Phthalic acid mono-2-ethylhexyl ester, a major bioactive metabolite of diethylhexyl phthalate (DEHP), exhibiting anti-estrogenic (IC50=125μM) and anti-androgenic effects (IC50=736μM) [1]. Phthalic acid mono-2-ethylhexyl ester impairs DNA methylation, histone modifications and levels of miRNAs and lncRNAs induce alterations in several placental functions[2]. Phthalic acid mono-2-ethylhexyl ester has been widely used to decrease estradiol and progesterone production in preovulatory granulosa cells[3].
In vitro, Phthalic acid mono-2-ethylhexyl ester treatment for 72h significantly inhibited the viability of TK6 cells, with an IC50 value of 80μM[4]. Treatment with 100μM Phthalic acid mono-2-ethylhexyl ester for 24 hours significantly increased the triglyceride levels in HepG2 cells, upregulated the expression of SREBP-1c and ChREBP genes, and enhanced the protein expressions of ChREBP1, ACC, FAS and SCD[5]. Treatment with 200μM Phthalic acid mono-2-ethylhexyl ester for 24 hours significantly inhibited the invasion of HTR-8/SVneo cells and activated the PPARγ pathway[6]. Phthalic acid mono-2-ethylhexyl ester (100μM; 36h) induced apoptosis in p53-silenced L02 cells, along with the up-regulations of Fas and FasL proteins as well as increased the Bax/Bcl-2 ratio and Caspase 3, 8, and 9 activities[7].
In vivo, Phthalic acid mono-2-ethylhexyl ester was administered to pregnant female mice for 24 hours by intragastric administration (360mg/kg; twice daily; at 08:30 and 18:30, respectively), which resulted in the loss of germ cells in the testes of the fetal mice, and the apoptosis rate significantly increased[8].
References:
[1] Kim D H, Park C G, Kim S H, et al. The effects of mono-(2-ethylhexyl) phthalate (MEHP) on human estrogen receptor (hER) and androgen receptor (hAR) by YES/YAS in vitro assay[J]. Molecules, 2019, 24(8): 1558.
[2] Martínez-Razo L D, Martínez-Ibarra A, Vázquez-Martínez E R, et al. The impact of Di-(2-ethylhexyl) Phthalate and Mono (2-ethylhexyl) Phthalate in placental development, function, and pathophysiology[J]. Environment International, 2021, 146: 106228.
[3] Reinsberg J, Wegener-Toper P, van der Ven K, et al. Effect of mono-(2-ethylhexyl) phthalate on steroid production of human granulosa cells[J]. Toxicology and applied pharmacology, 2009, 239(1): 116-123.
[4] Rosado-Berrios C A, Vélez C, Zayas B. Mitochondrial permeability and toxicity of diethylhexyl and monoethylhexyl phthalates on TK6 human lymphoblasts cells[J]. Toxicology in Vitro, 2011, 25(8): 2010-2016.
[5] Bai J, He Z, Li Y, et al. Mono-2-ethylhexyl phthalate induces the expression of genes involved in fatty acid synthesis in HepG2 cells[J]. Environmental Toxicology and Pharmacology, 2019, 69: 104-111.
[6] Gao F, Hu W, Li Y, et al. Mono-2-ethylhexyl phthalate inhibits human extravillous trophoblast invasion via the PPARγ pathway[J]. Toxicology and applied pharmacology, 2017, 327: 23-29.
[7] Yang G, Zhang W, Qin Q, et al. Mono (2‐ethylhexyl) phthalate induces apoptosis in p53‐silenced L02 cells via activation of both mitochondrial and death receptor pathways[J]. Environmental Toxicology, 2015, 30(10): 1178-1191.
[8] Muczynski V, Cravedi J P, Lehraiki A, et al. Effect of mono-(2-ethylhexyl) phthalate on human and mouse fetal testis: In vitro and in vivo approaches[J]. Toxicology and applied pharmacology, 2012, 261(1): 97-104.
















