No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Some Alkyl Hydroxy Benzoate Preservatives (Parabens) Are Estrogenic
Abstract
The inadvertent estrogenicity of certain synthetic chemicals, and their subsequent effects on the endocrine system of humans and wildlife, is of concern. In this paper we report findings from in vitro and in vivo (uterotrophic) studies which confirm that a range of alkyl hydroxy benzoate preservatives (parabens) are weakly estrogenic. In a receptor-binding assay, butylparaben was able to compete with 3H-estradiol for binding to the rat estrogen receptor with an affinity approximately 5 orders of magnitude lower than that of diethylstilboestrol, and between 1 and 2 orders of magnitude less than nonylphenol. In an in vitro yeast-based estrogen assay, the four most widely used parabens (namely methyl-, ethyl-, propyl-, and butylparaben) were all found to be weakly estrogenic with the most potent (butylparaben) being 10,000-fold less potent than 17 beta-estradiol. The estrogenic activity of parabens was inhibited by 4-hydroxy tamoxifen in vitro, illustrating the requirement of these chemicals to interact with the estrogen receptor in order to activate the yeast. When administered orally to immature rats, the parabens were inactive. However, subcutaneous administration of butylparaben produced a positive uterotrophic response in vivo, although it was approximately 100,000 times less potent than 17 beta-estradiol. Given their use in a wide range of commercially available topical preparations, it is suggested that the safety in use of these chemicals should be reassessed, with particular attention being paid to estimation of the actual levels of systemic exposure of humans exposed to these chemicals. The acquisition of such data is a prerequisite to the derivation of reliable estimates of the possible human risk of exposure to parabens.
... Parabens, similar to other endocrine disrupting chemicals (EDCs), mimic the properties of the main natural estrogen when bound to estrogen receptors (ERs) [19] . Routledge et al. (1998) were the first to report that the effect of the estrogenic activity of parabens is inhibited by 4-hydroxy tamoxifen [20] . ...
... Parabens, similar to other endocrine disrupting chemicals (EDCs), mimic the properties of the main natural estrogen when bound to estrogen receptors (ERs) [19] . Routledge et al. (1998) were the first to report that the effect of the estrogenic activity of parabens is inhibited by 4-hydroxy tamoxifen [20] . ...
... The relationship between MePB and the risk factor ER+ in this study is consistent with previous results that E+ breast cancer models exhibiting MePB had an increase in the gene expression of mammary stem cells, resulting in cancer cell resistance to chemotherapy [24,37,38] . In addition to the interaction of parabens with ER and PR receptors [19] , Pan et al found that HER ligands increase the potency of BuPB to stimulate oncogene expression and breast cancer cell proliferation in vitro by ERα [39] . ...
... Parabens, similar to other endocrine disrupting chemicals (EDCs), mimic the properties of the main natural estrogen when bound to estrogen receptors (ERs) [19] . Routledge et al. (1998) were the first to report that the effect of the estrogenic activity of parabens is inhibited by 4-hydroxy tamoxifen [20] . ...
... Parabens, similar to other endocrine disrupting chemicals (EDCs), mimic the properties of the main natural estrogen when bound to estrogen receptors (ERs) [19] . Routledge et al. (1998) were the first to report that the effect of the estrogenic activity of parabens is inhibited by 4-hydroxy tamoxifen [20] . ...
... The relationship between MePB and the risk factor ER+ in this study is consistent with previous results that E+ breast cancer models exhibiting MePB had an increase in the gene expression of mammary stem cells, resulting in cancer cell resistance to chemotherapy [24,37,38] . In addition to the interaction of parabens with ER and PR receptors [19] , Pan et al found that HER ligands increase the potency of BuPB to stimulate oncogene expression and breast cancer cell proliferation in vitro by ERα [39] . ...
... The selection of preservatives depends on their availability, cost, and performance. Artificial preservatives are now used globally to ensure the quality of food products (Routledge et al. 1998;Xiu-Qin et al. 2008). Currently, synthetic additives like sorbic acid, propanoic acid, benzoic acid, dehydroacetic acid and their salts, calcium (sodium), ethylparaben, methylparaben, butylparaben, propylparaben, isobutylparaben, heptylparaben, isopropylparaben, potassium sorbate, sodium benzoate, sulfur dioxide, and potassium metabisulfite are allowed in food products (Table 3) (Routledge et al. 1998;Xiu-Qin et al. 2008;Khan et al. 2014). ...
... Artificial preservatives are now used globally to ensure the quality of food products (Routledge et al. 1998;Xiu-Qin et al. 2008). Currently, synthetic additives like sorbic acid, propanoic acid, benzoic acid, dehydroacetic acid and their salts, calcium (sodium), ethylparaben, methylparaben, butylparaben, propylparaben, isobutylparaben, heptylparaben, isopropylparaben, potassium sorbate, sodium benzoate, sulfur dioxide, and potassium metabisulfite are allowed in food products (Table 3) (Routledge et al. 1998;Xiu-Qin et al. 2008;Khan et al. 2014). Some articles inform that the extensive use of food preservatives increases the probability of health hazards. ...
... Many stabilizers might be detrimental to consumers and cause allergic contact dermatitis. In vivo and in vitro assays in current studies have testified to the estrogenic activity of ethylparaben, butylparaben, methylparaben, and propylparaben and recommended that the paraben's safety must be readdressed (Routledge et al. 1998;Xiu-Qin et al. 2008). This research showed that butylparaben and propylparaben affect the function of the male reproductive system as well as the secretion of testosterone by exerting a weak estrogenic activity, whereas parabens in food products can cause the growth of breast cancer (Oishi 2002;Darbre et al. 2002Darbre et al. , 2003Darbre et al. , 2004Xiu-Qin et al. 2008 ...
Fruits are natural, healthy, economically feasible, ready to eat, and provide essential nutrients such as vitamins and minerals, making them a fascinating food. Deterioration of fruits during transportation can cause food security concerns and financial losses. Globally, about 45% of horticultural crops are spoiled and wasted for numerous reasons, such as environmental contamination during growth, harvesting under unsuitable conditions, and improper storage, handling, and display. There are three groups of factors affecting the spoilage of food: physical, chemical, and microbial, which damage the size, color, taste, and texture of fruits. Conventional methods of preserving food products comprise chemical preservation , freezing, drying, and pasteurization, which can result in the loss of nutrients and the addition of unwanted chemicals produced during processing. Therefore, "green" technology is required to preserve fresh produce, which protects and enhances nutritional value in equal measure. This review will present emerging trends and advancements in the biopreservation of fruits, such as lactic acid bacteria, essential oils, herbal extracts, nanoparticles, microcapsules, edible films and coatings, bacteriocins, and bacterio-phages. These biopreservative techniques should be easy, inexpensive, eco-friendly, and generally recognized as safe (GRAS) by the World Health Organization (WHO).
... The selection of preservatives depends on their availability, cost, and performance. Artificial preservatives are now used globally to ensure the quality of food products (Routledge et al. 1998;Xiu-Qin et al. 2008). Currently, synthetic additives like sorbic acid, propanoic acid, benzoic acid, dehydroacetic acid and their salts, calcium (sodium), ethylparaben, methylparaben, butylparaben, propylparaben, isobutylparaben, heptylparaben, isopropylparaben, potassium sorbate, sodium benzoate, sulfur dioxide, and potassium metabisulfite are allowed in food products (Table 3) (Routledge et al. 1998;Xiu-Qin et al. 2008;Khan et al. 2014). ...
... Artificial preservatives are now used globally to ensure the quality of food products (Routledge et al. 1998;Xiu-Qin et al. 2008). Currently, synthetic additives like sorbic acid, propanoic acid, benzoic acid, dehydroacetic acid and their salts, calcium (sodium), ethylparaben, methylparaben, butylparaben, propylparaben, isobutylparaben, heptylparaben, isopropylparaben, potassium sorbate, sodium benzoate, sulfur dioxide, and potassium metabisulfite are allowed in food products (Table 3) (Routledge et al. 1998;Xiu-Qin et al. 2008;Khan et al. 2014). Some articles inform that the extensive use of food preservatives increases the probability of health hazards. ...
... Many stabilizers might be detrimental to consumers and cause allergic contact dermatitis. In vivo and in vitro assays in current studies have testified to the estrogenic activity of ethylparaben, butylparaben, methylparaben, and propylparaben and recommended that the paraben's safety must be readdressed (Routledge et al. 1998;Xiu-Qin et al. 2008). This research showed that butylparaben and propylparaben affect the function of the male reproductive system as well as the secretion of testosterone by exerting a weak estrogenic activity, whereas parabens in food products can cause the growth of breast cancer (Oishi 2002;Darbre et al. 2002Darbre et al. , 2003Darbre et al. , 2004Xiu-Qin et al. 2008 ...
Fruits are natural, healthy, economically feasible, ready to eat, and provide essential nutrients such as vitamins and minerals, making them a fascinating food. Deterioration of fruits during transportation can cause food security concerns and financial losses. Globally, about 45% of horticultural crops are spoiled and wasted for numerous reasons, such as environmental contamination during growth, harvesting under unsuitable conditions, and improper storage, handling, and display. There are three groups of factors affecting the spoilage of food: physical, chemical, and microbial, which damage the size, color, taste, and texture of fruits. Conventional methods of preserving food products comprise chemical preservation, freezing, drying, and pasteurization, which can result in the loss of nutrients and the addition of unwanted chemicals produced during processing. Therefore, “green” technology is required to preserve fresh produce, which protects and enhances nutritional value in equal measure. This review will present emerging trends and advancements in the biopreservation of fruits, such as lactic acid bacteria, essential oils, herbal extracts, nanoparticles, microcapsules, edible films and coatings, bacteriocins, and bacteriophages. These biopreservative techniques should be easy, inexpensive, eco-friendly, and generally recognized as safe (GRAS) by the World Health Organization (WHO).
... The pathway enrichment analysis, together with the cMAP results indicate that the parabens, particularly at high concentrations, might have the ability to impact the estrogen pathway by modifying the expression of genes associated with this pathway, and thus potentially could modify the estrogenic response. The results are consistent with previous reports indicating that MP, EP, PP and BP have a weak estrogenic activity in vitro (Routledge et al., 1998) as well as in vivo (Routledge et al., 1998;Hossani et al., 2000;Lemini et al., 2003;Lemini et al., 2004). The results from an in vivo assay established as a reliable method to determine estrogenic activity for chemicals of concern, the rat uterotrophic assay, indicate that at the most MP, EP and BP have a weak estrogenic activity in vivo (Routledge et al., 1998;Hossaini et al., 2000;Lemini et al., 2004); TABLE 4 (Continued) Pathway enrichment analysis using the transcriptional profile identified in the cardiomyocytes exposed to CA or TP at 1,000 μM individually A) or by both CA and TP B). ...
... The pathway enrichment analysis, together with the cMAP results indicate that the parabens, particularly at high concentrations, might have the ability to impact the estrogen pathway by modifying the expression of genes associated with this pathway, and thus potentially could modify the estrogenic response. The results are consistent with previous reports indicating that MP, EP, PP and BP have a weak estrogenic activity in vitro (Routledge et al., 1998) as well as in vivo (Routledge et al., 1998;Hossani et al., 2000;Lemini et al., 2003;Lemini et al., 2004). The results from an in vivo assay established as a reliable method to determine estrogenic activity for chemicals of concern, the rat uterotrophic assay, indicate that at the most MP, EP and BP have a weak estrogenic activity in vivo (Routledge et al., 1998;Hossaini et al., 2000;Lemini et al., 2004); TABLE 4 (Continued) Pathway enrichment analysis using the transcriptional profile identified in the cardiomyocytes exposed to CA or TP at 1,000 μM individually A) or by both CA and TP B). ...
... The results are consistent with previous reports indicating that MP, EP, PP and BP have a weak estrogenic activity in vitro (Routledge et al., 1998) as well as in vivo (Routledge et al., 1998;Hossani et al., 2000;Lemini et al., 2003;Lemini et al., 2004). The results from an in vivo assay established as a reliable method to determine estrogenic activity for chemicals of concern, the rat uterotrophic assay, indicate that at the most MP, EP and BP have a weak estrogenic activity in vivo (Routledge et al., 1998;Hossaini et al., 2000;Lemini et al., 2004); TABLE 4 (Continued) Pathway enrichment analysis using the transcriptional profile identified in the cardiomyocytes exposed to CA or TP at 1,000 μM individually A) or by both CA and TP B). For this analysis the Molecular Signatures Database (MSigDB v7.5.1) was utilized, and only the top enriched gene sets identified with the up-regulated or down-regulated genes (FDR <0.05, and fold change of 1.2 >) either for CA or TP, individually or by both CA and TP (common genes affected in the same directions) are shown in the tables. ...
The objective of this work was to use transcriptional profiling to assess the biological activity of structurally related chemicals to define their biological similarity and with that, substantiate the validity of a read-across approach usable in risk assessment. Two case studies are presented, one with 4 short alkyl chain parabens: methyl (MP), ethyl (EP), butyl (BP), and propylparaben (PP), as well as their main metabolite, p-hydroxybenzoic acid (pHBA) with the assumption that propylparaben was the target chemical; and a second one with caffeine and its main metabolites theophylline, theobromine and paraxanthine where CA was the target chemical. The comprehensive transcriptional response of MCF7, HepG2, A549 and ICell cardiomyocytes was evaluated (TempO-Seq) after exposure to vehicle-control, each paraben or pHBA, CA or its metabolites, at 3 non-cytotoxic concentrations, for 6 h. Differentially expressed genes (FDR ≥0.05, and fold change ±1.2≥) were identified for each chemical, at each concentration, and used to determine similarities. Each of the chemicals is able to elicit changes in the expression of a number of genes, as compared to controls. Importantly, the transcriptional profile elicited by each of the parabens shares a high degree of similarity across the group. The highest number of genes commonly affected was between butylparaben and PP. The transcriptional profile of the parabens is similar to the one elicited by estrogen receptor agonists, with BP being the closest structural and biological analogue for PP. In the CA case, the transcriptional profile elicited of all four methylxanthines had a high degree of similarity across the cell types, with CA and theophylline being the most active. The most robust response was obtained in the cardiomyocytes with the highest transcriptional profile similarity between CA and TP. The transcriptional profile of the methylxanthines is similar to the one elicited by inhibitors of phosphatidylinositol 3-kinase as well as other kinase inhibitors. Overall, our results support the approach of incorporating transcriptional profiling in well-designed in vitro tests as one robust stream of data to support biological similarity driven read-across procedures and strengthening the traditional structure-based approaches useful in risk assessment.
... Propylparabens 30,000-fold less potent than 17β-estradiol. Routledge et al. 1998Miller et al 2001SCCS/1623 Final Opinion Opinion on Propylparaben ___________________________________________________________________________________________ The metabolite p-HBA, was 2.5 million-fold less potent as is considered non-estrogenic. Assaying estrogen-receptor (ER)-dependent proliferation of MCF-7 cells PP stimulated the proliferation to about the same level as the maximal cell yield attained with 3x10(-11) M 17β-estradiol, but at a concentration in the order of 10 5 to 10 7 higher than 17βestradiol. ...
... A study by Routledge et al (1998) showed early indications that parabens could be weakly estrogenic, finding propylparaben to be 30,000-fold less potent than 17β-estradiol in interacting with the ER in an in vitro recombinant yeast assay incorporating human estrogen receptor (ER). Subsequent in vitro studies suggested that propylparaben could be weakly estrogenic, because propylparaben: • binds with estrogen receptors (rat and/or human ERα and ERβ) (Blair et al., 2000;Watanabe et al 2013;Zhang et al 2013); ...
... • promotes human cancer cell proliferation in vitro (Okubo et al., 2001;Byford et al., 2002;Terasaka et al 2006;van Meeuwen et al 2008;Vo et al 2011;Marchese & Silva, 2012;Wrobel and Gregoraszczuk, 2013, 2014a, 2014bKlopcic et al 2015;Kolsek et al 2015); • induces ER reporter gene expression (Routledge et al., 1998;Miller et al., 2001;Watanabe et al., 2013;Bazin et al., 2013). In estrogen receptor (ER) competitive binding assays using the human MCF-7 breast cancer cell line and isolated ER from rat uteri, propylparaben showed a weak ER binding affinity with IC50 values of 1.65 -245 µM (Okubo et al., 2001;Byford et al., 2002;Blair et al., 2000;Vo et al., 2010). ...
SCCS OPINION ON Propylparaben - SCCS/1623/20 - Final Opinion
U. Bernauer, L. Bodin, Q. Chaudhry, P.J. Coenraads, M. Dusinska, J. Ezendam, E. Gaffet, C. L. Galli, B. Granum, E. Panteri, V. Rogiers, Ch. Rousselle, M. Stepnik, T. Vanhaecke, S. Wijnhoven, A. Koutsodimou, A. Simonnard, W. Uter, N. von Goetz
The SCCS adopted this document at its plenary meeting on 30-31 March 2021 (58 pages)
Published: 17 August 2022
Ed. Publications Office of the European Union, Luxembourg, Luxembourg (58 pages)
ISSN : 1831-4767
ISBN : 978-92-76-54756-3
DOI : https://data.europa.eu/doi/10.2875/607198
Catalog Number : EW-AQ-22-006-EN-N
https://op.europa.eu/fr/publication-detail/-/publication/4c6effa0-21c5-11ed-8fa0-01aa75ed71a1
https://op.europa.eu/fr/publication-detail/-/publication/4c6effa0-21c5-11ed-8fa0-01aa75ed71a1/language-en/format-PDF/source-264497172
... Parabens (PBs), an important group of EDCs, could bind to estrogenic receptors (ER), causing a series of adverse health effects. For instance, the exposure to PBs was related to the cancer incidence, even at negligible concentration [8][9][10]. PBs are mainly used in food additives, pharmaceuticals and personal care products as the most common typical preservative at present [2,11]. ...
... p-hydroxybenzoic acid (PHBA), as the common transformation product of parabens, is detected during the photo-driven transformation of PBs in laboratory experiments and in real environmental samples [21]. The estrogenic activity of PHBA was lower than the parent compound or even no estrogenic effect [10]. However, our previous study reported that the estrogenic activity increased during the EPB photolysis, and that a new transformation product, ethyl 4-hydroxy-3-(2-((4-hydroxybenzoyl) oxy) ethyl (hereinafter, dimer), had a higher estrogen effect compared with the parent compound [20]. ...
The environmental transformation and health effects of endocrine disruptors (EDCs) need urgent attention, particularly the formation of transformation products with higher toxicity than parent EDCs. In this paper, an important transformation product dimer (short for ethyl 4-hydroxy-3-(2-((4-hydroxybenzoyl) oxy) ethyl) benzoate) with estrogenic activity was investigated and detected in the photolysis of preservative ethyl-paraben (EPB) dissolved in actual water. The environmental factors, such as the higher initial concentration of EPB, the stronger optical power and the lower pH could stimulate the formation of the dimer. Simultaneously, the interaction of multiple environmental factors was significant, especially the initial concentration and pH using the response surface methodology. Furthermore, the relationship between the environmental factors and the formation of the product dimer was further explained and the empirical model equation was built for predicting the amount of dimer in actual water. Quantum chemical and toxicological calculations showed the estrogenic effect mechanism of the product dimer and it was revealed further that the hydrogen bonds of the dimer and ERα proteins (ARG-394, Glu-353, His-524, GYY-521) were formed, with a lowest binding energy of −8.38 Kcal/mol during molecular docking. In addition, the health effect risk of the product dimer was higher than the parent compound in the blood, cardiovascular system, gastrointestinal system, kidney and liver. In short, the present study was of great significance for the transformation product in pollution control and health effects in the photolysis of EDCs.
... Parabens' mechanism of estrogenic action in mammals is via binding and activating estrogen receptors alpha (ERα) and beta (ERβ) [3,33,43,51]. Their estrogenic activity increases with the increase of alkyl chain lengths [49,52,9]. In 2011, the Scientific Committee on Consumer Safety (SCCS) reported that methyl paraben and ethyl paraben are safe in cosmetic products at a concentration up to 0.4% for single paraben or 0.8% for their mixtures, whereas, the sum of the individual concentration of propyl paraben and butyl paraben was recognized as safe in cosmetic products at a concentration up to 0.19% [13]. ...
... The results of the present study were in agreement with the findings of Smith et al. [51] and Jurewicz et al. [25,24] who reported that a higher concentration of urinary PrP was associated with a higher serum concentration of FSH. An identical relationship between PrP and diminished ovarian reserve in both human and animal data represents the estrogenicity of parabens and, therefore, a greater potential of PrP for re-productive toxicity compared to MeP [49,52,9]. As described in Table 6, the EDI sum of MeP and EtP (0.90 +1.49) was 2.39 mg/kg.bw/day ...
Parabens are antimicrobial preservatives in a variety of processed foods and beverages, cosmetics, pharmaceuticals, and personal care products. Parabens may be associated with reproductive and endocrine disorders among women of reproductive age. The first objective of this study was to examine the association between urinary parabens concentrations and follicle-stimulating hormone(FSH), luteinizing hormone (LH), and prolactin disorders. The second objective of this study was to calculate the Hazard Quotient (HQ) and Margin of Exposure (MOE) to assess the potential risk for endocrine disrupts for each woman based on urinary paraben concentrations. To address these two objectives, a cross-sectional study was designed in the Imam Reza Hospital in Kermanshah. The association between early morning urinary paraben concentrations and the serum of fasting blood specimens was analyzed using multivariable linear regressions adjusted for confounding variables (i.e., creatinine, age, body mass index, and time spent on physical activity). Among the 96 women who participated in the study, those with BMI> 25 and aged 18–40 years showed higher levels of total urinary parabens. The highest sum of urinary parabens (54,955.16 µg/L) was observed among the women who were using toothpaste several times per day. Almost all the parabens such as methyl paraben(MeP), ethyl paraben(EtP), propyl paraben(PrP), butyl paraben(BuP) had a positive and negative significant association with serum concentrations of FSH and LH (p-value < 0.05). However, no significant association was found between any of the four parabens and serum prolactin hormone (p-value > 0.05). The Margin of Exposure (MOE) approach calculated for all parabens (
... PBs have endocrine disrupting activity, particularly estrogenic and antiandrogenic activity [18,19]. There is signi cant evidence from animal studies showing that PBs reduced sperm quality through estrogenic activity [20][21][22][23][24]. ...
... For example, PBs did not inhibit P. aeruginosa (G−) or E. coli (G−), but did inhibit S. aureus (G+) [45]. Although PBs have estrogenic activity [19], the estrogen receptor alpha binding properties decreased and antimicrobial properties of PBs were enhanced through a 3,5-substitution (the antimicrobial activity to G + S. aureus also increased 16-fold) [46]. This suggests that such structural features enable PBs to have dual biological effects on both antibacterial and estrogenic activity. ...
Background
The decline of human sperm quality has caused great concern. Whether exposure to parabens and the intestinal endotoxin (IE) they induce are related to sperm quality is a challenging scientific question.
Results
We measured seminal methyl-(MeP), ethyl-(EtP), propyl-(PrP), and butyl-(BuP) parabens, their metabolites PHBA and 3,4-DHB, semen parameters, and blood IE (lipopolysaccharide, LPS) of 315 healthy men. Bivariate correlation and multiple linear regression were used to evaluate their interrelationships. For the first time, we found that MeP, EtP, PrP, BuP, PHBA, and 3,4-DHB in semen were negatively correlated with sperm parameters (r = − 0.184 to − 0.438), with EtP showing the strongest correlation. LPS was detected in all plasma samples (0.021–0.195 EU/mL) and negatively correlated with sperm concentration and total sperm count with R² = 0.295 and R² = 0.236, respectively, when LPS was higher than 0.104 EU/mL. LPS was positively correlated with EtP and BuP.
Conclusion
We concluded that seminal parabens affected sperm quality possibly due to estrogenic activity. Parabens likely promote intestinal endotoxemia and affect sperm quality in healthy people by altering the composition of gut microbiota through antimicrobial activity. The finding that parabens exert dual toxicological effects on sperm quality provides novel insights for future research.
... As preservatives, parabens can be used because of their distinctive biological and physicochemical properties (e.g., neutral pH, lack of taste or smell, resistance to hydrolysis, persistence in air, and antibacterial activity) (Ito et al. 2015;Seidi et al. 2019). It is now categorized as one of the emerging contaminants due to its endocrine disrupting properties (Routledge et al. 1998). It is suspected to cause many life threatening disorders (e.g., breast cancer, detrimental reproductive functions, hypothyroidism in neonatal babies, pediatric respiratory disorders, adipocyte differentiation, and skin diseases) (Dubey et al. 2017;Nowak et al. 2018). ...
A new method is developed for the simultaneous detection and extraction of parabens, including methyl paraben (MP), ethyl paraben (EP), propyl paraben (PP), and butyl paraben (BP), based on magnetic graphene oxide carbon dot nanocomposites (Fe3O4@GO@CD). Fe3O4@GO@CD has been synthesized using one pot hydrothermal method by intercalating iron oxide and carbon dots between the layers of graphene oxide. Fe3O4@GO@CD was applied as the magnetic solid phase sorbent for the simultaneous extraction and detection of parabens from water (tap and river water) and cosmetic samples (hair serum and sunscreen cream). MP was measured at concentration of 0.25–0.26 ng/mL in hair serum, while PP at 0.32–0.33 ng/mL in sunscreen cream. Notably, good recoveries (88.74–98.03%; RSD = 2.31–6.88%) for river and tap water with detection limit of 0.039–0.046 ng/mL were attained. The method has good cyclability up to 16 cycles and was highly repeatable. All these findings suggest that the Fe3O4@GO@CD would be potential sorbent for the analysis of parabens.
Graphical Abstract
... Antimicrobial disinfectants and pesticides, such as triclosan, were detected in human breast milk [118]. Alkylphenol ethoxylates (household detergents), which break down into nonylphenols and parabens (antimicrobial preservatives), have been reported to possess estrogenic activity [119,120]. ...
... 24 Marketing of paraben-free formulations is popular due to public perception of the potential disruption of endocrine function, though this is not corroborated. 25 Formaldehyde Formaldehyde is a well-established irritant, allergen, and carcinogen. Although pure formaldehyde is not permitted to be incorporated into cosmetic formulations, concentrations of up to 2000 ppm are allowed in final products. ...
The incidence of allergic contact dermatitis (ACD) due to personal care products is rising in parallel with increasing product availability and consumer interest. Hair products specifically represent a significant source of potential allergens, including preservatives, surfactants, emulsifiers, fragrances, adhesives, and dyes. ACD due to hair care products can present as dermatitis in the distinctive "rinse-off" distribution, involving the neck, eyelids, and lateral face in addition to the scalp. Herein, the authors review ingredients in hair care products that can cause ACD and practical tips for allergen identification.
... As substâncias químicas conservantes, como os parabenos, em meados da década de 1920 já eram utilizadas em produtos farmacêuticos (ROUTLEDGE et al, 1998) e pela indústria de cosméticos, desde 1930de cosméticos, desde (SASSEVILLE, 2004, em razão da ação antimicrobiana, antibacteriana e antifúngica. ...
O presente artigo visa abordar a necessidade de regulação ambiental noBrasil, na formulação de cosméticos e produtos de higiene e cuidados pessoais (PCPs), com enfoque nos parabenos, conservantes antimicrobianos,utilizados na fabricação desses respectivos produtos. A presença dessassubstâncias na água ocasiona impactos ao meio ambiente aquático, comose apresenta nos estudos anteriores realizados, utilizando organismos vivos. Não há na legislação brasileira vedação expressa quanto ao uso dosparabenos, devendo ser observada a experiência legislativa internacional,como a proibição existente na União Européia. Objetiva-se, por meio dométodo dedutivo, utilizando pesquisa bibliográfica e documental, demonstrar a necessária observância do princípio da prevenção e da governança, com a cooperação das empresas que atuam no setor de produçãode PCPs, para o banimento dessas substâncias conservantes e adequadagestão dos recursos hídricos, frente à Agenda 2030, em especifico do ODS6, que tem como meta, melhorar a qualidade da água, reduzindo a poluição a proporção de águas residuais não tratadas e ODS 14, objetivando assegurar e preservar a vida aquática em prol da sustentabilidade global.
... As mentioned before, the uterotrophic responses of PrP are still in discussion [10,11]. The difference between the exposure routes has also been observed in many other independent studies [24,25]. The results of a previous study where Sprague-Dawley immature female rats were orally treated with PrP at doses of 62.5, 250, and 1,000 mg/kg, the uterotrophic responses were not observed are similar to our study results. ...
Recent studies reported bisphenol A (BPA) and propyl paraben (PrP) are found in human urine, blood, and breast milk samples as well as in food, packaging, socks, and clothes. This means that the two chemicals co-exist in consumer products, and humans are exposed simultaneously to the mixture chemicals. However, the studies on the mixture effects of the two chemicals on human health are not enough. This study was designed to elucidate the effects of orally administered PrP, BPA, and their mixture effects on the uterotrophic response using ovariectomized rats. In addition, the correlation between the uterotrophic response and tissue concentrations of the two chemicals was studied to investigate whether one chemical has any effect on the absorption, distribution, or excretion of the other chemical. Histopathology, hematology, and plasma biochemistry analysis were also performed to evaluate the chemicals’ toxicological effects in the treated rats. Although a significant increase in uterus weight (absolute and relative) was observed in the positive chemical (17β-estradiol) treated group, there were no statistical differences in the uterus weight between the vehicle control and the chemical-treated groups. However, a slight increase in the endometrial glands and a change in the cuboidal to columnar epithelium of the endometrial epithelium were observed in the mixture-treated group. There was no significant toxicity in all treated groups by the hematology and plasma biochemistry analysis results. The results of tissue distribution showed that BPA was mostly detected in the liver while PrP was not detected in most tissues, and the BPA level was higher when the rats were treated with PrP than without PrP, suggesting that PrP may increase the absorption of BPA after oral administration.
... After entering the body parabens quick absorption occurs in the gastrointestinal tract and blood (Darbre et al., 2004;Darbre et al., 2008;Soni et al., 2001). The osteogenic effect of paraben is not mysterious (Routledge et al., 1998). The effect has an association with female breast cancer incidence and the development of male reproductive system malignant melanoma (Tavares et al., 2009). ...
Plant-based hypoglycemic therapeutics have been increasing in consumption due to the escalation of type 2 diabetes and its related complications. However, the safety of the preparations is little understood. Parabens (alkyl esters of p-hydroxybenzoic acid) are widely used as preservatives in these pharmaceuticals. However, the presence of methylparaben in formulations raises anxiety due to its potential endocrine disruption functions. Endocrine disruption could lead to undesirable health abnormalities and carcinogenic, estrogenic, and adverse reproductive effects. The present investigation directs toward estimating of methylparaben in some anti-diabetic herbal preparations using UV- Vis spectrophotometric method abiding by International Conference on Harmonization (ICH) guidelines for validation. The analytical wavelength of methylparaben in methanol was determined and found at 256.5 nm. The method obeys Beer’s law in the analytical range and has a good coefficient of determination (r2= 0.9881). The limit of detection (LOD) and limit of quantification (LOQ) were 0.19 ppm and 0.57 ppm, respectively. Recoveries were 91.3-98.8% in analyte-free plant matrix and 91-105.8 % in a diluent. The coefficient of variation (CV%) varied between 0.005- 0.268% for different standards. Results of forty-eight anti-diabetic herbal preparations showed methylparaben was detected in thirty-four samples in the range of 13.12 – 325.13 mg/day with a mean exposure value of 78.25 mg/day. However, none of the samples raise concerns about safety (the safety ceiling for paraben is 420 mg/day). More investigation is required to determine, whether the herbal drugs are safe to consume in terms of methylparaben. J. Asiat. Soc. Bangladesh, Sci. 48(1-2): 41-52, June-December 2022
... Parabens exert estrogenic effects through ER that increase with the length and branching of the alkyl chain [55,58]. An increase in the size of the alkyl group may intensify paraben transactivation of ERs in vitro [59]. ...
Exposure to endocrine disrupting chemicals (EDCs) can result in alterations of the female reproductive system, including polycystic ovary syndrome (PCOS). The aim of this review was to summarize the knowledge about the association of EDCs (bisphenols, parabens, and triclosan) with PCOS. We conducted an electronic literature search using PubMed for studies published between January 2007 and October 2022 on EDCs related to PCOS, and evaluated the association of PCOS with bisphenols, parabens and triclosan in 15 articles. Most studies revealed significantly higher plasma, urinary or follicular fluid levels of bisphenol A (BPA) in women with PCOS, and some showed a positive correlation of BPA with insulin resistance, polycystic morphology on ultrasound, hepatic steatosis, bilirubin levels, as well as free androgen index, androstenedione and testosterone serum levels, and markers of low-grade chronic inflammation. There was a negative correlation of BPA with markers of ovarian reserve, sex hormone binding globulin and vitamin D–binding protein. Parabens and triclosan have been studied in only one study each, with no significant associations with PCOS observed. Our review revealed an association of BPA with PCOS and negative effects of BPA on human ovaries; more research is needed to assess the potential associations of parabens and triclosan with PCOS.
... 1,2 However recent studies have shown the affinity of parabens for binding to the estrogen. 3,4 Their estrogenic effect was assumed to be able to cause breast cancer. 5,6 In addition, some negative impacts on the male reproductive system were reported. ...
... In last two decades, especially their estrogenic activities were intensively examined [5], although their activity is several orders of magnitude smaller than that of estrogen [6]. The aquatic toxicity of parabens was examined on fishes, daphnia and algae, and was found lower for esters with a shorter alkyl chain length [7]. ...
The methyl ester of p-hydroxybenzoic acid (methylparaben, MP) is commonly used as a preservative in cosmetics, food and pharmaceuticals. Its widely examined interactions with aqueous system and human organisms prove a necessity of the monitoring of its release to natural environment and the efficiency of its removal from waters and wastewaters.
In this work, the yield of MP decomposition in aqueous solutions by gamma-radiation was investigated under oxidative conditions. The LC/MS, GC/MS and ion-chromatography were employed for examination of the yield of MP decomposition in function of the absorbed dose of radiation and for identification of stable products derived from MP formed during radiolysis prior to its complete mineralization. The studies were carried out in aerated aqueous solutions and under conditions with the predominance of OH radicals. The mechanisms of radical reactions were proposed leading to formation of the identified stable products. The irradiation of aerated MP solutions was assumed as a more favorable condition in terms of the yield of MP decomposition and a lack of changes of cytotoxicity towards 3 human cell lines was found. Under such conditions a 90% decomposition of MP at initial concentration 0.5 mg L⁻¹ was observed for 100 Gy absorbed dose, which for the employed ⁶⁰Co γ -source took 3.3 min. This provides a much better efficiency of MP decomposition in comparison to most of developed AOPs for this purpose.
... However, at the 67th Joint FAO/WHO Expert Meeting on Food Additives (JECFA), parabens were reported to have a weak estrogenic eff ect in in vitro test systems. It is estimated that the longer the alkyl chain of the paraben, the greater its endocrine-disrupting effect as well as its effect on reproductive function (Harvey and Darbre, 2004;Oishi, 2001 ;Okubo et al ., 2001 ;Routledge et al ., 1998 ). Moreover, parabens are percutaneously absorbed; therefore, personal care products (PCPs) must be considered in addition to food products ( Soni et al ., 2005 ). ...
In recent years, paraoxybenzoic acid esters (parabens) have been used in pharmaceuticals, cosmetics, and food additives. Parabens have been reported to have a weak estrogenic effect in in vitro test systems, and it is presumed that the longer the alkyl chain of the paraben, the greater its endocrine-disrupting and reproductive function effects. However, the effects of parabens on human health are still unclear. In this study, we evaluated the effects of six parabens (methyl p-hydroxybenzoate [MP], ethyl p-hydroxybenzoate [EP], propyl p-hydroxybenzoate [PP], isopropyl p-hydroxybenzoate [IPP], butyl p-hydroxybenzoate [BP], and isobutyl p-hydroxybenzoate [IBP]) on the reproductive function of the model organism Caenorhabditis elegans. We used 25, 50, and 100 µg/mL solutions of parabens in 0.1% dimethyl sulfoxide (DMSO). Bioassays (growth and maturation effect tests and reproduction effect tests) were performed on L1 larvae of wild-type C. elegans. In the growth effects test, all parabens were observed to have no effect. In the maturation effects test, there was a significant decrease in maturity at each concentration of five of the six parabens, with the exception being MP. In the reproduction effects test, a significant decrease in the number of lifetime offspring was observed at each concentration of five of the six parabens, with the exception being EP. This decrease was remarkable with PP, which has been reported to adversely affect reproductive function in rats. It is necessary to continue to focus on the estrogen-like action of parabens, including PP, and perform genetic analyses, such as RNA sequencing.
... additive modifier in plastic products and food packaging materials), which can mimic estrogen-like activity after exposure (Valcárcel et al., 2018). The estrogenic effects of butylparaben, widely used as a food additive and in cosmetics preservation, has also been reported in the literature, although its estrogenic potency are 10,000-fold lower compared to 17β-estradiol (Routledge et al., 1998). ...
An effect-directed analysis (EDA) approach was used to identify the compounds responsible for endocrine disruption in a hospital effluent (Basque Country). In order to facilitate the identification of the potentially toxic substances, a sample was collected using an automated onsite large volume solid phase extraction (LV-SPE) system. Then, it was fractionated with a two-step orthogonal chromatographic separation and tested for estrogenic effects with a recombinant yeast (A-YES) in-vitro bioassay. The fractionation method was optimized and validated for 184 compounds, and its application to the hospital effluent sample allowed reducing the number of unknowns from 292 in the raw sample to 35 after suspect analysis of the bioactive fractions. Among those, 7 of them were confirmed with chemical standards. In addition, target analysis of the raw sample confirmed the presence of mestranol, estrone and dodemorph in the fractions showing estrogenic activity. Predictive estrogenic activity modelling using quantitative structure-activity relationships indicated that the hormones mestranol (5840 ng/L) and estrone (128 ng/L), the plasticiser bisphenol A (9219 ng/L) and the preservative butylparaben (1224 ng/L) were the main contributors of the potential toxicity. Derived bioanalytical equivalents (BEQs) pointed mestranol and estrone as the main contributors (56 % and 43 %, respectively) of the 50 % of the sample's explained total estrogenic activity.
... In last two decades, especially their estrogenic activities were intensively examined [5], although their activity is several orders of magnitude smaller than that of estrogen [6]. The aquatic toxicity of parabens was examined on fishes, daphnia and algae, and was found lower for esters with a shorter alkyl chain length [7]. ...
... Recently, triclosan and triclocarban have gained attention because they have been considered to be an endocrine disruptor, which is capable of influencing reproductive functions [29,30]. These compounds are also considered to be emerging endocrine disruptors, which have the potential to cause health-related issues such as immune dysfunction, affect human reproductive outcomes [10,31,32], and are toxic to aquatic organisms such as algae, fish, and invertebrates [33][34][35]. ...
Triclosan (TCS) and triclocarban (TCC) are antimicrobial agents that have been used in personal care and consumer products in the past decades. In this study, influent, effluent, and sludge samples collected in selected wastewater treatment plants across the Durban metropolis were qualitatively and quantitatively investigated. It was revealed that the concentration of TCS ranged from 1.906 to 73.462 µg/L, from 1.732 to 6.980 µg/L, and from 0.138 to 2.455 µg/kg in influent, effluent, and sludge samples, respectively. The concentrations of TCC were found to be between 0.320 and 45.261 µg/L, <LOQ–1.103 µg/L, and from 0.107 to 8.827 µg/kg in the influent, effluent, and sludge samples, respectively. Higher concentrations of TCS as compared with TCC were observed in the aqueous samples. However, the concentrations of TCC in the sludge samples were significantly higher than the level of TCS. More water solubility of TCS could be responsible for the observed trend in the influent and effluent samples, while the trend observed in the sludge could be due to the more hydrophobicity character of TCC. The results of this study indicated that substantial amounts of TCS and TCC are been removed during the treatment process which could be a major reason for the decline in the levels recorded in the effluent samples, therefore, reducing the amount of the TCS and TCC that would eventually end up in the surface rivers. Qualitative analyses of the samples indicated the presence of caffeine, tert-butylhydroquinone, chloroxylenol, phenol, 4-(1,1,3,3-tetramethyl butyl), and dimethyl-bisphenol A. Further investigative ecological risk assessment studies are crucial due to the potential threat the contaminants may pose to aquatic lives and humans.
... According to Shao et al. (2019)'s findings, the different micropollutants as BPA, diuron, diclofenac, CBZ, and TCS, caused the mortality of Zebrafish embryos. Preservatives such as parabens cause weak estrogenic activity (Routledge et al., 1998). Inhibition of algae growth was detected for TCS and triclocarban (Yang et al., 2008). ...
Various emerging organic micropollutants, such as pharmaceuticals, have attracted the interest of the water industry during the last two decades due to their insufficient removal during conventional water and wastewater treatment methods and increasing demand for pharmaceuticals projected to climate change-related impacts and COVID-19, nanosorbents such as carbon nanotubes (CNTs), graphene oxides (GOs), and metallic organic frameworks (MOFs) have recently been extensively explored regarding their potential environmental applications. Due to their unique physicochemical features, the use of these nanoadsorbents for organic micropollutans in water and wastewater treatment processes has been a rapidly growing topic of research in recent literature. Adsorptive membranes, which include these nanosorbents, combine the benefits of adsorption with membrane separation, allowing for high flow rates and faster adsorption/desorption rates, and have received a lot of publicity in recent years. The most recent advances in the fabrication of adsorptive membranes (including homogeneous membranes, mixed matrix membranes, and composite membranes), as well as their basic principles and applications in water and wastewater treatment, are discussed in this review. This paper covers ten years, from 2011 to 2021, and examines over 100 published studies, highlighting that micropollutans can pose a serious threat to surface water environments and that adsorptive membranes are promising, particularly in the adsorption of trace substances with fast kinetics. Membrane fouling, on the other hand, should be given more attention in future studies due to the high costs and restricted reusability.
... The detection of parabens, specifically in human breast cancer tissue, moreover implied their potential to drive the sustained proliferation of breast epithelial cells that possess estrogen receptors (ER), specifically the estrogen receptor alpha (ERα). [5][6][7][8] The estrogenic activity of parabens has been described in correspondence to the binding affinity for ER (relevant binding affinity [RBA]) rather than their dose-dependent effects on the ER +ve cells. ...
Methyl paraben (MP) is an endocrine-disrupting compound that possesses es-trogenic properties and contributes to an aberrant burden of estrogen signaling in the human breast and subsequently increasing the risks for the development of breast cancer. The exact exposure, as well as the safe concentrations, are variable among daily products. The present study addresses the effects of exposure to escalated concentrations of MP on the proliferation of MCF-7 breast cancer cells in addition to exploring its other mechanisms of action. The study involved exposure of cultured MCF-7 breast cancer cells to seven MP concentrations, ranging from 40 to 800 µM for 5 days. Cell viability, apoptosis, and proliferation were respectively assessed using crystal violet test, flow cytometric analysis, and quantitative real-time polymerase chain reaction for Ki-67 expression. The estradiol (E2) secretion and oxidative stress were also assessed and analyzed in correlation to MP's proliferation and cytotoxicity potentials. The results showed that the maximum proliferative concentration of MP was 800 µM. At a concentration of 40 μM and higher, MP induced increased expression of Ki-67, denoting enhanced proliferation of the cells in monolayer culture. A positive correlation between the detrimental oxidative stress effect of MP's tested concentrations, cell proliferation, and viability was demonstrated (p < 0.05). Our results indicated that MP at high doses induced sustained cell proliferation due to E2 secretion as well as its antioxidant activity. Accordingly, it was concluded that high and unpredicted exposure to MP might carry a carcinogenic hazard on estrogen receptor-positive breast cancer cells. K E Y W O R D S cell proliferation, cell viability, estrogen hormone, Ki67, MCF-7 cells, methyl paraben, oxidative stress index J Biochem Mol Toxicol. 2022;e23012. wileyonlinelibrary.com/journal/jbt
... Methyl-paraben (MeP) is selected as the target pollutant because it is widely used as antimicrobial preservatives in cosmetics, foodstuffs, and pharmaceuticals [32][33][34][35][36]. This makes it continuously released into domestic and industrial wastewater and ng/L levels of MeP are known to remain detectable in treated wastewater [37][38][39][40]. ...
Solvent composition plays an important role in the synthesis of metal complex materials, but to date little work on this issue has been reported. Herein, a unique Schiff base Cu complex catalyst (DPDA-Cu-95EtOH) was designed based on polydopamine (PDA) and 3, 5-dibromosalicylaldehyde (DBSA), and the influence of H2O added during the synthesis process on its catalytic performance towards peroxymonosulfate (PMS) activation was comprehensively investigated. Our results demonstrated that adding a small amount (5%, v:v) of H2O to the solvent absolute ethanol (EtOH) can greatly increase the Cu loading (from 3.56 at% to 10.30 at%) on the catalyst, which significantly enhanced its catalytic ability, and promoted the removal of MeP for about 4.6 times higher than that synthesized without addition of H2O. Electron paramagnetic resonance (EPR) and quenching tests revealed that ¹O2, OH and SO4⁻ were responsible for the degradation of Methyl-paraben (MeP). Moreover, the DPDA-Cu-95EtOH/PMS system not only showed excellent stability and reusability, but also exhibited considerable removal efficiency of MeP in real wastewater. Overall, this study provides new insights into the controllable synthesis of Schiff base metal complex used for the efficient activation of PMS to remove micropollutants in wastewater.
Hazardous properties of a large number of esters of 4-hydroxybenzoic acid (parabens) have been proposed by ECHA to be assessed as a group. We recommend to restrict the grouping approach to short chain esters, i.e. methyl, ethyl, propyl and butyl paraben which are very similar in chemical structures, physicochemical properties, toxicokinetics, and hazardous properties. While these parabens show a weak estrogenicity in some in vitro or in vivo screening assays, they do not induce estrogen-receptor-mediated adverse effects in intact animals. Therefore, there is no support regarding classification and labeling of endocrine disruption or reproductive toxicity of these parabens.
Parabens are used as preservatives in various household products, including oral products, cosmetics, and hair/body washes. In recent years, the widespread use of parabens has raised concerns due to the potential health risks associated with their estrogenic effects. In the present study, we evaluated and compared the estrogenic activity of parabens using two cell-based in vitro tests: (1) bioluminescence resonance energy transfer (BRET)-based estrogen receptor alpha (ERα) dimerization using HEK293 cells that were stably transfected with ERα‐fused NanoLuc luciferase (Nluc) and HaloTag (HT) expression vector, and (2) stably transfected transcriptional activation (STTA) assays using ERα-HeLa9903 cells. The following parabens were tested using the BRET‐based ERα dimerization assay and showed estrogenic activity (PC20 values): methyl paraben (MP, 5.98 × 10−5 M), ethyl paraben (EP, 3.29 × 10−5 M), propylparaben (PP, 3.09 × 10−5 M), butyl paraben (BP, 2.58 × 10−5 M), isopropyl paraben (IsoPP, 1.37 × 10−5 M), and isobutyl paraben (IsoBP, 1.43 × 10−5 M). Except MP, all other parabens tested using the STTA assay also showed estrogenic activity: EP, 7.57 × 10−6 M; PP, 1.18 × 10−6 M; BP, 3.02 × 10−7 M; IsoPP, 3.58 × 10−7 M; and IsoBP, 1.80 × 10−7 M. Overall, EP, PP, BP, IsoPP, and IsoBP tested positive for estrogenic activity using both assays. These findings demonstrate that most parabens, albeit not all, induce ERα dimerization and possess estrogenic activity.
The endocrine-disrupting potential of parabens, as well as their relation to cancer, has sparked significant discussions over their impact. Consequently, analyses of cosmetic products are an essential necessity, particularly in terms of human health and safety. In this study, a highly accurate and sensitive liquid-phase-based microextraction method was developed to determine the five parabens at trace levels by high-performance liquid chromatography. All prominent parameters of the method such as extraction solvent type and amount (1,2-dichloroethane/250 μL), and dispersive solvent type and amount (isopropyl alcohol/2.0 mL) were optimized to enhance the extraction efficiency of the analytes. The mobile phase consisting of 50 mM ammonium formate aqueous solution (pH 4.0) and acetonitrile (60:40, v/v) was used to elute the analytes at a flow rate of 1.2 mL min-1 in the isocratic mode. Analytical performance of the optimum method for methyl, ethyl, propyl, butyl and benzyl parabens were determined and the analytes recorded detection limit values of 0.78, 0.75, 0.34, 0.33 and 0.75 μg kg-1, respectively. Four different lipstick samples were analyzed under optimum conditions of the developed method, and the amount of parabens quantified in the samples using matrix matched calibration standards was in the range of 0.11-1.03%.
Context
One in 8 women will develop breast cancer in their lifetime. Yet, the burden of disease is greater in Black women. Black women have a 40% higher mortality rate than White women, and a higher incidence of breast cancer at age 40 and younger. While the underlying cause of this disparity is multifactorial, exposure to endocrine disrupting chemicals (EDCs) in hair and other personal care products has been associated with an increased risk of breast cancer. Parabens are known EDCs that are commonly used as preservatives in hair and other personal care products, and Black women are disproportionately exposed to products containing parabens.
Objective
Studies have shown that parabens impact breast cancer cell proliferation, death, migration/invasion, and metabolism, as well as gene expression in vitro. However, these studies were conducted using cell lines of European ancestry; to date, no studies have utilized breast cancer cell lines of West African ancestry to examine the effects of parabens on breast cancer progression. Like breast cancer cell lines with European ancestry, we hypothesize that parabens promote protumorigenic effects in breast cancer cell lines of West African ancestry.
Methods
Luminal breast cancer cell lines with West African ancestry (HCC1500) and European ancestry (MCF-7) were treated with biologically relevant doses of methylparaben, propylparaben, and butylparaben.
Results
Following treatment, estrogen receptor target gene expression and cell viability were examined. We observed altered estrogen receptor target gene expression and cell viability that was paraben and cell line specific.
Conclusion
This study provides greater insight into the tumorigenic role of parabens in the progression of breast cancer in Black women.
Porous graphitic carbon (PGC) columns for liquid chromatography (LC) represent an alternative to octadecyl‑bonded silica columns for the separation of both polar and nonpolar molecules. This is accomplished by exploiting the polarizability of the stationary phase interacting with the functional groups of the analytes. However, the elution of nonpolar compounds requires a high percentage of organic solvent, losing the intrinsic advantage of reversed‑phase aqueous separations. In this article, we aimed to exploit an additional advantage of such columns, viz. the resistance at high temperatures. Superheated water was employed as the mobile phase, taking advantage of the decrease in water dielectric constant by increasing the temperature. In this context, our goal was to minimize the percentage of organic solvent utilizing high temperatures (up to 250 °C) to achieve fast and “green” separations. The new developed high-temperature LC instrument was applied to the analysis of parabens in food samples.
Background
The movement of conscious consumption is growing rapidly. The idea of leaving behind synthetic products and substances that generate waste from their production to their final disposal grows and widens the gap between the old capitalist paradigm and the concept of naturism. It includes environmental awareness, taking care of our body, and the conscious choice of what we eat, wear, and use in daily life, including cosmetic products.
Objective:
This study aimed to explore a new paradigm of formulation and consumption. A group of parabens was selected, and their replacement with preservatives approved for natural cosmetics was proposed. Some of the risks associated with the consumption of parabens in food, cosmetics, and medicines, were also examined. Moreover, the advantages and disadvantages of preservatives for the product and consumer were also discussed.
Methods:
For data collection, publications in indexed journals were searched, with the keywords: parabens, endocrine disrupting chemicals, and skin conditions related to the use of parabens.
Results:
Recent studies have reported that by using parabens in skin products, we create an imbalance in the skin flora. This preservative decreases the defense capacity of our first immune line and causes disorders that lead to irritation, rosacea spots, oiliness, and sectorized peeling. Furthermore, parabens are exogenous substances that alter the functions of the endocrine system and can cause adverse health effects.
Conclusion:
In Argentina, compounds from the paraben family are used by many brands as preservatives, which are dangerous to health and the environment. Therefore, a conscious, sustainable, biodegradable, and cruelty-free alternative is needed to replace parabens in cosmetics
Contamination in global water world has reached to such an extreme extent that scientist community is making tireless efforts to find the way to recycle, reuse or recirculate the wastewater by removing the sludge and other water pollutants apart. Newer water resources generation is another difficult but necessary challenge to increase the consumable water ratio in our environment which could be accomplished only by decontaminating them in a bulk measure. Ionic liquids (ILs) or deep eutectic solvents (DESs) have become unique in showing their capability of purifying or decontaminating considerable amount of water resources, be it wastewater from industries, sludge treatment or newer resources. Having some intricate and wide range of chemical properties, ILs and DESs with water-miscible, -immiscible or partially-miscible characters are becoming one of the choices of scientist community among other chemicals in solving the problem regarding removal of contaminants from water. Here in this article, we have highlighted some of the successful implementation of “green” ILs and DESs in addressing and participating in generation of consumable water by means of removal of several types of contaminants like, toxic metals and metal ions, organic wastes, surfactants, pesticides, dyestuffs, microplastics, lignocellulosic biomasses etc. It has been taken care of the concern about the possibilities of non-recovery costs of ILs and DESs in water due to usage of large amount of them which have been tried by recovering, removing or recycling them after accomplishing their decontamination role. Uniqueness, probable future prospects and the economic viability have been discussed and concluded comprehensively.Graphic abstract
A novel 4 + 2 covalent magnetic organic framework (COF) with core-shell structure was synthesized for the first time with N, N, N', N'-Tetrakis (4-aminophenyl)-1, 4- benzenediamine (TPDA) and 2, 6-Pyridinedicarboxaldehyde (PCBA) at room temperature. The synthesized magnetic TPDA-PCBA-COF has a large specific surface area and superparamagnetism, which makes it an ideal sorbent for trace analytes enrichment. To this end, we combined it with magnetic solid phase extraction (MSPE) to enrich trace parabens in environmental water. The parameters affecting the enrichment efficiency of magnetic solid phase extraction, such as the amount of Fe3O4@TPDA-PCBA-COF, extraction time, pH of samples, salt concentration, desorption solvent volume and desorption time, were optimized. A simple method for extraction and determination of parabens in water samples by MSPE combined with high performance liquid chromatography (HPLC) was established under optimized conditions. The validation results revealed that the linear ranges were at 1.0-5.0 × 102 ng mL-1 with R value between 0.9915 and 0.9999, the spiked recoveries were in the range of 82.8% to 99.9% and RSDs were lower than 10%. The method was further applied to the determination of parabens in water samples, with recoveries in the range of 82.2% to 110.0% and RSDs ≤ 7.7%. These results suggest that the magnetic TPDA-PCBA-COF could be used as a promising adsorbent for efficient extraction and quantitation of parabens in environmental water samples.
Since past year, natural products-based cosmeceuticals have gained a large amount of attention not only from researchers but also from the public due to the general belief that they are harmless. Notably, in present years, the demand for cosmeceuticals from the marine resources has been exponentially on the rise due to their unique chemical and biological properties that are not found in terrestrial resources. The recent review article delivered the importance of marine compounds, stressing new chemical entities with cosmeceutical potential from the marine natural resources and their mechanisms of action by which these compounds utilize the body functions as well as their related health benefits. The marine environments are the most important that give biologically active substances whose potential is still to be find for use as pharmaceuticals, nutraceuticals, and cosmeceuticals. The marine organisms are not only an consequence renewable source of valuable bulk compounds used in cosmetic industry such as agar and carrageenan, which are used as gelling and thickening agents to increase the viscosity of cosmetic formulations. The marine molecules can also function as active ingredients, being the main compounds that determine the function of cosmeceuticals. The recent review focus on the role of marine derived compound in human skin and their collection, isolation & extraction and application.
Endocrine-disrupting chemicals (EDCs) such as natural estrogens, bisphenol A, and nonylphenol are widely spread in the environment due to improper waste disposal. Emergence of EDCs mainly occurs from widely used consumer products like pharmaceuticals, personal care products, plastic preservatives, pesticides, and industrial lubricants. Both acute and chronic exposure of EDCs may influence the endocrine system of organisms arising severe health issues, thereby ultimately resulting in an imbalanced ecosystem. Degradation of EDCs has been largely studied in flocculation, precipitation, adsorption, and chemical oxidation-based wastewater treatment systems. Bioremediation of EDCs by a diverse range of taxonomical group’s microorganisms provides several advantages through economically adequate environmental protection. Microbial strains such as bacteria, microalgae, and fungi participate in the biodegradation and biotransformation processes of EDCs making them less endocrine-disrupting or harmful. Using various enzymes, microorganisms degrade complex EDCs into simple compounds or end products such as CO2 and H2O during their metabolic process. Fungi are the most widely used microorganism taxa for the degradation of a wide variety of EDCs. This chapter provides an overview of sources, pathways, and fate of EDCs in the environment and novel biodegradation approaches. Finally, future directions are identified in terms of unrevealed degradation mechanisms and field applications.
The increasing human population necessitates the creation of high-quality habitats and pure natural resources. Due to the growth of industries and other anthropogenic activities, the amounts of volatile organic compounds (VOCs) and odorants increase in the environment. Thus, the generation of high-quality effluent using appropriate treatment technology has become an essential requirement. These critical needs can be achieved with the aid of physical, chemical, and biological treatment technologies. The biological treatment techniques are considered to be the most advantageous technology for the treatment of volatile organic compounds (VOCs) and odorants because biological treatment technologies offer a cost-effective and environmentally friendly alternative to other pollution control technologies. The diverse biological treatment approaches for volatile organic compounds (VOCs) and odorants in bulk size and lab-scale research are discussed in this chapter.KeywordsVOCBiofiltersBioscrubbersBiotricklingOdorants
In this study, a new magnetic ionic liquid (MIL) was designed and prepared, containing a magnetic cation from the ligand N,N-dimethyl biguanide (DMBG) complexing with magnetic center Co2+ and a bis-trifluoromethanesulfonimide (NTf2-) anion. Using the MIL as the extraction solvent, a salting-out assisted dispersive liquid-liquid microextraction (SA-DLLME) combined with high performance liquid chromatography-ultraviolet detection (HPLC-UV) was established for the enrichment and detection of four parabens in environmental water samples. The one-factor-at-a-time experiment was employed to optimize the conditions affecting the extraction efficiency. Under the optimized extraction conditions, the limits of quantification (LOQs) of the four target analytes ranged from 2.0 ng mL-1 to 2.8 ng mL-1, and the coefficients of determination (R2) were above 0.9996 in the linear range of 2.8-400 ng mL-1. On the other hand, the method displayed good repeatability and accuracy with intra-day and inter-day relative standard deviations (RSDs) of 2.1-13.0% and recoveries of 82.0-114.6%. The established method was applied to real samples with recoveries within 81.6-125.4%, and the results demonstrated that the method was practical.
The widely used paraben preservatives have been frequently detected in human urine, and shown to disrupt the endocrine system. Recently, several epidemiologic studies have investigated the associations between paraben exposures and hypertension risk, but findings are inconsistent. Genetic susceptibility variation may contribute to the conflicting results. This study aimed to explore the associations of paraben exposures and their interactions with estrogen receptor genes 1 and 2 (ESR1 and ESR2) polymorphisms with hypertension. We conducted a hospital-based case-control study involving 396 hypertension cases and 396 controls in Wuhan, China. The urinary paraben concentrations were determined using a liquid chromatography-quadrupole time of flight mass spectrometer. The genotyping of ESR1 and ESR2 was performed using the Applied Biosystems 3730 XL sequencer. Multivariable logistic regression models were applied to examine the associations between urinary paraben concentrations and hypertension risk. Gene-environment interactions were estimated on both multiplicative and additive scales. The results showed that urinary ethylparaben (EtP), propylparaben (PrP), and ∑parabens (∑PBs) levels were positively associated with the risk of hypertension (Ptrend<0.05). Compared with their reference groups, subjects in the highest tertile of EtP, PrP, and ∑PBs had a 4.05-fold (95% CI: 2.56, 6.41), 2.72-fold (95% CI: 1.76, 4.20), and 1.60-fold (95% CI: 1.08, 2.36) increased risk of hypertension, respectively. When stratified by sex, the hypertensive effect of EtP was more pronounced in males (Pinteraction = 0.012). Furthermore, interaction analysis showed that PrP exposure interacted with ESR1 rs2234693 polymorphism on hypertension risk, with the significance of multiplicative (Pinteraction = 0.043) and additive (RERI = 1.27, AP = 0.52). Our results suggested that parabens exposure was positively related to hypertension risk, and that ESR1 rs2234693 polymorphism might modify the parabens exposure-related hypertensive effect.
Emerging contaminants (ECs) occur in extremely small concentrations; have a broad distribution, especially in water bodies; and have been identified to cause potential environmental and health risks. ECs comprise of chemical and biological micro-pollutants such as fertilizers and pesticides, pharmaceuticals, cosmeceuticals, nutraceuticals and other personal care products (PCPs), disinfectants, plastics, polycyclic aromatic hydrocarbons (PAH), dioxins, etc. that even in minor concentrations cause serious environmental threats and risks to the associated flora and fauna. The treatment of these ECs poses a major challenge to researchers, engineers and academicians. This chapter hence describes the types of ECs; the hazards associated with their widespread distribution in various fresh water bodies, groundwater and industrial wastewater; and also the associated modern remedial techniques. In order to tackle the bio-geo-environmental threats, various research efforts have been made to increase the efficiency of remediation techniques. Aerobic and anaerobic treatments, adsorption processes with activated carbon and clay minerals, hydrothermal carbonization of biomass, coagulation- flocculation, ozonation, advanced oxidation process (AOPs), UV irradiation, ultrafiltration (UF) membrane treatments, nanofiltration (NF), etc. are some effective treatment techniques for emerging contaminants in water and wastewater.
Naphthalene is a ubiquitous polycyclic aromatic hydrocarbon listed as a priority pollutant by the United States Environmental Protection Agency (USEPA). In this study, we have studied adsorption of naphthalene on biochar produced from sugarcane bagasse and ultrasonically removed the adsorbed naphthalene by low-frequency ultrasonication in a customized reactor. Biochar was produced from sugarcane bagasse (SB) at a pyrolytic temperature of 400 °C. UV and HPLC results suggest that 100% adsorption of naphthalene takes place in 75 min. X-ray diffraction results showed that SB biochar particles were amorphous. A known quantity of naphthalene adsorbed on 10 mg of SB biochar was subjected to ultrasonication in a customized cylindrical reactor (10 cm depth, 5.6 cm diameter) using low-frequency (40 kHz) sonication. More than 80% of naphthalene was desorbed from the biochar in 45 min. Therefore, low-frequency ultrasonication can be used as an effective treatment for the removal of such trace organic pollutants present in contaminated sites.KeywordsNaphthaleneBiocharAdsorptionUltrasonication
A rapid method for determination of parabens preservatives (methyl paraben, ethyl paraben, isopropyl paraben, propyl paraben, isobutyl paraben, and butyl paraben) in flavors was established by using supercritical fluid chromatography tandem mass spectrometry combined with dispersive solid phase extraction. After adding methanol and primary secondary amine to the sample simultaneously, high extraction efficiency and good sample cleanup could be obtained by simple shaking. Parabens were well separated on a Chiralpak IG‐3 column in 6 min by gradient elution. Recoveries from spiked blank samples at 0.5, 1.0, and 5.0 mg/kg were determined to be 88.3–106.6%with relative standard deviations less than 8.0%. All analytes achieved good linear relation (r≥0.999 2). The limits of detection for all analytes ranged from 0.03 to 0.09 mg/kg and the limits of quantification from 0.11 to 0.31 mg/kg, respectively. A total of 20 actual samples were successfully analyzed by taking the proposed method. Being simple, rapid, green and reliable, this method can be taken for the determination of parabens preservatives in flavors. This article is protected by copyright. All rights reserved
Benzylparaben (BzP) is a potential endocrine disruptor; however, its antioxidant defense, lipotoxicity and underlying mechanism of BzP in aquatic organisms are unknown. This study investigated the impacts of waterborne low-, environmental-related and high-level benzylparaben on the growth, antioxidant capacity, lipid metabolism and lipidomic response of Nile tilapia (Oreochromis niloticus). Juvenile tilapia (0.60 ± 0.11 g) were exposed to 0, 5, 50, 500 and 5000 ng/L benzylparaben for 8 weeks in quadruplicate for each group. Benzylparaben increased the body crude fat content but decreased brain acetylcholinesterase activity in O. niloticus. Benzylparaben caused oxidative stress, leading to hepatic morphology damage and lipid metabolism disorders in fish. Lipidomic analysis identified 13 lipid classes in fish liver. Benzylparaben exposure induced metabolic disorders of glycerol phospholipids, glycerolipids and sphingomyelins in fish liver. These findings indicate that environmentally related benzylparaben levels (5 to 50 ng/L) could induce an antioxidant response, result in triglyceride accumulation, and increase adipocyte formation and fatty acid intake in tilapia. However, high benzylparaben concentrations inhibit lipid deposition, presumably due to the effects of the antioxidant system, and induce tissue inflammation. Therefore, this study provides new insights into the toxic effects and potential mechanism of benzylparaben in fish, especially from the aspect of lipid metabolism.
Parabens are esters of para-hydroxybenzoic acid that have been used as preservatives in many types of products for decades including agrochemicals, pharmaceuticals, food and cosmetics. This illustrative case study with propylparaben (PP) demonstrates a 10-step read-across (RAX) framework in practice. It aims at establishing a proof-of-concept for the value added by new approach methodologies (NAMs) in read-across (RAX) for use in a next-generation risk assessment (NGRA) in order to assess consumer safety after exposure to PP-containing cosmetics. In addition to structural and physico-chemical properties, in silico information, toxicogenomics, in vitro toxicodynamic, toxicokinetic data from PBK models, and bioactivity data are used to provide evidence of the chemical and biological similarity of PP and analogues and to establish potency trends for observed effects in vitro. The chemical category under consideration is short (C1–C4) linear chain n-alkyl parabens: methylparaben, ethylparaben, propylparaben and butylparaben. The goal of this case study is to illustrate how a practical framework for RAX can be used to fill a hypothetical data gap for reproductive toxicity of the target chemical PP.
Endocrine-disrupting chemicals (EDCs) are known contributors to breast cancer development. EDC exposures commonly occur through food packaging, cookware, fabrics, and personal care products as well as through the environment. Increasing evidence highlights disparities in EDC exposure across racial/ethnic groups, yet breast cancer research continues to lack the inclusion necessary to positively impact treatment response and overall survival in these socially disadvantaged populations. Additionally, the inequity in environmental exposures has yet to be remedied. Exposure to EDCs due to structural racism poses an unequivocal risk to marginalized communities. In this review, we summarize recent epidemiological and molecular studies on two lesser-studied EDCs, per- and polyfluoroalkyl substances (PFAS) and parabens, the health disparities that exist in EDC exposure between populations and their association with breast carcinogenesis. We discuss the importance of understanding the relationship between EDC exposure and breast cancer development, particularly to promote efforts to mitigate exposures and improve breast cancer disparities in socially disadvantaged populations.
Parabens are widely used as preservatives in pharmaceuticals, cosmetics, and food products. Ethylparaben (EP) and propylparaben (PP) are particularly preferred because of their bactericidal and fungicidal effects. Although generally described as safe compounds, many studies have reported that parabens have estrogenic and endocrine-disrupting properties. In the present study, the effects of EP and PP (50 mM, 100 mM and 200 mM) on Drosophila melanogaster development and fecundity were investigated. No differences were found in the pupation and maturation percentages in all concentrations of parabens (p>0.05). However, it was found that the mean pupation and maturation times increased in all treatment groups (p<0.05). A statistically significant decrease (p<0.05) in the number of offspring of the 200 mM ethylparaben exposure group was observed. In all paraben groups, a significant reduction in mean fecundity was found compared to the control group (p<0.05).
An estrogen-inducible screen was developed in yeast (Saccharomyces cerevisiae) in order to assess whether surfactants and their major degradation products are estrogenic. The DNA sequence of the human estrogen receptor (hER) was integrated into the yeast genome, which also contained expression plasmids carrying estrogen-responsive sequences (ERE) controlling the expression of the reporter gene lac-Z (encoding the enzyme β-galactosidase). Thus, in the presence of estrogens, β-galactosidase is synthesized and secreted into the medium, where it causes a color change from yellow to red. This recombinant strain was used to determine whether representatives of major surfactant classes and some of their principal degradation products possess estrogenic activity. The results were compared to the effects of the main natural estrogen 17β-estradiol. None of the parent surfactants tested possessed estrogenic activity. However, one class of surfactants, the alkylphenol polyethoxylates, degrade to persistent metabolites that were weakly estrogenic. Another group of degradation products, the sulfophenyl carboxylates, which are derived from the biodegradation of linear alkylbenzene sulfonates, do not appear to possess estrogenic activity.
Alkylphenols are widely used as plastic additives and surfactants. We report the identification of an alkylphenol, nonylphenol, as an estrogenic substance released from plastic centrifuge tubes. This compound was extracted with methanol, purified by flash chromatography and reverse-phase high performance liquid chromatography, and identified by gas chromatography-mass spectrometry. Nonylphenol induced both cell proliferation and progesterone receptor in human estrogen-sensitive MCF7 breast tumor cells. Nonylphenol also triggered mitotic activity in rat endometrium; this result confirms the reliability of the MCF7 cell proliferation bioassay. The estrogenic properties of alkylphenols, specifically nonylphenols, indicate that the use of plasticware containing these chemicals in experimental and diagnostic tests may lead to spurious results, and these compounds as well as alkylphenol polyethoxylates may also be potentially harmful to exposed humans and the environment at large.
Male reproduction has been given little attention in science and in medical practice. However, a recent metaanalysis on semen quality, which clearly pointed to a decrease over the past 50 years, has been repeatedly quoted. Three recent reports have found that semen quality has declined among candidate semen donors during the past 20 years. The evidence of decline in the quality of semen is not the only indicator that the human testis is at risk. During the past 50 years, cancer of the testis has also become more common. This is a disorder of young men, and it is associated with a high rate of other abnormalities of the testis including undescended testis and poor semen quality. Furthermore, the incidence of both hypospadias and undescended testis has been reported to be rising in the general population. We believe that the evidence of declining semen quality should be seen in the light of these trends in other reproductive disorders of men. However, the etiology is unknown. A recent hypothesis that links the trends in the health of the male reproductive system to xenoestrogens in the environment is discussed.
This study assessed whether exposure of male rats to two estrogenic, environmental chemicals, 4-octylphenol (OP) and butyl benzyl phthalate (BBP) during gestation or during the first 21 days of postnatal life, affected testicular size or spermatogenesis in adulthood (90-95 days of age). Chemicals were administered via the drinking water at concentrations of 10-1000 μg/l (OP) or 1000 μg/l (BBP); diethylstilbestrol (DES; 100 μg/l) and an octylphenol polyethoxylate (OPP; 1000 μg/l), which is a weak estrogen or nonestrogenic in vitro, were administered as presumptive positive and negative controls, respectively. Controls received the vehicle (ethanol) in tapwater. In study 1, rats were treated from days 1-22 after birth; in studies 2 and 3, the mothers were treated for approximately 8-9 weeks, spanning a 2-week period before mating, throughout gestation and up until 22 days after giving birth. With the exception of DES, treatment generally had no major adverse effect on body weight: in most instances, treated animals were heavier than controls at day 22 and at days 90-95. Exposure to OP, OPP, or BBP at a concentration of 1000 μg/l resulted in a small (5-13%) but significant (p
The ability of certain man-made chemicals to mimic the effects of natural steroid hormones and their potential to disrupt
the delicate balance of the endocrine system in animals are of increasing concern. The growing list of reported hormone-mimics
includes the alkylphenolic (AP) compounds, a small number of which have been reported to be weakly estrogenic. In their most
basic form, APs are composed of an alkyl group, which can vary in size, branching, and position, joined to a phenolic ring.
The aim of this project was to identify the important structural features responsible for the estrogenic activity of AP chemicals.
This was achieved by incubating APs with different structural features in a medium containing a previously described estrogen-inducible
strain of yeast (Saccharomyces cerevisiae) expressing the human estrogen receptor and comparing their activity spectrophotometrically by the resulting color change
of the medium. The results were compared to the effects of the main natural estrogen 17β-estradiol. The data indicate that
both the position (para > meta > ortho) and branching (tertiary > secondary = normal) of the alkyl group affect estrogenicity. Optimal estrogenic activity requires
a single tertiary branched alkyl group composed of between 6 and 8 carbons located at the para position on an otherwise unhindered phenol ring. The results are discussed in relation to the purity and composition of the
chemicals tested.
Because of rampant concern that estrogenic chemicals in the environment may be adversely affecting the health of humans and wildlife, reliable methods for detecting and characterizing estrogenic chemicals are needed. It is important that general agreement be reached on which tests to use and that these tests then be applied to the testing of both man-made and naturally occurring chemicals. As a step toward developing a comprehensive approach to screening chemicals for estrogenic activity, three assays for detecting estrogenicity were conducted on 10 chemicals with known or suspected estrogenic activity. The assays were 1) competitive binding with the mouse uterine estrogen receptor, 2) transcriptional activation in HeLa cells transfected with plasmids containing an estrogen receptor and a response element, and 3) the uterotropic assay in mice. The chemicals studied were 17 beta-estradiol, diethylstilbestrol, tamoxifen, 4-hydroxytamoxifen, methoxychlor, the methoxychlor metabolite 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), endosulfan, nonylphenol, o,p'-DDT, and kepone. These studies were conducted to assess the utility of this three-assay combination in the routine screening of chemicals, or combinations of chemicals, for estrogenic activity. Results were consistent among the three assays with respect to what is known about the estrogenic activities of the chemicals tested and their requirements for metabolic activation. By providing information on three levels of hormonal activity (receptor binding, transcriptional activation, and an in vivo effect in an estrogen-responsive tissue), an informative profile of estrogenic activity is obtained with a reasonable investment of resources.
The sites of action and the physiological role of oestrogens in the male reproductive tract are poorly understood. We have undertaken a systematic study of the immunoexpression of oestrogen receptor-alpha (ER alpha) in the male rat from late fetal life through to adulthood and compared the findings with results obtained in the marmoset monkey (Callithrix jacchus) from neonatal to adult life. The testes, rete testis, efferent ducts and epididymis were examined from normal male rats (aged 4, 8, 10, 15, 20, 25, 38, 48 and 90 days) and from male rat fetuses on days 17.5 and 18.5 of gestation; comparable tissues were examined from neonatal, infantile, peripubertal and adult marmosets aged 8, 18-24, 54-62 and 92-112 weeks respectively. Immunolocalisation of ER alpha used antigen retrieval and a monoclonal antibody directed to the N-terminus, which had proved superior to six other antisera tested. ER alpha was immunoexpressed in interstitial cells, including the fetal/ neonatal generation of Leydig cells, in both the rat and marmoset. In the rat, the adult generation of Leydig cells were also immunopositive for ER alpha whereas the comparable cells in the marmoset were only weakly immunopositive. ER alpha was not expressed in Sertoli cells, peritubular myoid cells, blood vessels or germ cells at any time in either species. In late fetal life in the rat, ER alpha was immunoexpressed in cells surrounding the mesonephric tubules, whereas postnatally it was expressed in the epithelium of the rete testis and efferent ducts at all ages from 4 to 90 days; this immunoexpression was most pronounced in the efferent ducts. In the marmoset, the efferent ducts, but not the rete testis, also showed intense immunoexpression of ER alpha. Apart from sporadic immunostaining for ER alpha in the epididymal duct of the rat in the neonatal period, the caput, corpus and cauda epididymis were negative for immunoexpression of ER alpha at all ages in both species. These findings suggest that the main actions of oestrogens in the male reproductive tract, mediated by ER alpha, are related to the development and function of the efferent ducts and the Leydig cells. In consideration of data from this and previous studies of oestrogen binding, we predict possible sites of expression of other oestrogen receptors (e.g. ER beta) in Sertoli cells and the epididymis. Interactive effects, related to the relative levels of androgens and oestrogens, could be physiologically important in the excurrent ducts of the adult testis.
Oestrogen is considered to be the 'female' hormone, whereas testosterone is considered the 'male' hormone. However, both hormones are present in both sexes. Thus sexual distinctions are not qualitative differences, but rather result from quantitative divergence in hormone concentrations and differential expressions of steroid hormone receptors. In males, oestrogen is present in low concentrations in blood, but can be extraordinarily high in semen, and as high as 250 pg ml(-1) in rete testis fluids, which is higher than serum oestradiol in the female. It is well known that male reproductive tissues express oestrogen receptors, but the role of oestrogen in male reproduction has remained unclear. Here we provide evidence of a physiological role for oestrogen in male reproductive organs. We show that oestrogen regulates the reabsorption of luminal fluid in the head of the epididymis. Disruption of this essential function causes sperm to enter the epididymis diluted, rather than concentrated, resulting in infertility. This finding raises further concern over the potential direct effects of environmental oestrogens on male reproduction and reported declines in human sperm counts.
The understanding of estrogen's function in the male reproductive tract is limited, and estrogen receptor (ER) localization in the reproductive tract of the adult male rat has not been described. In the present study, ERalpha was localized by immunohistochemistry using ER21 antibody, which recognizes only ERalpha. Strongest immunoreactivity was seen in epithelia of ductuli efferentes and the initial segment of the epididymis. Nuclei of both ciliated and nonciliated cells were positive. The epithelium of the rete testis, and caput, corpus, and cauda epididymides stained less intensely for ERalpha. The vas deferens epithelium was ERalpha-negative. Stromal tissue in the excurrent ducts was also ERalpha-positive. Using 3H-estradiol autoradiography, specific binding of estradiol was seen in nuclei of ductuli efferentes. Estrogen receptor alpha mRNA expression was greatly enhanced in ductuli efferentes compared to other regions of the male tract and was 3.5x greater than in the uterus. For comparison, the presence of ERalpha was determined using reverse transcription-polymerase chain reaction (RT-PCR) amplification. Estrogen receptor beta mRNA was expressed throughout the male tract and in the prostate. These results indicate that all organs in the male excurrent ductal system of the rat express ERalpha and are potential targets of estrogen. However, the ductuli efferentes are the site of the most intense ERalpha expression. The role of ERbeta remains to be determined, but its expression appears ubiguitous in the male tract.
The Parabens are esters of p-hydroxybenzoic acid (PHBA) and are the most commonly used as preservatives in cosmetic formulations. Data obtained from chronic administration studies indicate that Parabens are rapidly absorbed, metabolized, and excreted.
Acute chronic and subchronic toxicity studies in animals indicate that Parabens are practically nontoxic by various routes of administration. Methylparaben and Ethylparaben at 100 percent concentration were slightly irritating when instilled into the eyes of rabbits.
Numerous in vitro mutagenicity studies indicate that the Parabens are non-mutagenic. Methylparaben was noncarcinogenic when injected in rodents or when administered intravaginally in rats. Cocarcinogenesis studies on Propyl- and Methylparaben were negative. Teratogenic studies on Methyl- and Ethylparaben were also negative.
Parabens are practically nonirritating and nonsensitizing in the human population with normal skin. Paraben sensitization has been reported when Paraben-containing medicaments have been applied to damaged or broken skin. Photo-contact sensitization and phototoxicity tests on product formations of Methyl-, Propyl-, and/or Butylparaben gave no evidence of significant photoreactivity.
It is concluded that Methylparaben, Ethylparaben, Propylparaben, and Butylparaben are safe as cosmetic ingredients in the present practices of use.
The biological fates of ethylparaben (EP) which has been widely used as a preservative for the pharmaceutical preparations and foods, and p-hydroxybenzoic acid (HB) which is the parent compound of EP, were investigated at the dose of practical usage (2 mg/kg) in rats. Although both EP and HB were metabolized to glycine conjugate (M1), ester type glucuronide (M3) and sulfate (M4) of HB and excreted in the urine and bile, the excretion ratios were different as compared with the results of higher dose experiments carried out by other authors, and a route dependency was also found in the rate of excretion in the bile. The excretion data obtained in this study are shown as follows: In intravenous administration of EP, the excreted total activity was 91.3% per dose in the urine and 5.97% in the bile, and percentages per dose of the major metabolites excreted in the urine were 8.14% of HB, 39.6% of M1, 29.5% of M3 and 6.48% of M4. In intraduodenal administration of EP, the excreted total activity (83.5%) and the activity excreted as HB (3.51%) decreased compared with the intravenous administration. In the HB administration, the route dependency of the total activity was not found, but a decrease in the excretion of HB in the intraduodenal administration was found. The excretion of total radioactivity almost ceased by 5 hr and the biological half-lives obtained from the β-phase of the sigma-minus plots of the metabolites excreted in the urine were 40-70 min. The results obtained in this study differ from those of other authors at the high dose experiments.
We have cloned a novel member of the nuclear receptor superfamily. The cDNA of clone 29 was isolated from a rat prostate cDNA library and it encodes a protein of 485 amino acid residues with a calculated molecular weight of 54.2 kDa. Clone 29 protein is unique in that it is highly homologous to the rat estrogen receptor (ER) protein, particularly in the DNA-binding domain (95%) and in the C-terminal ligand-binding domain (55%). Expression of clone 29 in rat tissues was investigated by in situ hybridization and prominent expression was found in prostate and ovary. In the prostate clone 29 is expressed in the epithelial cells of the secretory alveoli, whereas in the ovary the granulosa cells in primary, secondary, and mature follicles showed expression of clone 29. Saturation ligand-binding analysis of in vitro synthesized clone 29 protein revealed a single binding component for 17beta -estradiol (E2) with high affinity (Kd = 0.6 nM). In ligand-competition experiments the binding affinity decreased in the order E2 > diethylstilbestrol > estriol > estrone > 5alpha -androstane-3beta ,17beta -diol >> testosterone = progesterone = corticosterone = 5alpha -androstane-3alpha ,17beta -diol. In cotransfection experiments of Chinese hamster ovary cells with a clone 29 expression vector and an estrogen-regulated reporter gene, maximal stimulation (about 3-fold) of reporter gene activity was found during incubation with 10 nM of E2. Neither progesterone, testosterone, dexamethasone, thyroid hormone, all-trans-retinoic acid, nor 5alpha -androstane-3alpha ,17beta -diol could stimulate reporter gene activity, whereas estrone and 5alpha -androstane-3beta ,17beta -diol did. We conclude that clone 29 cDNA encodes a novel rat ER, which we suggest be named rat ERbeta to distinguish it from the previously cloned ER (ERalpha ) from rat uterus.
The understanding of estrogen's function in the male reproductive tract is limited, and estrogen receptor (ER) lo- calization in the reproductive tract of the adult male rat has not been described. In the present study, ERcs was localized by im- munohistochemistry using ER21 antibody, which recognizes only ERa. Strongest immunoreactivity was seen in epithelia of ductuli efferentes and the initial segment of the epididymis. Nuclei of both ciliated and nonciliated cells were positive. The epithelium of the rete testis, and caput, corpus, and cauda epididymides stained less intensely for ERa. The vas deferens epithelium was ERa-negative. Stromal tissue in the excurrent ducts was also ERa-positive. Using 3H-estradiol autoradiography, specific bind- ing of estradiol was seen in nuclei of ductuli efferentes. Estrogen receptor a mANA expression was greatly enhanced in ductuli ef- ferentes compared to other regions of the male tract and was 3.5x greater than in the uterus. For comparison, the presence of ERI3 was determined using reverse transcription-polymerase chain reaction (RT-PCR) amplification. Estrogen receptor 13 mRNA was expressed throughout the male tract and in the pros- tate. These results indicate that all organs in the male excurrent ductal system of the rat express ERa and are potential targets of estrogen. However, the ductuli efferentes are the site of the most intense ERrs expression. The role of ERI3 remains to be deter- mined, but its expression appears ubiguitous in the male tract.
The effect of lipophilicity on the mechanisms of drug absorption through biomembranes was investigated employing HPLC system
and the fluorescence technique. Human erythrocyte ghost membranes were used as a model biomembrane. A series of four parabens
(methyl, ethyl, propyl, and butyl) and p-hydroxybenzoic acid were used as the model drugs for lipophilicities and their partition
coefficients were measured in Sörensen’s phosphate buffer solution (pH 5)/octanol system. Absorption amount of parabens through
erythrocyte ghost membranes increased with an increase of lipophilicity resulted from the addition of methylene group to the
n-alkyl chain of parabens. And the effect of parabens on the fluidity of ghost membrane also increased with an increase of
their lipophilicities.
The use of transformations to stabilize the variance of binomial or Poisson data is familiar(Anscombe [1], Bartlett [2, 3], Curtiss [4], Eisenhart [5]). The comparison of transformed binomial or Poisson data with percentage points of the normal distribution to make approximate significance tests or to set approximate confidence intervals is less familiar. Mosteller and Tukey [6] have recently made a graphical application of a transformation related to the square-root transformation for such purposes, where the use of "binomial probability paper" avoids all computation. We report here on an empirical study of a number of approximations, some intended for significance and confidence work and others for variance stabilization. For significance testing and the setting of confidence limits, we should like to use the normal deviate $K$ exceeded with the same probability as the number of successes $x$ from $n$ in a binomial distribution with expectation $np$, which is defined by $\frac{1}{2\pi} \int^K_{-\infty} e^{-\frac{1}{2}t^2} dt = \operatorname{Prob} \{x \leq k |mid \operatorname{binomial}, n, p\}.$ The most useful approximations to $K$ that we can propose here are $N$ (very simple), $N^+$ (accurate near the usual percentage points), and $N^{\ast\ast}$ (quite accurate generally), where $N = 2 (\sqrt{(k + 1)q} - \sqrt{(n - k)p)}.$ (This is the approximation used with binomial probability paper.) $N^+ = N + \frac{N + 2p - 1}{12\sqrt{E}},\quad E = \text{lesser of} np \text{and} nq, N^\ast = N + \frac{(N - 2)(N + 2)}{12} \big(\frac{1}{\sqrt{np + 1}} - \frac{1}{\sqrt{nq + 1}}\big), N^{\ast\ast} = N^\ast + \frac{N^\ast + 2p - 1}{12 \sqrt{E}}\cdot\quad E = \text{lesser of} np \text{and} nq.$ For variance stabilization, the averaged angular transformation $\sin^{-1}\sqrt{\frac{x}{n + 1}} + \sin^{-1} \sqrt{\frac{x + 1}{n+1}}$ has variance within $\pm 6%$ of $\frac{1}{n + \frac{1}{2}} \text{(angles in radians)}, \frac{821}{n + \frac{1}{2}} \text{(angles in degrees)},$ for almost all cases where $np \geq 1$. In the Poisson case, this simplifies to using $\sqrt{x} + \sqrt{x + 1}$ as having variance 1.
Synopsis
Absorption through human skin of a series of six p ‐hydroxy‐benzoates (parabens) was studied in vitro. A diffusion chamber was used, where the receiving phase was a physiological solution of albumin. Maximum fluxes and permeability constants of the parabens were measured from different vehicles representing hydrophilic and lipophilic phases, and from different types of common commercial cosmetic emulsions, each containing a known quantity of a single member of the series. Significant skin absorption was observed, depending upon the partition coefficient (log P octanol/water) of the permeant, composition and time of storage of the emulsions. Fluxes from all types of emulsions were higher for methyl paraben and decreased with the increasing lipophilic character of the preservative. Comparatively, fluxes from oil/water emulsions were higher than from water/oil emulsions. Moreover, a clear dependence of preservatives’percutaneous absorption on the time of storage was observed, the fluxes becoming constant after about three months after the time of preparation. The relationship between preservative activity and percutaneous absorption is discussed.
Twelve straight-chain esters, C5 to C14, C16, and C18, of p-hydroxybenzoic acid were prepared, and their melting points, solubilities in water at 25°C, infrared spectra, dissociation
constants (pKa), and activities against Clostridium botulinum were determined. These studies also included four commercial straight-chain esters, C1 to C4. The most potent activity was exhibited by undecyl and dodecyl esters, which are about 300 times as active as sodium nitrite.
Quadratic and cubic equations were developed correlating the activity with pKa values and chain length of the esters, respectively.
Percutaneous absorption of aqueous butylparaben through guinea pig dorsal skin was studied using a diffusion chamber. Polysorbate 80 increased the solubilized concentration but decreased penetration of the preservative. Polyethylene glycol 400 also reduced the amount of penetration. Propylene glycol was less effective than polyethylene glycol 400. Preservative activities of these systems on several microorganisms were evaluated on agar plates. The relationship between the butylparaben penetration and preservative activity is discussed.
Cytosol receptor binding of 17β-estradiol in the mouse uterus was demonstrated in immature, ovariectomized, and intact animals. Quantification of specific binding by protamine sulfate precipitation was approximately 0.70 pmol estradiol bound/mg cytosol protein for all of the groups studied. Nuclear binding levels, assessed by the nuclear exchange assay, were 0.11-0.15 pmol/100 μg DNA. Stability of the nuclear receptor-estradiol complex was evaluated at 25, 30, and 37°C and was found to be inversely related to the incubation temperature. Linearity of the binding assays was demonstrated for cytosol and nuclear receptors compared to milligrams of cytosol protein or micrograms of DNA, respectively. The mouse uterine cytosol receptor-estradiol interaction was shown to be second order by association rate analysis (k1 = 2.0 x 105 M-1 sec-1). Dissociation of estradiol from the receptor complex (k-1) appeared to be first order, with a constant of 2.3 x 10-5 sec-1. Sucrose gradients performed in low salt buffer (10 mM Tris and 1.5 mM EDTA) resulted in the appearance of an 8S-sedimenting cytosol receptor. A cytosol receptor sedimenting at 6S was demonstrated on sucrose gradients in low salt buffer (10 mM Tris, 1 mM disodium EDTA, and 10% glycerol), while the same analysis in 0.4 M KCl buffer gave a 4S component. Sedimentation profiles of KCl extracts of nuclei showed a 5S moiety. A similar sedimenting component (5S) was demonstrable by a cell-free transformation of the cytosol preparation. Receptor specificity for estrogenic steroids was indicated from competitive equilibrium binding experiments with a variety of unlabeled steroids. Estrogenic compounds showed the following rank order: diethylstilbestrol ≥ 17β-estradiol ~ estrone estriol ≥ 17α-estradiol > R2858 [11β-methoxy-19-nor-1,3,5-(10)pregnatrien-20-yne-3,17-diol]3β,5α-androstanediol. Other androgens, progestogens, and glucocorticoids had no appreciable effect on the binding. The distribution pattern of the immature mouse uterine cytosol and nuclear receptors after an injection of estradiol (10 μg/kg) showed initial translocation at 1 h, with the appearance of a second nuclear peak approximately 708 h postinjection. The properties of this estrogen receptor system and the possible role of this biphasic nuclear increase is discussed as it relates to estrogen action in the mouse uterus.
To investigate whether semen quality has changed during the past 50 years.
Review of publications on semen quality in men without a history of infertility selected by means of Cumulated Index Medicus and Current List (1930-1965) and MEDLINE Silver Platter database (1966-August 1991).
14,947 men included in a total of 61 papers published between 1938 and 1991.
Mean sperm density and mean seminal volume.
Linear regression of data weighted by number of men in each study showed a significant decrease in mean sperm count from 113 x 10(6)/ml in 1940 to 66 x 10(6)/ml in 1990 (p < 0.0001) and in seminal volume from 3.40 ml to 2.75 ml (p = 0.027), indicating an even more pronounced decrease in sperm production than expressed by the decline in sperm density.
There has been a genuine decline in semen quality over the past 50 years. As male fertility is to some extent correlated with sperm count the results may reflect an overall reduction in male fertility. The biological significance of these changes is emphasised by a concomitant increase in the incidence of genitourinary abnormalities such as testicular cancer and possibly also cryptorchidism and hypospadias, suggesting a growing impact of factors with serious effects on male gonadal function.
Percutaneous penetration of 14C-butylparaben (BP) from a liposome suspension was studied in vitro using a flow-through type diffusion chamber. The amount of 14C-BP that penetrated through the skin of guinea pigs from liposome suspension decreased as the lipid content increased. This suggested that BP in the outer aqueous phase mainly contributed to the percutaneous penetration. However, 14C-BP in liposomes was also demonstrated to participate in the penetration to a small extent. Mathematical analysis based on diffusion theory supported these findings.Substantial entrapment of BP in liposomes was maintained during the period of the in vitro experiment (30 h), indicating that the free concentration of BP would be maintained in the donor region after the application of the liposome formulation to it. Furthermore, liposomes induced neither alteration of the barrier function of the stratum corneum nor denaturation of skin proteins in vitro. These findings are consistent with a contribution of direct BP absorption from liposomes at the skin surface.
The effect of surfactants on the percutaneous absorption of butylparaben from micellar solution was studied. Percutaneous absorption of butylparaben from aqueous solution containing the critical micellar concentration (cmc) of a surfactant was measured in order to determine the contribution of the free butylparaben. Percutaneous absorption of polysorbate 80 and octaethyleneglycol dodecyl ether was also measured in order to evaluate the effect of absorption of micelles, if any. The results indicated that the surfactants were scarcely absorbed, but the free concentration of butylparaben could not account for the total drug absorption from micellar solution. However, the amount of surfactant absorbed increased with increase in the surfactant concentration above the cmc, indicating that surfactant molecules in micelles could be absorbed. This suggests that some of the micelles were adsorbed and/or dissociated on the skin surface, so that the effective concentration of surfactant as well as that of butylparaben for percutaneous absorption would be increased.
The biological fates of ethyl paraben and p-hydroxybenzoic acid in rat were investigated after intravenous and intraduodenal administrations at the dose of 2 mg/kg. The blood concentrations were measured in detail from 3 min after the administration at appropriate time intervals until 90 min. Areas under the blood concentration curves and clearances were calculated from these time course data. Ethyl paraben was little detected in blood after intraduodenal administration. It is suggested that the intestinal metabolism and the first pass effect in liver greatly contribute to the hydrolysis of ethyl paraben. Total radio activity after intraduodenal administration did not show the maximum peak and decreased rapidly. The maximum peak was not observed also in the time course of p-hydroxyhippuric acid after intravenous administration. It shows that not only the rate of hydrolysis but also absorption and conjugation are very rapid. The differences of the areas under the blood concentration curves of p-hydroxybenzoic acid or p-hydroxyhippuric acid was found between the routes or chemical forms of administration. The complex kinetic mechanisms were assumed in the biological fates of these compounds as follows: Conjugation to p-hydroxyhippuric acid is excellent in ethyl paraben administration than p-hydroxybenzoic acid, and in intraduodenal administration than intravenous administration. These phenomenon can not be explained by the conventional kinetic model which is constructed with the connected blood compartments in series. The kinetic models including the assumed routes conjugating directly ethyl paraben in blood or intestine to p-hydroxyhippuric acid were presented, and the least square curve fitting analyses were carried out on these kinetic models.
The contents of methyl-, ethyl-, propyl-, butyl- and benzylparaben in 215 cosmetic products have been determined to elucidate the concentration and frequency of use of these parabens in cosmetic products, and to monitor whether the products complied with the Danish and EEC regulations. The results showed that 77% of the products investigated contained 0.01%-0.87% parabens. Nearly all (99%) of the leave-on cosmetics and 77% of rinse-off cosmetics were found to contain parabens. A maximum of 0.32% methyl- and propylparaben, 0.19% ethylparaben, and 0.07% butyl- and benzylparaben were present in paraben-positive cosmetics. A preferential use of methyl-/ethyl-/propyl-/butyl-/benzylparaben in various groups of cosmetic products was revealed.
Several studies have suggested a population-wide decline in the quality of semen over the past 50 years, but clear evidence for decreasing semen quality in recent decades is lacking.
From 1973 through 1992 we measured the volume of seminal fluid, the sperm concentration, and the percentages of motile and morphologically normal spermatozoa in 1351 healthy fertile men. The data on the semen samples were collected at one sperm bank in Paris. The data in each calendar year were analyzed as a function of the year of donation, the age of each patient, the year of birth, and the duration of sexual abstinence before semen collection.
There was no change in semen volume during the study period. The mean concentration of sperm decreased by 2.1 percent per year, from 89 x 10(6) per milliliter in 1973 to 60 x 10(6) per milliliter in 1992 (P < 0.001). During the same period the percentages of motile and normal spermatozoa decreased by 0.6 percent and 0.5 percent per year, respectively (both P < 0.001). After adjustment in multiple regression analyses for age and the duration of sexual abstinence, each successive calendar year of birth accounted for 2.6 percent of the yearly decline in the sperm concentration and for 0.3 percent and 0.7 percent, respectively, of the yearly declines in the percentages of motile and normal spermatozoa (all P < 0.001).
During the past 20 years, there has been a decline in the concentration and motility of sperm and in the percentage of morphologically normal spermatozoa in fertile men that is independent of the age of the men.
Comparative molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (3D-QSAR) paradigm, was used to examine the estrogen receptor (ER) binding affinities of a series of structurally diverse natural, synthetic, and environmental chemicals of interest. The CoMFA/3D-QSAR model is statistically robust and internally consistent, and successfully illustrates that the overall steric and electrostatic properties of structurally diverse ligands for the estrogen receptor are both necessary and sufficient to describe the binding affinity. The ability of the model to accurately predict the ER binding affinity of an external test set of molecules suggests that structure-based 3D-QSAR models may be used to supplement the process of endocrine disruptor identification through prioritization of novel compounds for bioassay. The general application of this 3D-QSAR model within a toxicological framework is, at present, limited only by the quantity and quality of biological data for relevant biomarkers of toxicity and hormonal responsiveness.
The major protocol features of the immature rat uterotrophic assay have been evaluated using a range of reference chemicals. The protocol variables considered include the selection of the test species and route of chemical administration, the age of the test animals, the maintenance diet used, and the specificity of the assay for estrogens. It is concluded that three daily oral administrations of test chemicals to 21- to 22-day-old rats, followed by determination of absolute uterus weights on the fourth day, provide a sensitive and toxicologically relevant in vivo estrogenicity assay. Rats are favored over mice for reasons of toxicological practice, but the choice of test species is probably not a critical protocol variable, as evidenced by the similar sensitivity of rats and mice to the uterotrophic activity of methoxychlor. Vaginal opening is shown to be a useful, but nondefinitive, adjunct to the uterotrophic assay. The ability of test chemicals to reduce or abolish the uterotrophic response of estradiol is suggested to provide a useful extension of the uterotrophic assay for the purpose of detecting antiestrogens. The results of a series of studies on the environmental estrogen nonyl phenol (NP), and its linear isomer n-nonyl phenol, confirm that branching of the aliphatic side chain is important for activity. 17beta-Desoxyestradiol is shown to be of similar activity to estradiol in the uterotrophic assay and is suggested to represent the "parent" estrogen of NP. Benzoylation of NP and 17-desoxyestradiol did not affect their uterotrophic activity, in contrast to the enhancing effect of benzoylation on estradiol. Selected chemicals shown to be active in the immature rat uterotrophic assay were also evaluated in an in vitro yeast human estrogen receptor transactivation assay. Most of the chemicals gave similar qualitative responses to those seen in the uterotrophic assay, and the detection of the estrogen methoxychlor by the yeast assay evidenced a degree of intrinsic metabolic competence. However, the assay had a reduced ability (compared to rodents) to hydrolyze the benzoate ester of estradiol, and the estrogenic benzoate derivative of NP was not active in the yeast assay. These last results indicate that current metabolic deficiencies of in vitro estrogenicity assays will limit the value of negative data for the immediate future. The results described illustrate the intrinsic complexity of evaluating chemicals for estrogenic activities and confirm the need for rigorous attention to experimental design and criteria for assessing estrogenic activity.
Effects of skin metabolism on percutaneous penetration of drugs with high lipophilicity were studied in vitro using rat skin pretreated with and without an esterase inhibitor, diisopropyl phosphorofluoridate [also known as diisopropyl fluorophosphate (DFP)]. Without DFP, about 96% of the total penetrated amount appeared as metabolized p-hydroxybenzoic acid in the receptor fluid after application of butylparaben, whereas about 30% penetrated as intact form after application of propylparaben. On the other hand, metabolized p-hydroxybenzoic acid was not defected in the receptor fluid under pretreatment with DFP. DFP significantly decreased (p < 0.05) the total amount that penetrated after application of butylparaben, but it did not significantly affect that of propylparaben. The results indicate that skin metabolism directly affects total amount that penetrated in the case of highly lipophilic drugs, and it was found that the higher metabolic rate to hydrophilic drugs is, the greater the amount that penetrated the skin would be. Thus, when optimal prodrugs are designed for the purpose of enhancing percutaneous penetration, we propose that the bioconversion rate to parent drugs as well as the lipophilicity of prodrugs becomes an important consideration.
Raloxifene is generally regarded as a tissue-selective estrogen agonist, being capable of selectively counter-acting both the loss of bone density and the increase in serum cholesterol that occur in rats following ovariectomy, without the induction of a trophic effect on the rat uterus. An implication of this activity profile is that reliance cannot be placed on the rat uterotrophic assay for the detection and assessment of xenobiotic estrogens. Within that context the estrogenic activity of raloxifene has been reevaluated in immature and ovariectomized rat uterotrophic assays. Four separate experiments were conducted. In the first two a reproducible increase (1.7-fold) was observed in the uterus wet weights of immature rats administered three daily doses of raloxifene. The maximum uterotrophic response observed over the dose range 0.01-2 mg/kg was for 0.1 mg/kg raloxifene. Further experiments utilized three daily doses of 0.1 mg/kg raloxifene. In the third experiment the uterotrophic response elicited by raloxifene in immature rats was abolished by coadministration of the estrogen receptor blocking agent Faslodex (ICI 182,780). This confirmed the direct involvement of estrogen receptors in the uterotrophic response elicited by raloxifene. Two further indications of the estrogenicity of raloxifene were obtained in this experiment. First, dry uterus weights were also shown to be increased by raloxifene administration, thereby eliminating water retention as the sole cause of the observed increases in uterus weights. Second, the height of the surface epithelium was increased by 1.7-fold in the raloxifene-treated animals, an effect that was accompanied by increases in mitotic activity and glandular formation in the stromal endometrium. The endometrial epithelium of the treated rats also showed evidence of vacuolation and, occasionally, the presence of degenerating cells. Raloxifene did not, however, cause premature vaginal opening in immature rats, unlike estradiol. In the fourth experiment the uterotrophic activity of raloxifene was confirmed in ovariectomized rats, although the response was less (1.2-fold) than in immature rats. In contrast to the effects seen for the positive control agent estradiol, the uterotrophic responses observed for raloxifene in ovariectomized animals were not accompanied by cornification of the vaginal epithelium. Premature vaginal opening and vaginal cornification may be less sensitive markers of estrogenic activity than the uterotrophic response. These collected observations confirm that raloxifene exerts a genuine trophic effect on the rat uterus, and as a consequence, the uterotrophic assay can be relied upon to detect estrogens with only a marginal effect on the uterus.
It has been suggested that chemicals and complex mixtures capable of modulating the endocrine system may contribute to adverse health, reproduction, and developmental effects in humans and wildlife. These effects include increased incidence of hormone-dependent cancers, compromised reproductive fitness, and abnormal reproductive system development. In response to public concern, regulatory agencies in North America and Europe are formulating potential strategies to systematically test chemicals and complex mixtures for their endocrine-disrupting activities. Because of the complexity of the endocrine system and the number of potential endocrine disruptor targets, a tiered approach involving a complementary battery of short- and long-term in vivo and in vitro assays that assesses both receptor and nonreceptor-mediated mechanisms of action is being considered. However, the available established assays use a limited number of end points, and significant information gaps exist for other potential targets in the endocrine system. In addition to discussing the merits and limitations of the assays that may be adopted, this paper also highlights potential problems associated with the use of a tiered testing strategy.
Lefevre for the estrogen receptor binding assay data, and the European Commission for funding
- P A We
We thank P.A. Lefevre for the estrogen receptor binding assay data, and the European Commission for funding (Contract number ENV4-CT96-0240).
Application of ethyl p-hydroxybenzoate in maintenance of sterility, in sterilization and in disinfection
- Sabalitschka
Sabalitschka, T. (1930). Application of ethyl p-hydroxybenzoate in maintenance of sterility, in sterilization and in disinfection. Arch. Pharm. 268,
653-673.
SAS/STATS User's guide, Version 6
SAS Institute Inc. (1989). SAS/STATS User's guide, Version 6, 4th ed., Vol.
2. SAS Institute Inc., Cary, NC.
Evidence for decreasing quality of semen during past 50 years
- Carlsen
P-nonylphenol: An estrogenic xenobiotic released from modified polystyrene
- Soto