Potential Estrogenic and Antiestrogenic Activity of the Cyclic Siloxane Octamethylcyclotetrasiloxane (D4) and the Linear Siloxane Hexamethyldisiloxane (HMDS) in Immature Rats Using the Uterotrophic Assay

Abstract

The cyclic siloxane octamethylcyclotetrasiloxane (D4) and the linear siloxane hexamethyldisiloxane (HMDS) have numerous industrial and consumer applications and thus have the potential for human exposure. The present study was undertaken to examine potential estrogenic and antiestrogenic activities of D4 and HMDS. To address potential differences in sensitivity between rat strains the study used both Sprague-Dawley (SD) and Fischer 344 (F-344) rats. Estrogenicity of the test compounds was determined by measuring absolute and relative uterine weights in immature rats and by monitoring uterine epithelial cell height. In order to place the data obtained for D4 into perspective relative to strong and weak estrogenic compounds, the response produced by D4 at 0, 10, 50, 100, 250, 500, and 1000 mg/kg/day was compared to responses produced by ethinyl estradiol (EE) (1, 3, 10, or 30 microg/kg/day), diethylstilbestrol dipropionate (DES-DP) (0.5, 1.5, 5, 15 microg/kg/day), and coumestrol (CE) (10, 35, 75, 150 mg/kg/day). Antiestrogenic effects were evaluated by co-administering D4 (500 mg/kg/day) with EE at 1, 3, 10, and 30 microg /kg/day. All compounds were administered in sesame oil at a volume of 5 mL/kg by oral gavage. Beginning on postnatal day 18 (SD) or 21 (F-344) each pup (12 per group) received a single dose of test compound once a day for 4 consecutive days. The pups were euthanized the morning after the last treatment and their uteri removed, weighed, and processed for histological examination. EE and DES-DP produced a significant dose-dependent increase in absolute and relative uterine weights and uterine cell height. The maximum increase in uterine weight following EE exposure was approximately 350% relative to controls in both strains. The weak phytoestrogen CE also produced a dose-related increase in absolute and relative uterine weight and epithelial cell height, but the response occurred over a much higher range of doses. At the highest dose of CE, uterine weight was increased approximately 230% relative to controls. Following exposure to D4, absolute and relative uterine weights and uterine epithelial cell height were statistically significantly increased in both strains of rats at doses above 100 mg/kg/day. In terms of uterine weight, D4 was approximately 0.6 million times less potent than EE or DES-DP in SD pups and 3.8 million times less potent than EE or DES-DP in F-344 pups. The maximal increase in uterine weight, relative to controls, produced by D4 at 1000 mg/kg/day was approximately 160% in SD rats, while the maximum increase produced by D4 in F-344 rats was 86%. D4 co-administered over a wide range of EE doses, resulted in a significant reduction in uterine weight compared to EE alone. HMDS was evaluated in SD rats only. The response produced by HMDS (600 and 1200 mg/kg/day) was compared to EE (3 microg/kg/day). Antiestrogenic effects were evaluated by co-administering HMDS (1200 mg/kg/day) with EE at 3 microg/kg/day. HMDS had no measurable effect on uterine weight under the experimental condition...

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)]. …”

Oestrogenic activity of benzyl salicylate, benzyl benzoate and butylphenylmethylpropional (Lilial) in MCF7 human breast cancer cells in vitro

“…Methylparaben, ethylparaben, n-propylparaben, n-butylparaben and isobutylparaben are the most widely used esters in consumer products and these have all now been shown to possess oestrogenic activity in assay systems in vitro and in vivo (Routledge et al, 1998;Blair et al, 2000;Hossaini et al, 2000;Jin-Sung et al, 2000;Nishihara et al, 2000;Pedersen et al, 2000;Fang et al, 2001;Okubo et al, 2001;Byford et al, 2002;Darbre et al, 2002Darbre et al, , 2003Lemini et al, 2003;summary table in Darbre and Harvey, 2008) and have been detected in human breast tumours . Further groups of oestrogenic chemicals in cosmetic products include the polycyclic musks (Gomez et al, 2005;Schreurs et al, 2005;Mori et al, 2007), UV filters (Schlumpf et al, 2001;Inui et al, 2003;Heneweer et al, 2005: Koda et al, 2005Kunz and Fent, 2006a), aluminium chlorhydrate (Darbre, 2006b), triclosan (Gee et al, 2008), phthalates (Jobling et al, 1995;Harris et al, 1997;Okubo et al, 2003) and cyclosiloxanes (Hayden and Barlow, 1972;McKim et al, 2001;He et al, 2003), all of which except the cyclosiloxanes have been measured in either breast milk or breast tissue (see Table 1 for references).…”

Endocrine Disruptors as Pollutants in Marine Ecosystem: A Case Study in Egypt

“…The substance also showed weak antiestrogenic properties by partially blocking EE (ethinylestradiol) induced uterine weight increases (competitive inhibition of estrogen receptor binding or D4 acting as a partial estrogen agonist). Estrogenic and antiestrogenic effects of D4 were several orders of magnitude 50 less potent than EE, and many times less potent than the weak phytoestrogen CE [34].…”