369–382
Sakuma S, Sumida M, Endoh Y, Kurita A, Yamaguchi A, Watanabe T, Kohda T, Tsukiyama Y, Fujimoto Y (2017) Curcumin inhibits adipogenesis induced by benzyl butyl phthalate in 3 T3-L1 cells. Toxicol Appl Pharmacol 329:158–164
Salamonsen LA (1999) Role of proteases in implantation. Rev Reprod 4:11–22
Scarano WR, De Toledo FC, Guerra MT, De Campos SGP, JÚnior LAJ, Felisbino SL, Anselmo-Franci JA, Taboga SR, Kempinas WDG (2009) Long-term effects of developmental exposure to di-n-butyl-phthalate (Dbp) on rat prostate: proliferative and inflammatory disorders and a possible role of androgens. Toxicology 262:215–223
Shanle EK, Xu W (2010) Endocrine disrupting chemicals targeting estrogen receptor signaling: identification and mechanisms of action. Chem Res Toxicol 24:6–19
Shao P, Wang Y, Zhang M, Wen X, Zhang J, Xu Z, Hu M, Jiang J, Liu T (2019) The interference of Dehp in precocious puberty of females mediated by the hypothalamic Igf-1/Pi3K/Akt/mtor signaling pathway. Ecotoxicol Environ Saf 181:362–369
Shaw P, Mondal P, Bandyopadhyay A, Chattopadhyay A (2019) Environmentally relevant concentration of chromium activates Nrf2 and alters transcription of related Xme genes in liver of zebrafish. Chemosphere 214:35–46
Sheikh IA, Abu-Elmagd M, Turki RF, Damanhouri GA, Beg MA, Al-Qahtani M (2016) Endocrine disruption: in silico perspectives of interactions of di-(2-ethylhexyl) phthalate and its five major metabolites with progesterone receptor. BMC Struct Biol 16:1–10
Shen O, Du G, Sun H, Wu W, Jiang Y, Song L, Wang X (2009) Comparison of in vitro hormone activities of selected phthalates using reporter gene assays. Toxicol Lett 191:9–14
Shen W-J, Zaidi SK, Patel S, Cortez Y, Ueno M, Azhar R, Azhar S, Kraemer FB (2012) Ablation of vimentin results in defective steroidogenesis. Endocrinology 153:3249–3257
Shen B, Wang W, Ding L, Sao Y, Huang Y, Shen Z, Zhuo Y, Wei Z, Zhang W (2015) Nuclear factor erythroid 2-related factor 2 rescues the oxidative stress induced by di-N-butylphthalate in testicular Leydig cells. Hum Exp Toxicol 34:145–152
Shen G, Zhou L, Liu W, Cui Y, Xie W, Chen H, Yu W, Li W, Li H (2017) Di (2-ethylhexyl) phthalate alters the synthesis and β-oxidation of fatty acids and hinders Atp supply in mouse testes via Uplc-Q-Exactive Orbitrap Ms-based Metabonomics study. J Agric Food Chem 65:5056–5063
Shih M-F, Pan K-H, Cherng JY (2015a) Possible mechanisms of Di (2-ethylhexyl) phthalate-induced Mmp-2 and Mmp-9 expression in A7r5 Rat vascular smooth muscle cells. Int J Mol Sci 16:28800–28811
Shih R-H, Wang C-Y, Yang C-M (2015b) Nf-kappaB signaling pathways in neurological inflammation: a mini review. Front Mol Neurosci 8:77
Shoaito H, Petit J, Chissey A, Auzeil N, Guibourdenche J, Gil S, Laprévote O, Fournier T, Degrelle SA (2019) The role of peroxisome proliferator–activated receptor gamma (Pparγ) in mono(2-ethylhexyl) phthalate (Mehp)-mediated cytotrophoblast differentiation. Environ Health Perspect 127:27003
Singh S, Li SS-L (2011) Phthalates: toxicogenomics and inferred human diseases. Genomics 97:148–157
Siomek A (2012) Nf-κB signaling pathway and free radical impact. Acta Biochim Pol 59
Sladek FM (2011) What are nuclear receptor ligands? Mol Cell Endocrinol 334:3–13
Sm H, Aylward LL, Kirman CR, Krishnan K, Nong A (2011) Biomonitoring equivalents for di-isononyl phthalate (Dinp). Regul Toxicol Pharmacol 60:181–188
Sohn J, Kim S, Koschorreck J, Kho Y, Choi K (2016) Alteration of sex hormone levels and steroidogenic pathway by several low molecular weight phthalates and their metabolites in male zebrafish (Danio rerio) and/or human adrenal cell (H295R) line. J Hazard Mater 320:45–54
Somasundaram DB, Selvanesan BC, Ramachandran I, Bhaskaran RS (2016) Lactational exposure to di (2-ethylhexyl) phthalate impairs the ovarian and uterine function of adult offspring rat. Reprod Sci 23:549–559
Somasundaram D, Manokaran K, Selvanesan B, Bhaskaran R (2017) Impact of di-(2-ethylhexyl) phthalate on the uterus of adult Wistar rats. Hum Exp Toxicol 36:565–572
Sonkar R, Powell CA, Choudhury M (2016) Benzyl butyl phthalate induces epigenetic stress to enhance adipogenesis in mesenchymal stem cells. Mol Cell Endocrinol 431:109–122
Stejskalova L, Dvorak Z, Pavek P (2011) Endogenous and exogenous ligands of aryl hydrocarbon receptor: current state of art. Curr Drug Metab 12:198–212
Stiles BL (2009) Pi-3-K and Akt: onto the mitochondria. Adv Drug Deliv Rev 61:1276–1282
Su C-H, Wang C-Y, Lan K-H, Li C-P, Chao Y, Lin H-C, Lee S-D, Lee W-P (2011) Akt phosphorylation at Thr308 and Ser473 is required for Chip-mediated ubiquitination of the kinase. Cell Signal 23:1824–1830
Sun X, Lin Y, Huang Q, Shi J, Qiu L, Kang M, Chen Y, Fang C, Ye T, Dong S (2015) Di (2-ethylhexyl) phthalate-induced apoptosis in rat Ins-1 cells is dependent on activation of endoplasmic reticulum stress and suppression of antioxidant protection. J Cell Mol Med 19:581–594
Sun W-L, Zhu Y-P, Ni X-S, Jing D-D, Yao Y-T, Ding W, Liu Z-H, Ding G-X, Jiang J-T (2018) Potential involvement of Fgf10/Fgfr2 and androgen receptor (Ar) in renal fibrosis in adult male rat offspring subjected to prenatal exposure to di-n-butyl phthalate (Dbp). Toxicol Lett 282:37–42
Tang C, Deng Y, Duan H, Zhang Y, Li Y, Qiu D, Zhou K, Hua Y, Wang C (2018a) The effect of maternal exposure to di-(2-ethylhexyl)-phthalate on fetal cardiac development in mice. J Appl Toxicol 38:834–842
Tang X, Wu S, Shen L, Wei Y, Cao X, Wang Y, Long C, Zhou Y, Li D, Huang F (2018b) Di-(2-ethylhexyl) phthalate (Dehp)-induced testicular toxicity through Nrf2-mediated Notch1 signaling pathway in Sprague–Dawley rats. Environ Toxicol 33:720–728
Tang C, Luo C, Hua Y, Zhou K, Duan H, Ma F, Zhang Y, Li Y, Qiu D, Wang C (2019) Placental P-glycoprotein inhibition enhances susceptibility to Di-(2-ethylhexyl)-phthalate induced cardiac malformations in mice: A possibly promising target for congenital heart defects prevention. PLoS One 14:e0214873
Tolson AH, Wang H (2010) Regulation of drug-metabolizing enzymes by xenobiotic receptors: Pxr and Car. Adv Drug Deliv Rev 62:1238–1249
Tsai C-F, Hsieh T-H, Lee J-N, Hsu C-Y, Wang Y-C, Lai F-J, Kuo K-K, Wu H-L, Tsai E-M, Kuo P-L (2014) Benzyl butyl phthalate induces migration, invasion, and angiogenesis of Huh7 hepatocellular carcinoma cells through nongenomic AhR/G-protein signaling. BMC Cancer 14:556
Tsai C-F, Hsieh T-H, Lee J-N, Hsu C-Y, Wang Y-C, Kuo K-K, Wu H-L, Chiu C-C, Tsai E-M, Kuo P-L (2015) Curcumin suppresses phthalate-induced metastasis and the proportion of cancer stem cell (Csc)-like cells via the inhibition of AhR/Erk/Sk1 signaling in hepatocellular carcinoma. J Agric Food Chem 63:10388–10398
Tsai C-Y, Wu JC, Fang C, Chang AY (2017) Pten, a negative regulator of Pi3K/Akt signaling, sustains brain stem cardiovascular regulation during mevinphos intoxication. Neuropharmacology 123:175–185
Tu Z, Mu X, Chen X, Geng Y, Zhang Y, Li Q, Gao R, Liu T, Wang Y, He J (2019) Dibutyl phthalate exposure disrupts the progression of meiotic prophase I by interfering with homologous recombination in fetal mouse oocytes. Environ Pollut 252:388–398
Uren-Webster TM, Lewis C, Filby AL, Paull GC, Santos EM (2010) Mechanisms of toxicity of di(2-ethylhexyl) phthalate on the reproductive health of male zebrafish. Aquat Toxicol 99:360–369
Vannuccini S, Clifton VL, Fraser IS, Taylor HS, Critchley H, Giudice LC, Petraglia F (2016) Infertility and reproductive disorders: impact of hormonal and inflammatory mechanisms on pregnancy outcome. Hum Reprod Update 22:104–115
Vetrano AM, Laskin DL, Archer F, Syed K, Gray JP, Laskin JD, Nwebube N, Weinberger B (2010) Inflammatory effects of phthalates in neonatal neutrophils. Pediatr Res 68:134–139
Vo TT, Jung E-M, Dang VH, Jung K, Baek J, Choi K-C, Jeung E-B (2009) Differential effects of flutamide and di-(2-ethylhexyl) phthalate on male reproductive organs in a rat model. J Reprod Dev:0904090159–0904090159
Wakui S, Shirai M, Motohashi M, Mutou T, Oyama N, Wempe MF, Takahashi H, Inomata T, Ikegami M, Endou H (2014) Effects of in utero exposure to di (n-butyl) phthalate for estrogen receptors α, β, and androgen receptor of Leydig cell on rats. Toxicol Pathol 42:877–887
Wang J, Liao Y, Fan J, Ye T, Sun X, Dong S (2012a) Apigenin inhibits the expression of Il-6, Il-8, and Icam-1 in Dehp-stimulated human umbilical vein endothelial cells and in vivo. Inflammation 35:1466–1476
Wang W, Craig ZR, Basavarajappa MS, Gupta RK, Flaws JA (2012b) Di (2-ethylhexyl) phthalate inhibits growth of mouse ovarian antral follicles through an oxidative stress pathway. Toxicol Appl Pharmacol 258:288–295
Wang S, Wang SS, Wu D, Lin Y, Ku C, Wu C, Chai C, Lee J, Tsai E, Lin C-L (2013) Androgen receptor-mediated apoptosis in bovine testicular induced pluripotent stem cells in response to phthalate esters. Cell Death Dis 4:e907–e907
Wang D-C, Chen T-J, Lin M-L, Jhong Y-C, Chen S-C (2014) Exercise prevents the increased anxiety-like behavior in lactational di-(2-ethylhexyl) phthalate-exposed female rats in late adolescence by improving the regulation of hypothalamus-pituitary-adrenal axis. Horm Behav 66:674–684
Wang R, Xu X, Zhu Q (2016a) Pubertal exposure to di-(2-ethylhexyl) phthalate influences social behavior and dopamine receptor D2 of adult female mice. Chemosphere 144:1771–1779
Wang XK, Agarwal M, Parobchak N, Rosen A, Vetrano AM, Srinivasan A, Wang B, Rosen T (2016b) Mono-(2-ethylhexyl) phthalate promotes pro-labor gene expression in the human placenta. PLoS One 11:e0147013
Wang Y-C, Tsai C-F, Chuang H-L, Chang Y-C, Chen H-S, Lee J-N, Tsai E-M (2016c) Benzyl butyl phthalate promotes breast cancer stem cell expansion via Sphk1/S1P/S1pr3 signaling. Oncotarget 7(29563):29576
Wang H, Wang J, Zhang J, Jin S, Li H (2017a) Role of Pi3K/Akt/mtor signaling pathway in Dbp-induced apoptosis of testicular Sertoli cells in vitro. Environ Toxicol Pharmacol 53:145–150
Wang Y, Chen B, Lin T, Wu S, Wei G (2017b) Protective effects of vitamin E against reproductive toxicity induced by di (2-ethylhexyl) phthalate via Ppar-dependent mechanisms. Toxicol Mech Methods 27:551–559
Wang Y, Zhao M, Liu J, Ni J, Jiao Y, Bai C (2017c) Up regulation of Il-6 is involved in di (2-ethylhexyl) phthalate (Dehp) induced migration and invasion of non small cell lung cancer (Nsclc) cells. Biomed Pharmacother 89:1037–1044
Wang Z, Shao M, Liu Y (2017d) Promotion of Wilms’ tumor cells migration and invasion by mono-2-ethyhexyl phthalate (Mehp) via activation of Nf-κB signals. Chem Biol Interact 270:1–8
Wang, H., Guan, T.-Q., Sun, J.-X., Talukder, M., Huang, Y.-Q., Li, Y.-H. & Li, J.-L. 2020a. Di-(2-ethylhexyl) phthalate induced nephrotoxicity in quail (Coturnix japonica) by triggering nuclear xenobiotic receptors and modulating the cytochrome P450 system. Environmental Pollution, 114162.
Wang X, Han B, Wu P, Li S, Lv Y, Lu J, Yang Q, Li J, Zhu Y, Zhang Z (2020b) Dibutyl phthalate induces allergic airway inflammation in rats via inhibition of the Nrf2/Tslp/Jak1 pathway. Environ Pollut 267:115564
Wang X, Yan X, Yang Y, Yang W, Zhang Y, Wang J, Ye D, Wu Y, Ma P, Yan B (2020c) Dibutyl phthalate-mediated oxidative stress induces splenic injury in mice and the attenuating effects of vitamin E and curcumin. Food Chem Toxicol 136:110955
Wei Z, Song L, Wei J, Chen T, Chen J, Lin Y, Xia W, Xu B, Li X, Chen X (2012) Maternal exposure to di-(2-ethylhexyl) phthalate alters kidney development through the renin–angiotensin system in offspring. Toxicol Lett 212:212–221
Wei N, Feng X, Xie Z, Zhang Y, Feng Y (2017) Long-term di (2-ethylhexyl)-phthalate exposure promotes proliferation and survival of HepG2 cells via activation of NfκB. Toxicol in Vitro 42:86–92
Win-Shwe TT, Yanagisawa R, Koike E, Nitta H, Takano H (2013) Expression levels of neuroimmune biomarkers in hypothalamus of allergic mice after phthalate exposure. J Appl Toxicol 33:1070–1078
WÓjtowicz AK, Szychowski KA, Wnuk A, Kajta M (2017) Dibutyl phthalate (Dbp)-induced apoptosis and neurotoxicity are mediated via the aryl hydrocarbon receptor (AhR) but not by estrogen receptor alpha (Erα), estrogen receptor beta (Erβ), or peroxisome proliferator-activated receptor gamma (Pparγ) in mouse cortical neurons. Neurotox Res 31:77–89
WÓjtowicz AK, Sitarz-GŁownia AM, SzczĘsna M, Szychowski KA (2019) The action of di-(2-ethylhexyl) phthalate (Dehp) in mouse cerebral cells involves an impairment in aryl hydrocarbon receptor (AhR) signaling. Neurotox Res 35:183–195
Wong K-K, Engelman JA, Cantley LC (2010) Targeting the Pi3K signaling pathway in cancer. Curr Opin Genet Dev 20:87–90
Wong JH, Wang YS, Nam S, Ho KH, Chang CM, Chen KC, Chen YF, Chang WC (2019) Phthalate plasticizer di (2-ethyl-hexyl) phthalate induces cyclooxygenase-2 expression in gastric adenocarcinoma cells. Environ Toxicol 34:1191–1198
Wood CE, Jokinen MP, Johnson CL, Olson GR, Hester S, George M, Chorley BN, Carswell G, Carter JH, Wood CR (2014) Comparative time course profiles of phthalate stereoisomers in mice. Toxicol Sci 139:21–34
Wu C-T, Wang C-C, Huang L-C, Liu S-H, Chiang C-K (2018) Plasticizer di-(2-ethylhexyl) phthalate induces epithelial-to-mesenchymal transition and renal fibrosis in vitro and in vivo. Toxicol Sci 164:363–374
Xiao-Feng Z, Nai-Qiang Q, Jing Z, Zi L, Yang Z (2009) Di (n-butyl) phthalate inhibits testosterone synthesis through a glucocorticoid-mediated pathway in rats. Int J Toxicol 28:448–456
Xu Q, Fitzsimmons B, Steinauer J, O’neill A, Newton AC, Hua X-Y, Yaksh TL (2011) Spinal phosphinositide 3-Kinase–Akt–Mammalian target of rapamycin signaling cascades in inflammation-induced hyperalgesia. J Neurosci 31:2113–2124
Xu X, Yang Y, Wang R, Wang Y, Ruan Q, Lu Y (2015) Perinatal exposure to di-(2-ethylhexyl) phthalate affects anxiety-and depression-like behaviors in mice. Chemosphere 124:22–31
Xu S, Zhang H, Pao PC, Lee A, Wang J, Suen Chan Y, Manno Iii FAM, Wan Chan S, Han Cheng S, Chen X (2020) Exposure to phthalates impaired neurodevelopment through estrogenic effects and induced Dna damage in neurons. Aquat Toxicol 222:105469
YaŞar P, Ayaz G, User SD, GÜPÜR G, Muyan M (2017) Molecular mechanism of estrogen–estrogen receptor signaling. Reproductive medicine and biology 16:4–20
Ye T, Kang M, Huang Q, Fang C, Chen Y, Liu L, Dong S (2016) Accumulation of di (2-ethylhexyl) phthalate causes endocrine-disruptive effects in marine medaka (O ryzias melastigma) embryos. Environ Toxicol 31:116–127
Yin L, Yu KS, Lu K, Yu X (2016) Benzyl butyl phthalate promotes adipogenesis in 3T3-L1 preadipocytes: a high content cellomics and metabolomic analysis. Toxicol in Vitro 32:297–309
Yu L, Li HX, Guo J-Y, Huang Y-Q, Wang H, Talukder M, Li J-L (2019) Di (2-ethyl hexyl) phthalate (Dehp)-induced spleen toxicity in quail (Coturnix japonica) via disturbing Nrf2-mediated defense response. Environ Pollut 251:984–989
Yurdakok-Dikmen B, Stelletta C, Tekin K, Kuzukiran O, Daskin A, Filazi A (2019) Effects of phthalates on bovine primary testicular culture and spermatozoa. Cytotechnology 71:935–947
Zb Z, Ji K, Shen X, Ww Z, Wang R, Xu W, Wei W (2019) Di (2-ethylhexyl) phthalate promotes hepatic fibrosis by regulation of oxidative stress and inflammation responses in rats. Environ Toxicol Pharmacol 68:109–119
Zhang L-F, Qin C, Wei Y-F, Wang Y, Chang J-K, Mi Y-Y, Ma L, Jiang J-T, Feng N-H, Wang Z-J (2011) Differential expression of the Wnt/β-catenin pathway in the genital tubercle (Gt) of fetal male rat following maternal exposure to di-n-butyl phthalate (Dbp). Syst Biol Reprod Med 57:244–250
Zhang X, Liu W, Yang H, Tan L, Ao L, Liu J, Cao J, Cui Z (2014) Inhibition of Pparα attenuates vimentin phosphorylation on Ser-83 and collapse of vimentin filaments during exposure of rat Sertoli cells in vitro to Dbp. Reprod Toxicol 50:11–18
Zhang S, Ma J, Fu Z, Zhang Z, Cao J, Huang L, Li W, Xu P, Cao X (2016) Promotion of breast cancer cells Mda-Mb-231 invasion by di (2-ethylhexyl) phthalate through matrix metalloproteinase-2/-9 overexpression. Environ Sci Pollut Res 23:9742–9749
Zhang, L., Gao, M., Zhang, T., Chong, T., Wang, Z., Zhai, X., Wu, Z. & Li, H. 2017a. Protective effects of genistein against mono-(2-ethylhexyl) phthalate-induced oxidative damage in prepubertal Sertoli cells. BioMed research international, 2017.
Zhang W, Shen X-Y, Zhang W-W, Chen H, Xu W-P, Wei W (2017b) Di-(2-ethylhexyl) phthalate could disrupt the insulin signaling pathway in liver of Sd rats and L02 cells via Pparγ. Toxicol Appl Pharmacol 316:17–26
Zhang W, Shen X-Y, Zhang W-W, Chen H, Xu W, Wei W (2017c) The effects of di 2-ethyl hexyl phthalate (Dehp) on cellular lipid accumulation in HepG2 cells and its potential mechanisms in the molecular level. Toxicol Mech Methods 27:245–252
Zhang YZ, Zuo Y-Z, Du Z-H, Xia J, Zhang C, Wang H, Li X-N, Li J-L (2018) Di (2-ethylhexyl) phthalate (Dehp)-induced hepatotoxicity in quails (Coturnix japonica) via triggering nuclear xenobiotic receptors and modulating cytochrome P450 systems. Food Chem Toxicol 120:287–293
Zhang C, Gong P, Ye Y, Zhang L, Chen M, Hu Y, Gu A, Chen S, Wang Y (2018a) Nf-κB-vimentin is involved in steroidogenesis stimulated by di-n-butyl phthalate in prepubertal female rats. Toxicology research 7:826–833
Zhang L, Li H, Gao M, Zhang T, Wu Z, Wang Z, Chong T (2018b) Genistein attenuates di-(2-ethylhexyl) phthalate-induced testicular injuries via activation of Nrf2/Ho-1 following prepubertal exposure. Int J Mol Med 41:1437–1446
Zhang G, Yang W, Jiang F, Zou P, Zeng Y, Ling X, Zhou Z, Cao J, Ao L (2019a) Perk regulates Nrf2/Are antioxidant pathway against dibutyl phthalate-induced mitochondrial damage and apoptosis dependent of reactive oxygen species in mouse spermatocyte-derived cells. Toxicol Lett 308(24):33
Zhang L, Sun W, Duan X, Duan Y, Sun H (2019b) Promoting differentiation and lipid metabolism are the primary effects for Dinp exposure on 3T3-L1 preadipocytes. Environ Pollut 255:113154
Zhang Q, Zhao Y, Talukder M, Han Y, Zhang C, Li X-N, Li J-L (2019c) Di (2-ethylhexyl) phthalate induced hepatotoxicity in quail (Coturnix japonica) via modulating the mitochondrial unfolded protein response and Nrf2 mediated antioxidant defense. Sci Total Environ 651:885–894
Zhang J, Yao Y, Pan J, Guo X, Han X, Zhou J, Meng X (2020a) Maternal exposure to Di-(2-ethylhexyl) phthalate (Dehp) activates the Pi3K/Akt/mtor signaling pathway in F1 and F2 generation adult mouse testis. Exp Cell Res 394:112151
Zhang S, Sun C, Zhao S, Wang B, Wang H, Zhang J, Wang Y, Cheng H, Zhu L, Shen R (2020b) Exposure to Dehp or its metabolite Mehp promotes progesterone secretion and inhibits proliferation in mouse placenta or Jeg-3 cells. Environ Pollut 257:113593
Zhao S, Li D, Bei X-Y, Zhu Y-P, Sun W-L, Shen C, Wood K, Han B-M, Jiang J-T (2018a) Maternal exposure to di-n-butyl phthalate (Dbp) promotes epithelial-mesenchymal transition via regulation of autophagy in uroepithelial cell. Toxicology 406:114–122
Zhao Y, Du Z-H, Talukder M, Lin J, Li X-N, Zhang C, Li J-L (2018b) Crosstalk between unfolded protein response and Nrf2-mediated antioxidant defense in Di-(2-ethylhexyl) phthalate-induced renal injury in quail (Coturnix japonica). Environ Pollut 242:1871–1879
Zhao, T.-X., Wang, J.-K., Shen, L.-J., Long, C.-L., Liu, B., Wei, Y., Han, L.-D., Wei, Y.-X., Wu, S.-D. & Wei, G.-H. 2020a. Increased m6A Rna modification is related to the inhibition of the Nrf2-mediated antioxidant response in di-(2-ethylhexyl) phthalate-induced prepubertal testicular injury. Environmental Pollution, 113911.
Zhao T-X, Wei Y-X, Wang J-K, Han L-D, Sun M, Wu Y-H, Shen L-J, Long C-L, Wu S-D, Wei G-H (2020b) The gut-microbiota-testis axis mediated by the activation of the Nrf2 antioxidant pathway is related to prepuberal steroidogenesis disorders induced by di-(2-ethylhexyl) phthalate. Environ Sci Pollut Res 27:35261–35271
Zhao Y, Li MZ, Shen Y, Lin J, Wang HR, Talukder M, Li JL (2020c) Lycopene Prevents Dehp-induced Leydig cell damage with the Nrf2 antioxidant signaling pathway in mice. J Agric Food Chem 68:2031–2040
Zhao Y, Lin J, Talukder M, Zhu S-Y, Mz L, Wang H, Li J (2020d) Aryl hydrocarbon receptor as a target for lycopene preventing Dehp-induced spermatogenic disorders. J Agric Food Chem
Zhao Y, Ma D, Wang H, Li M, Talukder M, Wang H, Jl L (2020e) Lycopene prevents Dehp-induced liver lipid metabolism disorder by inhibiting the Hif-1α-induced Pparα/Pparγ/Fxr/Lxr system. J Agric Food Chem 68:11468–11479
Zheng M, Son M-Y, Park C, Park J-I, Ek J, Yoon W, Park S, Bd H, Lim K (2005) Transcriptional repression of vimentin gene expression by pyrroline dithiocarbamate during 12-O-tetradecanoylphorbol-13-acetate-dependent differentiation of Hl-60 cells. Oncol Rep 14:713–717
Zhou Y, Ma T, Yan M, Meng X, Wu J, Ding J, Han X, Li D (2020) Exposure of Dbp in gestation induces inflammation of testicular Sertoli cells in progeny by activating Nlrp3 inflammasomes. Sci Total Environ 707:136139
Zhu H, Zheng J, Xiao X, Zheng S, Dong K, Liu J, Wang Y (2010) Environmental endocrine disruptors promote invasion and metastasis of Sk-N-Sh human neuroblastoma cells. Oncol Rep 23:129–139
Availability of data and materials
Not applicable.
Funding
This study was supported by a grant from the student research committee of Mazandaran University of Medical Sciences [IR.MAZUMS.REC.1400.111].
Author information
Authors and Affiliations
Contributions
Sorour Ashari collected and summarized articles, extracted and interpreted the results, prepared tables, and wrote the manuscript. Hamidreza Mohammadi cooperated in manuscript writing and table preparation. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Additional information
Responsible Editor: Ludek Blaha
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Mohammadi, H., Ashari, S. Mechanistic insight into toxicity of phthalates, the involved receptors, and the role of Nrf2, NF-κB, and PI3K/AKT signaling pathways. Environ Sci Pollut Res 28, 35488–35527 (2021). https://doi.org/10.1007/s11356-021-14466-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-021-14466-5