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A Ternary Mixture of Common Chemicals Perturbs Benign Human Breast Epithelial Cells More Than the Same Chemicals Do Individually.

ABSTRACT: As a continuous source of hormonal stimulation, environmentally ubiquitous estrogenic chemicals, ie, xenoestrogens (XEs), are a potential risk factor for breast carcinogenesis. Given their wide distribution in the environment and the fact that bisphenol-A (BPA), methylparaben (MP), and perfluorooctanoic acid (PFOA) are uniformly detected in unselected body fluid samples, it must be assumed that humans are simultaneously exposed to these chemicals almost daily. We studied the effects of a ternary mixture of BPA, MP, and PFOA on benign breast epithelial cells at the range of concentrations observed for single chemicals in human samples. Measurements of exposure impact relevant to the breast were based on endpoints associated with "hallmarks" of cancer and "key characteristics" of carcinogens. These included modulation of total estrogen receptor (ER)?, phosphorylated ER? (pER?), total ER?, S-phase induction, and apoptotic evasion. Data from live cell measurements were fit to a log-linear dose-response model. Concentration-dependent reduction of ER? and apoptosis evasion was observed concurrently with the induction of ER?, pER?, and S-phase fraction, and an increased rate of cell proliferation. Beyond additive effects predicted by the sum of individual test XEs, mixture treatment demonstrated synergism for the ER? and apoptosis suppression phenotypes (p > .001). Nonmalignant breast cells were more sensitive than commonly used breast cancer lines to XE treatment in 3 of 5 endpoints. All observations were validated with cells isolated from the normal breast tissue of 14 individuals. At relatively low concentrations, a chemical mixture has striking effects on normal cell function that are missed by evaluation of single components.

SUBMITTER: Dairkee SH

PROVIDER: S-EPMC6135635 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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A Ternary Mixture of Common Chemicals Perturbs Benign Human Breast Epithelial Cells More Than the Same Chemicals Do Individually.

Dairkee Shanaz H SH Luciani-Torres Gloria G Moore Dan H DH Jaffee Ian M IM Goodson William H WH

Toxicological sciences : an official journal of the Society of Toxicology 20180901 1

As a continuous source of hormonal stimulation, environmentally ubiquitous estrogenic chemicals, ie, xenoestrogens (XEs), are a potential risk factor for breast carcinogenesis. Given their wide distribution in the environment and the fact that bisphenol-A (BPA), methylparaben (MP), and perfluorooctanoic acid (PFOA) are uniformly detected in unselected body fluid samples, it must be assumed that humans are simultaneously exposed to these chemicals almost daily. We studied the effects of a ternary ...[more]

PMID: 29846718

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Project description:AIMS:Many glandular lesions can mimic prostate cancer microscopically, including atrophic glands, adenosis and prostatic intraepithelial neoplasia. While the characteristic histopathological and immunohistochemical features of these lesions have been well established, little is known about their three-dimensional architecture. Our objective was to evaluate the three-dimensional organisation of common prostate epithelial lesions. METHODS AND RESULTS:500 ?m-thick punches (n = 42) were taken from radical prostatectomy specimens, and stained with antibodies targeting keratin 8-18 and keratin 5 for identification of luminal and basal cells, respectively. Tissue samples were optically cleared in benzyl alcohol:benzyl benzoate and imaged using a confocal laser scanning microscope. The three-dimensional architecture of peripheral and transition zone glands was acinar, composed of interconnecting and blind-ending saccular tubules. In simple atrophy, partial atrophy and post-atrophic hyperplasia, the acinar structure was attenuated with branching blind-ending tubules from parental tubular structures. Three-dimensional imaging revealed a novel variant of prostate atrophy characterised by large Golgi-like atrophic spaces parallel to the prostate surface, which were represented by thin, elongated tubular structures on haematoxylin and eosin (H&E) slides. Conversely, adenosis lacked acinar organisation, so that it closely mimicked low-grade prostate cancer. High-grade prostatic intraepithelial neoplasia displayed prominent papillary intraluminal protrusions but retained an acinar organisation, whereas intraductal carcinoma predominantly consisted of cribriform proliferations with either spheroid, ellipsoid or complex interconnecting lumens. CONCLUSIONS:While various prostate epithelial lesions might mimic malignancy on H&E slides, their three-dimensional architecture is acinar and clearly different from the tubular structure of prostate cancer, with adenosis as an exception.

Project description:BackgroundCommon cold and cough preparations represent a huge segment of the global pharmaceutical market. Recently, cold/cough formulations containing paracetamol (PAR) have attracted significant attention as PAR has been implemented into the supportive treatment of mild cases of COVID-19 as the first-line antipyretic. From a literature review, no method has been reported yet for simultaneous estimation of PAR, pseudoephedrine hydrochloride (PSE) and carbinoxamine maleate (CRX) in any matrix. Thus, there is an urgent need for smart and green methods that would enable quantification of the cited components in their challenging ratio.ObjectivesThe aim of this work is to develop and validate the first UV spectrophotometric methods for simultaneous determination of the selected drugs taking into consideration the list of challenges including the highly overlapping features and spectral interferences in the cited mixture.MethodsNamely, the proposed methods are: direct spectrophotometry, dual wavelength, first derivative, derivative ratio, ratio difference, constant center coupled with spectrum subtraction, and the constant multiplication method paired with spectrum subtraction.ResultsThese methods were linear over the concentration range of 2.5-35, 1.5-20, and 4.5-35 μg/mL for PAR, PSE and CRX, respectively. These methods fulfill the validity parameters according to International Conference on Harmonization (ICH) guidelines. The results obtained were statistically benchmarked to the official ones where no significant difference was noticed.ConclusionThe developed methods are successfully applied for concurrent quantification of the studied components in the marketed dosage form without interference from matrix excipients. The impact on the environment was assessed by five green metrics, namely a recent Analytical greenness (AGREE) metric algorithm based on the green analytical chemistry framework, Green Analytical Procedure Index (GAPI), Eco-Scale, Assessment of Green Profile (AGP), and National Environmental Methods Index (NEMI).HighlightsEco-friendly and successive spectrophotometric methods were firstly developed in this work, for the simultaneous quantification of PAR, PSE and CRX. These approaches incorporate a simple enrichment-aided technique to augment their spectrophotometric signals, facilitating the accurate quantitation of the minor component in the cited mixture.

Dataset Information

A Ternary Mixture of Common Chemicals Perturbs Benign Human Breast Epithelial Cells More Than the Same Chemicals Do Individually.

Publications

A Ternary Mixture of Common Chemicals Perturbs Benign Human Breast Epithelial Cells More Than the Same Chemicals Do Individually.

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