Chronic exposure to parabens promotes non-alcoholic fatty liver disease in association with the changes of the gut microbiota and lipid metabolism.

Non-alcoholic fatty liver disease (NAFLD) has become a serious public health issue due to changing dietary patterns and composition. However, the relationship between NAFLD occurrence and food additives, such as preservatives, remains unknown. This study aimed to evaluate the toxicity of parabens, namely methylparaben (MeP) and ethylparaben (EtP), in relation to NAFLD occurrence in mice under different dietary conditions. Exposure to MeP and EtP exacerbated high-fat diet (HFD)-induced obesity, glucose intolerance, higher serum lipid concentrations, and fat accumulation by upregulating genes involved in lipid metabolism. Untargeted metabolomics revealed that arachidonic acid (AA) metabolism was the top enriched pathway upon MeP and EtP exposure in the presence of HFD. 11,12-Epoxyeicosatrienoic acid (11,12-EET) was the most abundant AA metabolite and was significantly reduced upon exposure to MeP or EtP. Moreover, an integrative analysis of differential fecal taxa at the genus level and serum AA metabolites revealed significant associations. In addition, MeP and EtP enhanced lipid accumulation in AML12 cells and HepG2 cells cultured with oleic acid. 11,12-EET supplementation could significantly alleviate lipid accumulation by suppressing the expression of lipid metabolism-related genes and proteins. The present study suggests that chronic exposure to MeP and EtP promoted NAFLD via gut microbiota-dependent AA metabolism. These results highlight the need for reducing oral exposure to synthetic preservatives to improve metabolic disturbance under HFD conditions.

Methylparaben toxicity and its removal by microalgae Chlorella vulgaris and Phaeodactylum tricornutum.

The widespread occurrence of methylparaben (MPB) has aroused great concern due to its weak estrogenic endocrine-disrupting property and potential toxic effects. However, the degradation potential and pathway of MPB by microalgae have rarely been reported. Here, microalgae Chlorella vulgaris and Phaeodactylum tricornutum were used to investigate their responses, degradation potential and mechanisms towards MPB. MPB showed low-dose stimulation (by 86.02 ± 0.07% at 1 mg/L) and high-dose inhibition (by 60.17 ± 0.05% at 80 mg/L) towards the growth of C. vulgaris, while showed inhibition for P. tricornutum (by 6.99 ± 0.05%-20.14 ± 0.19%). The degradation efficiencies and rates of MPB were higher in C. vulgaris (100%, 1.66 ± 0.54-5.60 ± 0.86 day-1) than in P. tricornutum (4.3-34.2%, 0.04 ± 0.01-0.08 ± 0.00 day-1), which could be explained by the significantly higher extracellular enzyme activity and more fluctuation of the protein ratio for C. vulgaris, indicating a higher ability of C. vulgaris to adapt to pollutant stress. Biodegradation was the main removal mechanism of MPB for both the two microalgae. Furthermore, two different degradation pathways of MPB by the two microalgae were proposed. MPB could be mineralized and completely detoxified by C. vulgaris. Overall, this study provides novel insights into MPB degradation by microalgae and strategies for simultaneous biodegradation and detoxification of MPB in the environment.

Multiple Endocrine Disrupting Effects in Rats Perinatally Exposed to Butylparaben.

Parabens comprise a group of preservatives commonly added to cosmetics, lotions, and other consumer products. Butylparaben has estrogenic and antiandrogenic properties and is known to reduce sperm counts in rats following perinatal exposure. Whether butylparaben exposure can affect other endocrine sensitive endpoints, however, remains largely unknown. In this study, time-mated Wistar rats (n = 18) were orally exposed to 0, 10, 100, or 500 mg/kg bw/d of butylparaben from gestation day 7 to pup day 22. Several endocrine-sensitive endpoints were adversely affected. In the 2 highest dose groups, the anogenital distance of newborn male and female offspring was significantly reduced, and in prepubertal females, ovary weights were reduced and mammary gland outgrowth was increased. In male offspring, sperm count was significantly reduced at all doses from 10 mg/kg bw/d. Testicular CYP19a1 (aromatase) expression was reduced in prepubertal, but not adult animals exposed to butylparaben. In adult testes, Nr5a1 expression was reduced at all doses, indicating persistent disruption of steroidogenesis. Prostate histology was altered at prepuberty and adult prostate weights were reduced in the high dose group. Thus, butylparaben exerted endocrine disrupting effects on both male and female offspring. The observed adverse developmental effect on sperm count at the lowest dose is highly relevant to risk assessment, as this is the lowest observed adverse effect level in a study on perinatal exposure to butylparaben.

Toxicological evaluation of isopropylparaben and isobutylparaben mixture in Sprague-Dawley rats following 28 days of dermal exposure.

The alkyl esters of p-hydroxybenzoic acid (Parabens) have been of concern due to their probable endocrine disrupting property especially in baby consumer products. The safety of parabens for use as a preservative in cosmetics has come into controversy, and thus consumer demand for paraben-free products is ever increasing. Thus, more comprehensive studies are needed to conclusively determine the safety of the multiple prolonged exposure to parabens with cosmetic ingredients. This study was conducted to investigate the potential repeated 28 days dermal toxicity (50, 100, 300, or 600 mg/kg bw/day) of isopropylparaben (IPP), isobutylparaben (IBP), or the mixture of IPP and IBP in rats. There were no significant changes in body and organ weights in any group. However, histopathological examinations showed that weak or moderate skin damages were observed in female rats by macroscopic and microscopic evaluations. In female rats, no observed adverse effect levels (NOAELs) of IPP with no skin lesion and IBP for skin hyperkeratosis, were estimated to be 600 mg/kg bw/day, and 50 mg/kg bw/day, respectively. With regard skin hyperkeratosis, the lowest observed adverse effect level (LOAEL) of the mixture of IPP and IBP was estimated to be 50 mg/kg bw/day. Analysis of six serum hormones (estrogen, testosterone, insulin, T3, TSH, or FSH) in animals showed that only FSH was dose-dependently decreased in the mixture groups of 100 mg/kg bw/day or higher. These data suggest that the mixture of IPP and IBP showed a synergistic dermal toxicity in rats and should be considered for future use in consumer products.

Parabens. From environmental studies to human health.

Parabens are a group of substances commonly employed as preservatives, mainly in personal care products, pharmaceuticals and food. Scientific reports concerning their endocrine disrupting potential and the possible link with breast cancer raised wide discussion about parabens' impact and safety. This paper provides holistic overview of paraben usage, occurrence in the environment, methods of their degradation and removal from aqueous solution, as well as hazards related to their endocrine disrupting potential and possible involvement in carcinogenesis.

Influence of Genista tinctoria L. or methylparaben on subchronic toxicity of bisphenol A in rats.

OBJECTIVE: To evaluate the influence of an extract of Genista tinctoria L. herba (GT) or methylparaben (MP) on histopathological changes and 2 biomarkers of oxidative stress in rats subchronicly exposed to bisphenol A (BPA). METHODS: Adult female Wistar rats were orally exposed for 90 d to BPA (50 mg/kg), BPA+GT (35 mg isoflavones/kg) or BPA+MP (250 mg/kg). Plasma and tissue samples were taken from liver, kidney, thyroid, uterus, ovary, and mammary gland after 30, 60, and 90 d of exposure respectively. Lipid peroxidation and in vivo hydroxyl radical production were evaluated by histological analysis along with malondialdehyde and 2,3-dihydroxybenzoic acid detection. RESULTS: The severity of histopathological changes in liver and kidneys was lower after GT treatment than after BPA or BPA+MP treatment. A minimal thyroid receptor antagonist effect was only observed after BPA+MP treatment. The abnormal folliculogenesis increased in a time-dependent manner, and the number of corpus luteum decreased. No significant histological alterations were found in the uterus. The mammary gland displayed specific estrogen stimulation changes at all periods. Both MP and GT revealed antioxidant properties reducing lipid peroxidation and BPA-induced hydroxyl radical generation. CONCLUSION: GT L. extract ameliorates the toxic effects of BPA and is proved to have antioxidant potential and antitoxic effect. MP has antioxidant properties, but has either no effect or exacerbates the BPA-induced histopathological changes.

Toxicological evaluation of three contaminants of emerging concern by use of the Allium cepa test.

Di(2-ethylhexyl)phthalate, triclosan and propylparaben are contaminants of emerging concern that have been subjected to extensive toxicological studies, but for which limited information is currently available concerning adverse effects on terrestrial plant systems. The Allium cepa test, which is considered one of the most efficient approaches to assess toxic effects of environmental chemicals, was selected to evaluate the potential risks of these ubiquitous pollutants. Our data demonstrate that all three compounds studied may in some way be considered toxic, but different effects were noted depending on the chemical and the end point analysed. Results derived from the analysis of macroscopic parameters used in testing for general toxicity, revealed that while di(2-ethylhexyl)phthalate had no apparent effects, the other two chemicals inhibited A. cepa root growth in a dose-dependent manner. On the other hand, although all three compounds caused alterations in the mitotic index of root-tip cells, propylparaben was the only one that did not show evidence of genotoxicity in assays for chromosome aberrations and micronuclei. The results of the present study clearly indicate that sensitive plant bioassays are useful and complementary tools to determine environmental impact of contaminants of emerging concern.

Toxic effects of the easily avoidable phthalates and parabens.

Some environmental toxins like DDT and other chlorinated compounds accumulate in the body because of their fat-soluble nature. Other compounds do not stay long in the body, but still cause toxic effects during the time they are present. For serious health problems to arise, exposure to these rapidly-clearing compounds must occur on a daily basis. Two such classes of compounds are the phthalate plasticizers and parabens, both of which are used in many personal care products, some medications, and even foods and food preservation. The phthalates are commonly found in foods and household dust. Even though they have relatively short half-lives in humans, phthalates have been associated with a number of serious health problems, including infertility, testicular dysgenesis, obesity, asthma, and allergies, as well as leiomyomas and breast cancer. Parabens, which can be dermally absorbed, are present in many cosmetic products, including antiperspirants. Their estrogenicity and tissue presence are a cause for concern regarding breast cancer. Fortunately, these compounds are relatively easy to avoid and such steps can result in dramatic reductions of urinary levels of these compounds.

Ameliorative effects of ginger extract on paraben-induced lipid peroxidation in the liver of mice.

We have evaluated the ameliorative effect of ginger extract on paraben (p-hydroxybenzoic acid)-induced lipid peroxidation in the liver of mice. Adult female albino mice were orally administered with 2.25 or 4.50 mg of paraben in 0.2 mL olive/animal/day (67.5 and 135 mg/kg of body weight) for 30 days. The results revealed significantly higher (p < or = 0.05) lipid peroxidation in the liver of paraben-treated mice than that of controls. As compared with the controls, the levels of non-enzymatic antioxidants: glutathione and ascorbic acid, as well as the enzymatic antioxidants: superoxide dismutase, glutathione peroxidase and catalase were significantly (p < or = 0.05) lowered in the liver of paraben-treated mice. Oral administration of aqueous extract of Zinziber officinale (3 mg/animal/day) along with paraben for 30 days (Groups 6 and 7) caused significant (p < or = 0.05) amelioration in paraben-induced lipid peroxidation and increased significantly (p < or = 0.05) the activities of enzymatic (superoxide dismutase, glutathione peroxidase, catalase) and contents of non-enzymatic (glutathione and ascorbic acid) antioxidants in the liver of mice, as compared with those given paraben alone (Groups 4, 5). Thus, oral administration of aqueous extract of Zinziber officinale along with paraben significantly (p < or = 0.05) ameliorates paraben-induced lipid peroxidation in the liver of mice.

Comparative toxicity of preservatives on immortalized corneal and conjunctival epithelial cells.

PURPOSE: Nearly all eye drops contain preservatives to decrease contamination. Nonpreservatives such as disodium-ethylene diamine tetra-acetate (EDTA) and phosphate-buffered saline are also regularly added as buffering agents. These components can add to the toxicity of eye drops and cause ocular surface disease. To evaluate the potential toxicity of these common components and their comparative effects on the ocular surface, a tissue culture model utilizing immortalized corneal and conjunctival epithelial cells was utilized. METHODS: Immortalized human conjunctival and corneal epithelial cells were grown. At confluency, medium was replaced with 100 microL of varying concentrations of preservatives: benzalkonium chloride (BAK), methyl paraben (MP), sodium perborate (SP), chlorobutanol (Cbl), and stabilized thimerosal (Thi); varying concentrations of buffer: EDTA; media (viable control); and formalin (dead control). After 1 h, solutions were replaced with 150 microL of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazonium bromide). After 4 h, solutions decanted, 100 microL of acid isopropanol added, and the optical density determined at 572 nm to evaluate cell viability. RESULTS: Conjunctival and corneal cell toxicity was seen with all preservatives. Depending upon concentration, BAK exhibited from 56% to 89% toxicity. In comparison, Cbl exhibited from 50% to 86%, MP from 30% to 76%, SP from 23% to 59%, and Thi from 70% to 95%. EDTA with minimal toxicity (from 6% to 59%) was indistinguishable from SP. CONCLUSIONS: Generally, the order of decreasing toxicity at the most commonly used concentrations: Thi (0.0025%) > BAK (0.025%) > Cbl (0.25%) > MP (0.01%) > SP (0.0025%) approximately EDTA (0.01%). Even at low concentration, these agents will cause some degree of ocular tissue damage.

Images, femininity and cancer: an analysis of an international patient education programme.

This article is an analysis of a cancer patient education programme run by cosmetic companies. I focus on an analysis of imagery, arguing that there are particular discursive elements that the cosmetic companies use in order to make productive the relationship between femininity and cancer. I contextualize this education programme by presenting the controversies regarding cosmetics as they relate to the growth of breast tumours. In doing so, I conclude that conversations and questions about a link between chemicals and cancer are subverted by both ;horror' narratives of cancer and the provocative use of standards of beauty. Such discursive dominance in patient education programmes makes it difficult to engage in a more public understanding of cancer growth as affected by cosmetic chemicals.

Antioxidative effect of rhizome of Zinziber officinale on paraben induced lipid peroxidation: an in vitro study.

Antioxidative effect of aqueous extract of rhizome of Ginger (Zinziber officinale) was examined on p-hydroxybenzoic acid (paraben) induced lipid peroxidation. Addition of paraben (25-150 microg/mL) to liver and kidney homogenates significantly increases H2O2 induced lipid peroxidation in vitro. Effect was dose dependent up to 100 microg/mL concentration. An addition of aqueous extract of ginger significantly reduced paraben (100 microg/mL) induced lipid peroxidation in liver and kidney homogenates. The effect was concentration dependent.

Ginger extract ameliorates paraben induced biochemical changes in liver and kidney of mice.

The present investigation was undertaken to evaluate the effect of paraben (p-hydroxybenzoic acid) on acidic, basic, and neutral proteins content, as well as carbohydrate and cholesterol contents in liver and kidney of mice. Adult female albino mice were orally administrated with 2.25 and 4.5 mg of paraben in 0.2 mL of olive/animal/day for thirty days. The results revealed dose dependent, significant reduction in acidic, basic, and neutral protein, carbohydrate contents and an increase in cholesterol content of the investigated liver and kidney. Oral administration of aqueous extract of Zinziber officinale (3 mg/animal/day) along with paraben for thirty days caused significant amelioration in all the protein types, carbohydrate and cholesterol of liver and kidney.

Environmental oestrogens, cosmetics and breast cancer.

The established role of oestrogen in the development and progression of breast cancer raises questions concerning a potential contribution from the many chemicals in the environment which can enter the human breast and which have oestrogenic activity. A range of organochlorine pesticides and polychlorinated biphenyls possess oestrogen-mimicking properties and have been measured in human breast adipose tissue and in human milk. These enter the breast from varied environmental contamination of food, water and air, and due to their lipophilic properties can accumulate in breast fat. However, it is emerging that the breast is also exposed to a range of oestrogenic chemicals applied as cosmetics to the underarm and breast area. These cosmetics are left on the skin in the appropriate area, allowing a more direct dermal absorption route for breast exposure to oestrogenic chemicals and allowing absorbed chemicals to escape systemic metabolism. This review considers evidence in support of a functional role for the combined interactions of cosmetic chemicals with environmental oestrogens, pharmacological oestrogens, phyto-oestrogens and physiological oestrogens in the rising incidence of breast cancer.

Developmental toxicity evaluation of butylparaben in Sprague-Dawley rats.

The developmental toxicity potential of butylparaben (CAS No. 94-26-8) was evaluated in rats. Sprague-Dawley rats were administered butylparaben in 0.5% carboxymethylcellulose by oral gavage at dose levels of 0, 10, 100, or 1,000 mg/kg/day on gestation days (GD) 6-19 (sperm positive day = GD 0). Caesarean sections were performed on GD 20 and fetuses were evaluated for viability, growth, and external, visceral, and skeletal abnormalities. Each group consisted of 25 females, with at least 21 per group being pregnant. The highest dose level caused decreases in maternal weight gain during some of the measurement intervals and was statistically significant during the GD 18-20 interval. Maternal food consumption was significantly decreased in the highest dose group over the dosing period (GD 6-20). There were no differences from control in any of the developmental parameters measured, including embryo/fetal viability, fetal weight, malformations, or variations. Based on the results of this study, the maternal NOAEL for butylparaben was 100 mg/kg/day. Butylparaben does not have the potential to cause developmental toxicity in the Sprague-Dawley rat at oral dosages up to 1000 mg/kg/day.

Effects of butylparaben on the male reproductive system in rats.

Parabens are a group of compounds widely used as preservatives in foodstuffs, cosmetics, toiletries and pharmaceuticals. These compounds are known to exert a weak estrogenic activity, with butylparaben showing the most potent activity among methyl-, ethyl- and propyl esters in in vitro recombinant yeast assay and in in vivo uterotrophic assay. To account for potential reproductive effects in male animals, butylparaben was administered to 3-week-old Wistar rats divided in groups of eight subjects, at doses of 0.00%, 0.01%, 0.10% and 1.00% with the animal's diet. After 8 weeks, the rats were killed by decapitation and the weights of the testes, epididymides, prostates, seminal vesicles and preputial glands were recorded. The absolute and relative weights of epididymides were decreased in a dose-dependent manner and the decrease was statistically significant at 0.10% and above. The cauda epididymal sperm reserve of all treated groups was significantly decreased. The sperm count of the group receiving the highest dose was 58.2% of control values. The daily sperm production (DSP) in the testis was also significantly lower in all treated groups when compared to controls. Serum testosterone concentration was lowered dose-dependently and was significant at 0.1% or more. The daily intake of butylparaben that caused these disruptions is similar to the lower level of acceptable daily intake (ADI) for parabens in the European Community (EC) and in Japan. The results of the present experiments show for the first time that exposure of a postweaning mammal to butylparaben had an adverse effect on the secretion of testosterone and in the functions of the male reproductive system.

Lidocaine-induced bronchoconstriction in asthmatic patients. Relation to histamine airway responsiveness and effect of preservative.

Inhaled topical lidocaine, used to produce anesthesia of the respiratory tract prior to bronchoscopy, may cause bronchoconstriction in asthmatic patients. We investigated whether the degree of histamine airway responsiveness would predict the development and extent of lidocaine-induced bronchoconstriction in 20 asthmatic patients. The provocation concentration of histamine producing a 20 percent fall in FEV1 (PC20) was measured. On a separate day, challenge with 6 ml 4 percent lidocaine (Xylocaine 4 percent topical) was performed. There was no correlation between the response to lidocaine and the histamine PC20. Five patients (25 percent) showed a fall in FEV1 of greater than 15 percent (max 42.1 percent). Three responders were rechallenged double-blind with the commercial 4 percent lidocaine preparation and with a 4 percent preservative-free lidocaine solution. There was no difference in the response to these two solutions. These results demonstrate that inhaled topical lidocaine induces bronchoconstriction in a significant proportion of patients with asthma. This response is not related to airway histamine responsiveness or to the preservative in the lidocaine preparation.