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Estrogenic activities of parabens



Objective: Studies indicated that parabens, used as anti-microbial agents in food, cosmetics, and pharmaceuticals, produced a positive uterotrophic response in vivo. They also damaged the late stages of spermatogenesis, altered proportion of pups born alive, and body weight of offspring. They reduced the number of sperm in the epididymis, and the sperm motile activity in male offspring. Parabens could compete with [3H] 17beta-estradiol for binding to the estrogen receptor. The proliferation of two estrogen-dependent cell lines MCF-7 and ZR-75-1 could be increased by parabens. They also increased expression of both transfected and endogenous estrogen-regulated genes in MCF-7 cells. The studies demonstrated parabens were weakly estrogenic.
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... Recently, a variety of studies have focused on the hormonelike activities of environmental chemicals well known as xenobiotic estrogens in the environment, especially those related to the food industry or cosmetic products. It is reported that parabens possess a weak estrogenic activity (Ge and Chang, 2006;Lemini et al., 2003). These chemicals might cause disruption of endocrine systems and consequently influence the growth, differentiation, and function of reproductive systems. ...
... As parabens can mimic the effects of physiological estrogen, they bind to ERs, stimulate the ER-dependent response, and/or influence the expression of estrogen-responsive genes, including estrogen receptor alpha (ER-a), progesterone receptor (PR), and pS2 Okubo et al., 2001). ERdependent estrogenic activities of parabens were demonstrated in MCF-7 human breast cancer cells Okubo et al., 2001;Vanparys et al., 2006), ZR-75-1 cell lines (Darbre et al., 2004;Ge and Chang, 2006), rodent models (Darbre et al., 2003;Harvey, 2003;Kang et al., 2002;Oishi, 2002a,b), and fish (Inui et al., 2003). The estrogenic potency of parabens has been shown to depend on the lengths of their alkyl side chains (Darbre et al., 2003;Okubo et al., 2001). ...
In the present study, calbindin-D9k (CaBP-9k), a potent biomarker for screening estrogen-like environmental chemicals in vivo and in vitro, was adopted to examine the potential estrogen-like property of the following parabens: propyl-, isopropyl-, butyl-, and isobutylparaben. Immature female rats were administered for 3 days from postnatal day 14 to 16 with 17alpha-ethinylestradiol (EE, 1 mg/kg body weight [BW]/day) or parabens (62.5, 250, and 1000 mg/kg BW/day). In uterotrophic assays, significantly increased uterus weights were detected in the EE-treated group and in the groups treated with the highest dose of isopropyl-, butyl-, and isobutylparaben. In addition, these parabens induced uterine CaBP-9k messenger RNA (mRNA) and protein levels, whereas cotreatment of parabens and fulvestrant, a pure estrogen receptor (ER) antagonist, completely reversed the paraben-induced gene expression and increased uterine weights. To investigate the ER-mediated mechanism(s) by which parabens exert their effects, the expression level of ER-alpha and progesterone receptor (PR) was analyzed. Exposure to EE or parabens caused a dramatic decrease in expression of both ER-alpha mRNA and protein levels, whereas cotreatment with fulvestrant reversed these effects. These data showed the difference of CaBP-9k and ER-alpha expression, suggesting that CaBP-9k may not express via ER-alpha pathway. In the effect of parabens on CaBP-9k expression through PR mediation, a significantly increased expression of uterine PR gene, a well-known ER-regulating gene, at both transcriptional and translational levels was indicated in the highest dose of isopropyl- and butylparaben. These parabens-induced PR gene expression was completely blocked by fulvestrant. This result indicates that CaBP-9k expression may involve with PR mediates in the estrogenic effect of paraben in immature rat uteri. Taken together, parabens exhibited an estrogen-like property in vivo, which may be mediated by a PR and/or ER-alpha signaling pathway. In addition, our results expanded the current understanding of the potential adverse effects of parabens associated with their estrogen-like activities. Further investigation is needed to elucidate in greater detail the adverse effects of parabens in humans and wildlife.
... Le coefficient de partition octanol/eau (K ow ) des parabènes augmente avec la longueur de la chaîne alkyle ainsi ceux à longues chaînes ont une tendance plus élevée à s'accumuler dans les tissus riches en lipides(Soni et al., 2005). Structures chimiques des acide fér ulique, acide caféique, acide p-hydroxybenzoïque, méthylparabène, éthylparabène, propylparabène, butylparabène, benzylparabène, tyrosol et hydroxytyrosol.55 ...
Les cucurbitacines et les parabènes sont des substances d'origine naturelle appartenant à la famille des triterpéniques cycliques et des esters de l'acide-hydroxybenzoïque, respectivement. Ils sont connus pour posséder chez l'homme plusieurs effets pharmacologiques potentiellement intéressants. Le but de ce travail est d'étudier la biotransformation d'une série de trois cucurbitacines et de cinq parabènes dans le foie humain in vitro, essentiellement par glucuronoconjugaison et hydrolyse et caractériser l'effet cytotoxique des cucurbitacines sur une lignée cellulaire du chondrosarcome humain SW 1353. Les résultats ont montré que les cucurbitacines I et D sont plus cytotoxiques que la cytochalasine D vis-à-vis SW 1353 et entraînent l'apoptose des cellules après 12h de traitement à 1 µM alors que la cucurbitacine E présente une cytotoxicité à 10 µM. L'étude in vitro de biotransformation chez l'homme montre que les cucurbitacines sont surtout sulfo- et glucuronoconjuguées (méthodes radiochimiques) par les isoformes de la famille 1A essentiellement. La cucurbitacine E est également activement hydrolysées (Km 22 µM et Vmax 571 nmol/mg /min) en cucurbitacine I dans le foie humain. Par contre, ces substances sont très faiblement hydroxylées. Les acides oléanolique, ursolique et l'érythrodiol, de structure apparentée aux cucurbitacines, sont aussi glucuronoconjuguées au même taux dans les microsomes hépatiques humains mais avec des affinités 100 fois plus élevées. Les parabènes sont rapidement hydrolysés par des estérases dans les microsomes hépatiques humains en acide 4-hydroxybenzoïque, et leur hydrolyse diminue avec la longueur de la chaîne alkyle. Les parabènes, l'acide caféique, le tyrosol et l'hydroxytyrosol, de structure apparentée aux parabènes, sont activement glucuronoconjuguées par les UGTs des familles 1A et 2B. Cependant, l?acide 4-hydroxybenzoïque n'est pas un bon substrat pour les UGTs
... The detection of estrogenic activity of any new compound or substance is very important and especially when it is related to food industry. Ge and Chang (2006) 28 ;Lemini et al (1997Lemini et al ( , 2003 [29][30] reported that ester derivatives of phydroxybenzoic acid (parabens) that are structurally similar to 17-beta estradiol exhibited estrogen like property in vivo. Examples of parabens that possess estrogenic activity are methyl paraben, ethyl paraben, propyl paraben, butyl paraben, isopropyl paraben, ISSN 0976 -044X ...
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p-hydroxy benzoic acid (PHBA) is an organic chemical which can be obtained naturally as well as synthetically. The literature survey reveals its various biological properties viz. antimicrobial, antialgal, antimutagenic, antiestrogenic, hypoglycemic, anti-inflammatory, anti-platelet aggregating, nematicidal, antiviral, antioxidant etc. It is also reported to be used as preservative in many drugs, cosmetic products, pharmaceuticals, food and beverages. Some derivatives of 4-hydroxybenzoicacid are found to possess direct action on Hbs molecules, inhibit acetic acid induced oedema and used in management of sickle cell disease. The present study will give comprehensive information of the biological activities of this p-hydroxy benzoic acid and its derivatives.
Endocrine disruptors (EDs) have estrogenic activity and can cause physiological estrogenic responses. Octylphenol (OP) is one of the alkylphenolic compounds known as environmental xenoestrogens because they strongly compete with endogenous estrogens to bind to estrogen receptors (ERs). Isobutyl paraben (IBP), a widely used preservative, also exhibits estrogenic activity. Calbindin-D₉k (CaBP-9k) is a novel biomarker for the detection of EDs used in our previous studies. In this study, the CaBP-9k gene was utilized as a marker for the estrogenic activity of combined OP and IBP to investigate possible additive, synergistic or antagonistic effects of these compounds in GH3 rat pituitary cells. GH3 cells were treated with different individual or combined doses of OP and IBP. In addition, the antiestrogen ICI 182,780 was used to examine the potential involvement of ERs in the induction of CaBP-9k expression by EDs. It was found that CaBP-9k expression was significantly increased at a high-dose of OP (1 µM) combined with each dose of IBP (0.1, 1 or 10 µM) compared to all single doses of IBP and OP. A synergistic increase in luciferase activity and CaBP-9k expression was observed following combination treatment with OP and IBP. Expression of the progesterone receptor (PR) gene was similarly induced by combined treatment with OP and IBP. In addition, pre-treatment with ICI 182,780, an estrogen antagonist, significantly blunted ED-induced CaBP-9k and PR expression. In summary, the expression of CaBP-9k and PR was induced more potently by combined OP and IBP than by treatment with either ED alone. ICI 182,780 treatment reversed ED-induced CaBP-9k and PR expression in these cells. Taken together, these results indicate that combined exposure to OP and IBP has a synergistic effect on the induction of CaBP-9k and PR gene expression via an ER-dependent pathway in GH3 cells.
The effects of paraben, a xenoestrogen with known endocrine disrupting bioactivity were evaluated. We used the induction of an estrogenic biomarker gene - Calbindin-D(9k) (CaBP-9k) to investigate the xenoestrogenic activity of a panel of parabens (methyl-, ethyl-, propyl-, isopropyl-, butyl-, and isobutylparabens) in GH3 rat pituitary cancer cell line. Following 24-h treatment, a significant increase in CaBP-9k expression of transcript and protein was dependent on the concentration-treated as well as the linear length of the alkyl chain from methyl- to isobutylparabens. Interestingly, co-treatment with fulvestrant, a pure antiestrogen largely reversed the paraben-dependent induction of CaBP-9k mRNA and protein in GH3 cell line. To better understand the mechanism of CaBP-9k induction by these endocrine disrupting compounds, we measured the levels of estrogen receptor (ERα) and progesterone receptor (PR) expression following parabens exposure. Also, we monitored the transiently transfected with plasmids containing of estrogen response element (ERE) sequence into GH3. In the GH3 cells, a large increase in PR mRNA and protein was observed in a concentration-dependent manner after parabens treatment that was effectively blocked in the presence of antagonist of 17β-estradiol (fulvestrant). And, luciferase activity was expressed from the putative ERE and expression was stimulated by parabens. To confirm that ERα signaling is involved in parabens induction of CaBP-9k and PR mRNA and protein, we treated GH3 cells with an antiestrogen, fulvestrant, which blocked the paraben-induced upregulation of CaBP-9k and PR. Taken together, these results indicate that CaBP-9k and PR is induced by parabens via the ER pathway in GH3 cell line.
In this study, a female pubertal assay on the effects of parabens, including methyl-, ethyl-, propyl-, isopropyl-, butyl-, and isobutylparaben, was performed in a female Sprague-Dawley rat model during the juvenile-peripubertal period. The rats were orally treated with these parabens from postnatal day 21-40 in a dose-dependent manner (62.5, 250 and 1000 mg/kg body weight [BW]/day). 17alpha-Ethinylestradiol (1mg/kg BW/day) was used as a positive control and corn oil as a vehicle. A high dose of methyl- and isopropylparaben (1000 mg/kg BW/day) resulted in a significant delay in the date of vaginal opening and a decrease in length of the estrous cycle. In measurements of organ weight and body weight, we observed significant weight changes in ovaries, adrenal glands, thyroid glands, liver, and kidneys; conversely, body weight was not altered following paraben treatment. The potential effects of parabens on estrogenicity were shown in histopathological abnormities in the reproductive organs. Histological analysis of the ovaries from the peripubertal rats revealed a decrease of corpora lutea, increase in the number of cystic follicles, and thinning of the follicular epithelium. In addition, morphological studies of the uterus revealed the myometrial hypertrophy by a high dose of propyl- and isopropylparaben (1000 mg/kg-day), and in all dose groups of butyl- and isobutylparabens. However, no significant histopathological changes were observed in the other organs (i.e. adrenal and thyroid glands). We also observed a significant decrease in serum estradiol and thyroxine concentrations in methyl-, ethyl-, propyl-, isopropyl-, and isobutylparaben-treated groups. A receptor-binding assay indicated that the relative binding affinities of parabens to estrogen receptors occurred in the order: isobutylparaben>butylparaben>isopropylparaben=propylparaben>ethylparaben. These values were much lower than the binding affinity for 17beta-estradiol. Taken together, long-term exposure to parabens, which show less estrogenic activity than estradiol, can produce suppressive effects on hormonal responsiveness and can disrupt the morphology of reproductive target tissues. In addition, the relation between thyroid weight and thyroid hormone may influence circulating levels of parabens, suggesting the effects of parabens as thyrotoxic during this critical stage of development in female rats.
The alkyl esters of p-hydroxybenzoic acid (parabens) are used widely as preservatives in foods, pharmaceuticals and cosmetics to which the human population is exposed. Recent studies have reported that methylparaben, ethylparaben, n-propylparaben and n-butylparaben all possess oestrogenic activity in several in vitro assays and in animal models in vivo. This study reports on the oestrogenic activity of isobutylparaben in a panel of assays in vitro and in vivo. Isobutylparaben was able to displace [(3)H]oestradiol from cytosolic oestrogen receptor alpha of MCF7 human breast cancer cells by 81% at 100 000-fold molar excess. Using a clonal line of MCF7 cells containing a stably transfected oestrogen-responsive ERE-CAT reporter gene, CAT gene expression could be increased by isobutylparaben such that the magnitude of the response was the same at 10(-5) M isobutylparaben as with 10(-8) M 17beta-oestradiol. Isobutylparaben could also increase expression of the endogenous oestrogen-responsive pS2 gene in MCF7 cells and maximal expression at 10(-5) M isobutylparaben could be inhibited with the anti-oestrogen ICI 182 780. The proliferation of two oestrogen-dependent human breast cancer cell lines MCF7 and ZR-75-1 could be increased with isobutylparaben such that at concentrations of 10(-5) M the proliferation response was of the same magnitude as with 10(-8) M 17beta-oestradiol. Evidence for oestrogen receptor mediation of proliferation effects was provided by the inability of isobutylparaben to influence the growth of oestrogen-unresponsive MDA-MB-231 human breast cancer cells and by the ability of the anti-oestrogen ICI 182 780 to inhibit the isobutylparaben effects on MCF7 cell growth. The proliferation response to 10(-10) M 17beta-oestradiol was not antagonized with isobutylparaben at any concentration from 10(-9) M to 10(-4) M in either MCF7 or ZR-75-1 cells. Finally, subcutaneous administration of isobutylparaben was able to increase the uterine weight in the immature mouse after three daily doses of 1.2 or 12.0 mg per mouse. Previous work using linear-alkyl-chain parabens has shown that oestrogenic activity increases with alkyl chain length from methylparaben to n-butylparaben. The results here show that branching of the alkyl chain to isobutylparaben increases oestrogenic activity beyond that of the equivalent length linear alkyl chain in n-butylparaben.
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