Estimation of Estrogenic and Anti-estrogenic Activities of Some Phthalate Diesters and Monoesters by MCF-7 Cell Proliferation Assay in Vitro

Abstract

Phthalates are widespread in food and the environment due to their use as plasticizers in consumer products, food packaging materials and biomedical devices. 1) Phthalates are produced industrially in large quantities, mainly to impart flexibility to plastics. More than 400000 tons of phthalate plasticizers, such as di(2-ethylhexyl) phthalate (DEHP), di-nbutyl phthalate (DBP), dimethyl phthalate (DMP), diethyl phthalate (DEP) and butyl benzyl phthalate (BBP), are produced industrially each year in Japan.2) The ubiquity of these compounds in the aqueous environment is well known, and their presence has been reported in river water, sewage effluent samples, and drinking water. DMP, DBP and DHEP and their corresponding monoesters, monomethyl phthalate (MMP), mono-n-butyl phthalate (MBP) and mono(2-ethylhexyl) phthalate (MEHP), were detected in samples of the Tama river at levels of micrograms per liter.3) Phthalates are frequently detected in outdoor and indoor air. Measurement of the concentrations of phthalates in a newly built house revealed that those of DEHP and DBP were 1046 and 871 ng/m 3 , respectively, and small amounts of DMP, DEP, BBP, diisobutyl phthalate and dicyclohexyl phthalate (DCHP) were also detected. 4) DEHP has been known to cause liver tumors in rodents 5) and to enhance tumor promotion in skin 6) and liver 7) of mice. However, in 2000 IARC (the International Agency for Research on Cancer) downgraded DEHP from 2B to 3, "not classifiable as to its carcinogenicity to humans." 8) On the other hand, DEHP 9) and BBP 10) caused adverse effects in male reproductive organs in mice and rats, respectively. Gestational exposure of female rats to BBP 11) and DBP 12,13) caused malformation of reproductive organs in male offspring. MEHP suppressed proliferation of Sertoli cells in neonatal rats 14) and had toxic effects on testes of prepubertal male rats. 15) DBP is toxic to testes possibly through its metabolite, MBP. 16,17) Phthalate monoesters such as MEHP are formed as metabolites by various tissue enzymes in mammals from phthalic acid diesters. [18][19][20] To examine the human health risks of exposure to dialkyl or aryl phthalate, levels of urinary phthalate monoesters were assessed, and ethyl, benzyl and butyl phthalate were detected, reflecting exposure to high levels of DEP, DBP, and BBP. 21)Some phthalate diesters have been found to be weakly estrogenic. [22][23][24][25] However, estrogenic activities of phthalate monoesters have not been studied, though they are found in the environment; their anti-estrogenic activities are not fully understood, though they are as important as estrogenic activities. One approach might be an in vitro experimental system that can avoid complex factors of the in vivo system. In the present study, we examined both anti-estrogenic and estrogenic activities of 8 phthalate diesters that are commonly present in the environment, and 11 monoesters, which could be derived from the diesters, using estrogen-dependent human breast cancer MCF-7 cells in vitro, to clarify the ch...

Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism

“…BBP is the most active compound and the induction level of VEGF at 10 K4 M is similar to that observed with 1 nM E 2 . BBP and DEHP are considered as weak xenoestrogens in vitro, using MCF-7 proliferation test or the yeast model ( Jobling et al 1995, Soto et al 1995, Andersen et al 1999, Picard et al 2001, Okubo et al 2003, in agreement with this study.…”

Role of Some Risk Factors in the Etiology of Breast Cancer in the Sudan

“…This compound has shown to be weakly estrogenic [23] and to induce adverse effects on the development of male reproductive system; thus acting as an endocrine disruptor. BBP has shown endocrine-disrupting properties, thus having a potential effect on hormonesensitive tissues [24].…”

Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks

“…Harvey and Darbre (2004) and Harvey and Everett (2006) have noted that all types of bodycare cosmetics applied to the skin (not just underarm cosmetics) can be a source of local oestrogenic chemical input to the breast and should be considered in risk assessments. Furthermore, there are also an increasing number of other ingredients in various cosmetics that have been shown to be endocrine active or oestrogenic [for example polycyclic musks (Gomez et al, 2005;Schreurs et al, 2005), UV ¼lters (Schlumpf et al, 2001;Inui et al, 2003;Koda et al, 2005), aluminium chlorhydrate (Darbre, 2006b), triclosan (Gee et al, 2008), phthalates (Jobling et al, 1995;Harris et al, 1997;Okubo et al, 2003), cyclosiloxanes (McKim et al, 2001;He et al, 2003)] and risk assessments should take into account mixture and combined repeated exposure effects.…”

“…Thus common coingredients in cosmetic formulations may interact in mixtures, resulting in higher skin and body burdens of parabens [and other endocrine active compounds common in cosmetics, e.g. phthalates (Jobling et al, 1995;Harris et al, 1997;Okubo et al, 2003), polycyclic musks (Gomez et al, 2005;Schreurs et al, 2005), UV ¼lters (Schlumpf et al, 2001;Inui et al, 2003;Janjua et al, 2004;Koda et al, 2005), aluminium chlorhydrate (Darbre, 2006b), triclosan (Gee et al, 2008) and cyclosiloxanes (McKim et al, 2001;He et al, 2003)]. …”