In utero exposure to endocrine-disrupting chemicals,maternal factors and alterations in the epigenetic landscape underlying later-life health effects

Widespread persistence of endocrine-disrupting chemicals (EDCs) in the environment has mandated the need to study their potential effects on an individual's long-term health after both acute and chronic exposure periods. In this review article a particular focus is given on in utero exposure to EDCs in rodent models which resulted in altered epigenetic programming and transgenerational effects in the offspring causing disrupted reproductive and metabolic phenotypes. The literature to date establishes the impact of transgenerational effects of EDCs potentially associated with epigenetic mediated mechanisms. Therefore, this review aims to provide a comprehensive overview of epigenetic programming and it’s regulation in mammals, primarily focusing on the epigenetic plasticity and susceptibility to exogenous hormone active chemicals during the early developmental period. Further, we have also in depth discussed the epigenetic alterations associated with the exposure to selected EDCs such as Bisphenol A (BPA), di-2-ethylhexyl phthalate (DEHP) and vinclozlin upon in utero exposure especially in rodent models.     

环境内分泌干扰物的检测分析研究近况

综述近年来国内外针对不同环境样品中内分泌干扰物的检测分析研究，分类介绍了液体、固体或类固体环境样品的前处理技术以及环境内分泌干扰物的各种仪器分析和生物学分析方法。     

棉酚与人血清白蛋白相互作用及其分子模拟研究

摘 要 目的： 探讨棉酚与人血清白蛋白(HSA)的相互作用。方法: 采用荧光光谱方法研究在生理条件下,棉酚与人血清白蛋白（HSA）的相互作用,并采用分子对接软件模拟棉酚与人血清白蛋相互作用。结果:棉酚与HSA的结合常数为2.390 6×10⁵ L·mol^-1 (293K) 和3.576 8×10³ L·mol^-1（303K）, 具有一个结合位点,结合反应的主要作用力为氢键和范德华力,结合位置更接近于人血清白蛋白的酪氨酸残基,分子模拟分析也证实此结果。结论: 棉酚对人血清白蛋白的荧光猝灭机制属于静态荧光猝灭。     

Selected polychlorobiphenyls congeners bind to estrogen receptor alpha in human umbilical vascular endothelial (HUVE) cells modulating angiogenesis

Endocrine disrupting chemicals (EDCs) can behave as agonists or antagonists of several hormone receptors, thus mimicking or antagonizing the physiological activity of endogenous ligands. The involvement of estrogens in the regulation of angiogenesis has convincingly been demonstrated by a large body of experimental studies. Some polychlorobiphenyls (PCBs), considered EDCs, interact with estrogen receptors (ERs), so it is possible that these exogenous compounds affect the angiogenic process. Using fluorescence polarization, we firstly assayed whether PCB 77 (3,3',4,4'-tetrachlorobiphenyl), PCB 153 (2,2',4,4',5,5'-hexachlorobiphenyl) and PCB 156 (2,3,3',4,4',5-hexachlorobiphenyl) were able to bind to the alpha isoform of ER, recently found to be involved in angiogenesis. To discriminate the putative agonist or antagonist binding behaviour of these compounds, we tested their ability to activate, similarly to the natural ligand 17-beta-estradiol (17betaE(2)), the extracellular-signal-regulated kinase (Erk) 1/2 in human umbilical vascular endothelial (HUVE) cells. Finally, by using a new angiogenic assay, we evaluated the effect of PCBs treatment on microvessels neoformation. The data obtained in the present study showed that all the PCBs tested were able to bind to ERalpha and to elicit a response which can be agonistic or antagonistic; moreover, PCB 153 and PCB 77 can either positively or negatively modulate the angiogenic process, thus behaving as EDCs in endothelial cells.     

Transcriptional and morphological effects of tamoxifen on the early development of zebrafish (Danio rerio)

Tamoxifen is a widely used anticancer drug with both an estrogen agonist and antagonist effect. This study focused on its endocrine disrupting effect, and overall environmental significance. Zebrafish embryos were exposed to different concentrations (0.5, 5, 50 and 500 µg l^–1) of tamoxifen for 96 h. The results showed a complex effect of tamoxifen on zebrafish embryo development. For the 500 µg l^–1 exposure group, the heart rate was decreased by 20% and mild defects in caudal fin and skin were observed. Expressions of a series of genes related to endocrine and morphological changes were subsequently tested through quantitative real‐time polymerase chain reaction. Bisphenol A as a known estrogen was also tested as an endocrine‐related comparison. Among the expression of endocrine‐related genes, esr1, ar, cyp19a1b, hsd3b1 and ugt1a1 were all increased by tamoxifen exposure, similar to bisphenol A. The cyp19a1b is a key gene that controls estrogen synthesis. Exposure to 0.5, 5, 50 and 500 µg l^–1 of tamoxifen caused upregulation of cyp19a1b expression to 152%, 568%, 953% and 2024% compared to controls, higher than the effects from the same concentrations of bisphenol A treatment, yet vtg1 was suppressed by 24% from exposure to 500 µg l^–1 tamoxifen. The expression of metabolic‐related genes such as cyp1a, cyp1c2, cyp3a65, gpx1a, gstp1, gsr and genes related to observed morphological changes such as krt17 were also found to be upregulated by high concentrations of tamoxifen. These findings indicated the potential environmental effect of tamoxifen on teleost early development. Copyright © 2015 John Wiley & Sons, Ltd.     

Advancing research on endocrine disrupting chemicals in breast cancer: Expert panel recommendations

Breast cancer incidence continues to increase in the US and Europe, a reflection of the growing influence of environment factors that interact with personal genetics. The US Environmental Protection Agency estimates that there are approximately 10,000 endocrine disrupting chemicals among the common daily exposures that could affect the risk of disease. The daunting tasks of identifying, characterizing, and elucidating the mechanisms of endocrine disrupting chemicals in breast cancer need to be addressed to produce a comprehensive model that will facilitate preventive strategies and public policy. An expert panel met to describe and bring attention to needs linking common environmental exposures, critical windows of exposure, and optimal times of assessment in investigating breast cancer risk. The group included investigators with extensive experience in the use of rodent models and in leading population studies and produced a set of recommendations for effective approaches to gaining insights into the environmental origins of breast cancer across the lifespan.     

What is in our environment that effects puberty?

Recent studies indicate that the onset of puberty is occurring at increasingly younger ages. Many etiologies have been hypothesized to be involved, but environmental exposures are among the most worrisome. Multiple organizations have endorsed the need to study and provide clinical awareness regarding the effect of a child's environment on pubertal timing. This review article summarizes the current understanding of the major environmental influences on pubertal timing, focusing on factors for which the most scientific evidence exists. The research reviewed addresses intrinsic factors unique to each individual, naturally occurring endocrine disruptors and chemical endocrine disruptors. In each category, evidence was found for and against the involvement of specific environmental factors on pubertal timing. Ultimately, an individual's environment is likely comprised of many aspects that collectively contribute to the timing of puberty. The need for research aimed at elucidating the effects of numerous specific yet disparate forms of exposures is emphasized.     

Characterization of the mangiferin–human serum albumin complex by spectroscopic and molecular modeling approaches

The interactions between mangiferin and human serum albumin (HSA) were investigated by spectroscopy and molecular modeling. The results proved the formation of complex between mangiferin and HSA. Hydrophobic interaction dominated in the association reaction. Mangiferin statically quenched the fluorescence of HSA in a concentration dependent manner positively deviating from the linear Scatchard equation. The binding of mangiferin to HSA lead to changes in the conformation of HSA according to synchronous fluorescence spectra, FT-IR, UV–vis and CD data. The presence of amino acids and metal ion affected the binding constant of mangiferin–HSA complex. Computational mapping of the possible binding sites of mangiferin revealed the molecule to be bound in the large hydrophobic cavity of subdomain IIA.     

Effects of endocrine active contaminating pesticides on RACK1 expression and immunological consequences in THP-1 cells

We have previously demonstrated that RACK1, which expression is under steroid hormone control, plays an important role in the activation of immune cells and its expression can be useful to evaluate the immunotoxic profile of endocrine disrupting chemicals (EDCs). Hence, we investigated the effects of three contaminating and persistent pesticides: the fungicide vinclozolin (VIN), the herbicide atrazine (ATR) and the insecticide cypermethrin (CYP) on RACK1 expression and on innate immune response. VIN resulted in modest alteration of RACK1 while ATR and CYP reduced in a dose dependent manner RACK1 expression, ultimately leading to the decrease in lipopolysaccharide‐induced IL‐8 and TNF-α release and CD86 and CD54 surface marker expression. Moreover, our data indicate that, after exposure to EDCs, alterations of RACK1 expression can also occur with mechanisms not directly mediated by an interaction with a nuclear or membrane steroid receptors. Therefore, RACK1 could represent a useful EDCs screening tool to evaluate their immunotoxic potential and to dissect their mechanisms of action.     

Preferential binding of insecticide phorate with sub-domain IIA of human serum albumin induces protein damage and its toxicological significance

Phorate, an organophosphorus insecticide is known for its adverse effects on acetylcholinesterase, and other neuronal and pulmonary activities. Most likely, the toxicity of drugs/agrochemicals is modulated through cellular distribution bound to plasma proteins. Therefore, the in vitro interaction of phorate with human serum albumin (HSA) has been investigated, using sensitive techniques like fluorescence spectroscopy and circular dichroism, to ascertain its binding mechanism and toxicological implications. Fluorescence studies revealed the quenching constant (Ksv) as 2.5 × 10⁴ M⁻¹ and binding affinity (Ka) as 2.96 × 10⁴ M⁻¹ (r² = 0.99), with a primary binding site of phorate at sub-domain IIA of HSA. Circular dichroism (CD) data demonstrated a noticeable reduction in secondary structure (α-helical content) of phorate treated HSA. Albumin treated with 200-1000 μM phorate released significant amounts of acid soluble amino and carbonyl groups, whereas higher concentrations resulted in protein fragmentation. It is postulated that the 1′-O and 3-O alkyl groups of phorate have a role in binding with electrophilic centers of Trp 214, and Arg 218/Lys 195, respectively. Moreover, the significant ultrastructural changes, reactive oxygen species (ROS) generation, mitochondrial damage and cell death in phorate treated cultured human amnion epithelial (WISH) cells, elucidated phorate induced cellular toxicity.