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In vivo and in vitro estrogen bioactivities of alkyl parabens

Departamento de Farmacología, Universidad Nacional Autónoma de México, Ciudad Universitaria, Apartado Postal 70-297, CP 04510, D. F. México, clemini{at}servidor.unam.mx

Ruth Jaimez

Departamento de Farmacología, Universidad Nacional Autónoma de México, Ciudad Universitaria, Apartado Postal 70-297, CP 04510, D. F. México

María Estela Ávila

Departamento de Farmacología, Universidad Nacional Autónoma de México, Ciudad Universitaria, Apartado Postal 70-297, CP 04510, D. F. México

Yanira Franco

Departamento de Farmacología, Universidad Nacional Autónoma de México, Ciudad Universitaria, Apartado Postal 70-297, CP 04510, D. F. México

Fernando Larrea

Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, D. F. México

Ana Elena Lemus

Departamento de Biología de la Reproducción, UAM-Iztapalapa, D. F. México

The alkyl esters of p-hydroxybenzoic acid known as parabens (Pbens) are used as preservatives in food, pharmaceutical and cosmetic formulations. They have been reported as estrogenic. Here, we present evidence for the in vivo and in vitro bioactivities and receptor binding affinities of methylparaben (MePben), ethylparaben (EtPben), propylparaben (PrPben), and butylparaben (BuPben) compared with those of estradiol (E₂). Estrogenicity was studied using the uterotrophic assay in immature (Im) and adult ovariectomized (Ovx) CD1 mice, and in immature female Wistar rats (IW). Animals were subcutaneously (sc) treated for three consecutive days with different molar equivalent doses ranging from 3.62 to 1086 mmol/kg body weight of Pbens, E₂ (0.036 mmol/kg), or vehicle. Pbens increased uterine weight in Im and Ovx animals and their relative uterotrophic effect to E₂ (100) (RUEE₂) were from 34 to 91. The relative uterotrophic potencies related to E₂ (100) (RUPE₂) of these compounds were from 0.003 to 0.007. The E₂ ED₅₀ for CD1 animals able to increase the uterine weight was 7 mg/kg (0.9 -55 confidence limits); and that of Pbens ranged from 18 to 74 mg/kg. In IW rats, the ED₅₀ were from 33 to 338 mg/kg. All Pbens, except MePb, competed with [³H]E₂ for the estrogen receptor binding sites. The uterotrophic effects of Pbens in Im mice have a positive correlation with the side-chain length of the ester group of these compounds. The E₂ and Pbens relative binding affinities (RBA) and K_i values correlated to their estrogenic activity. The NOELs values for Pbens uterotrophic activity in Im were from 0.6 to 6.5 mg/kg per day; and Ovx from 6 to 55 mg/kg. The NOELs IW ranged from 16.5 to 70 mg/kg indicating that Im were more susceptible than Ovx and IW to these effects. The data shown here confirm the estrogenicity of Pbens.

Key Words: endocrine disruptors • environmental estrogens • estrogenic effects • parabens • uterotrophic effects

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