The Pragmatic Strategy to Detect Endocrine-Disrupting Activity of Xenobiotics in Food

Endocrine-disrupting activity induced by xenobiotics might pose a possible health threat. Facing so many chemicals, there is an issue on how we detect them precisely and effectively. The whole embryo culture (WEC) test, an ex vivo exposure lasting 48 hours with rat embryos of 10.5 days old, is used to detect prenatal developmental toxicity. We extended the WEC function to detect the endocrine-disrupting activity induced by environmental chemicals. Results showed that in the development of rat embryo, basically 17ß-estradiol, triiodothyronine, triadimefon, penconazole, and propiconazole exhibited no significant effect on yolk sac circulatory system, allantois, flexion, heart caudal neural tube, hindbrain, midbrain, forebrain, otic system, optic system, olfactory system, maxillary process, forelimb, hind limb, yolk sac diameter, crown-rump length, head length, and developmental score. In the immunohistochemistry, the positive control of 17ß-estradiol showed positive effect for its receptor expressions. These three triazoles induced expressions of ERα and ERß in WEC. This result basically meets the mode of action that triazoles were designed to disrupt the synthesis of steroid hormone. Here we gave a strategy to detect possible endocrine-disrupting activity induced by xenobiotics in food. This strategy is quick to initiate the whole rat embryo culture with 10.5 days to detect the hormone receptors such as androgen, estrogen, thyroid, aromatase activity and its related receptors

Epigenetic Effects and Molecular Mechanisms of Tumorigenesis Induced by Cigarette Smoke: An Overview

Cigarette smoking is one of the major causes of carcinogenesis. Direct genotoxicity induced by cigarette smoke leads to initiation of carcinogenesis. Nongenotoxic (epigenetic) effects of cigarette smoke also act as modulators altering cellular functions. These two effects underlie the mechanisms of tumor promotion and progression. While there is no lack of general reviews on the genotoxic and carcinogenic potentials of cigarette smoke in lung carcinogenesis, updated review on the epigenetic effects and molecular mechanisms of cigarette smoke and carcinogenesis, not limited to lung, is lacking. We are presenting a comprehensive review of recent investigations on cigarette smoke, with special attentions to nicotine, NNK, and PAHs. The current understanding on their molecular mechanisms include (1) receptors, (2) cell cycle regulators, (3) signaling pathways, (4) apoptosis mediators, (5) angiogenic factors, and (6) invasive and metastasis mediators. This review highlighted the complexity biological responses to cigarette smoke components and their involvements in tumorigenesis

Deltamethrin Alters Thyroid Hormones and Delays Pubertal Development in Male and Female Rats

Pyrethroid insecticides are suspected endocrine-disrupting chemicals. Deltamethrin has been reported to antagonize thyroid hormone receptor activity in a reporter assay. We hypothesized that deltamethrin alters thyroid function. Male and female rats were administered daily oral gavages with 0, 0.3, 1, or 3 mg/kg/day deltamethrin on postnatal days 23–53 and 22–42, respectively. Results showed that deltamethrin decreased the relative thyroid weight in 0.3 and 1 mg/kg/day in female but not in male rats. Although the histology and several parameters of thyroid were not affected, the decreased relative weight exhibited underlying meaning. Deltamethrin delayed the age of vaginal opening (VO) and increased body weight upon VO in 3 mg/kg/day. Deltamethrin failed to delay the age of preputial separation in male rats. In the respective of serum hormone concentration, deltamethrin increased 17β-estradiol (E2) with dose-dependent manner in female rats. The novel finding is that deltamethrin decreased thyroxine (T4), triiodothyronine (T3), and thyroid-stimulating hormone (TSH) in the female rats. In contrast, deltamethrin increased T3 and TSH but not in T4 in male rats. We inferred that deltamethrin disrupts thyroid hormone and might be related to estrogen receptor agonist. The future work is to investigate if deltamethrin disrupts the hypothalamus-pituitary-thyroid axis

Persistent Tissue Kinetics and Redistribution of Nanoparticles, Quantum Dot 705, in Mice: ICP-MS Quantitative Assessment

Background: Quantum dots (QDs) are autofluorescent semiconductor nanocrystals that can be used for in vivo biomedical imaging. However, we know little about their in vivo disposition and health consequences. Objectives: We assessed the tissue disposition and pharmacokinetics of QD705 in mice. Methods: We determined quantitatively the blood and tissue kinetics of QD705 in mice after single intravenous (iv) injection at the dose of 40 pmol for up to 28 days. Inductively coupled plasma–mass spectrometry (ICP-MS) measurement of cadmium was the primary method of quantification of QD705. Fluorescence light microscopy revealed the localization of QD705 in tissues. Results: Plasma half-life of QD705 in mice was short (18.5 hr), but ICP-MS analyses revealed QD705 persisted and even continued to increase in the spleen, liver, and kidney 28 days after an iv dose. Considerable time-dependent redistribution from body mass to liver and kidney was apparent between 1 and 28 days postdosing. The recoveries at both time points were near 100%; all QD705s reside in the body. Neither fecal nor urinary excretion of QD705 was detected appreciably in 28 days postdosing. Fluorescence microscopy demonstrated deposition of QD705 in the liver, spleen, and kidneys. Conclusion: Judging from the continued increase in the liver (29–42% of the administered dose), kidney (1.5–9.2%), and spleen (4.8–5.2%) between 1 and 28 days without any appreciable excretion, QD705 has a very long half-life, potentially weeks or even months, in the body and its health consequences deserve serious consideration

Mitochondrial Apoptosis and FAK Signaling Disruption by a Novel Histone Deacetylase Inhibitor, HTPB, in Antitumor and Antimetastatic Mouse Models

BACKGROUND: Compound targeting histone deacetylase (HDAC) represents a new era in molecular cancer therapeutics. However, effective HDAC inhibitors for the treatment of solid tumors remain to be developed. METHODOLOGY/PRINCIPAL FINDINGS: Here, we propose a novel HDAC inhibitor, N-Hydroxy-4-(4-phenylbutyryl-amino) benzamide (HTPB), as a potential chemotherapeutic drug for solid tumors. The HDAC inhibition of HTPB was confirmed using HDAC activity assay. The antiproliferative and anti-migratory mechanisms of HTPB were investigated by cell proliferation, flow cytometry, DNA ladder, caspase activity, Rho activity, F-actin polymerization, and gelatin-zymography for matrix metalloproteinases (MMPs). Mice with tumor xenograft and experimental metastasis model were used to evaluate effects on tumor growth and metastasis. Our results indicated that HTPB was a pan-HDAC inhibitor in suppressing cell viability specifically of lung cancer cells but not of the normal lung cells. Upon HTPB treatment, cell cycle arrest was induced and subsequently led to mitochondria-mediated apoptosis. HTPB disrupted F-actin dynamics via downregulating RhoA activity. Moreover, HTPB inhibited activity of MMP2 and MMP9, reduced integrin-β1/focal adhesion complex formation and decreased pericellular poly-fibronectin assemblies. Finally, intraperitoneal injection or oral administration of HTPB efficiently inhibited A549 xenograft tumor growth in vivo without side effects. HTPB delayed lung metastasis of 4T1 mouse breast cancer cells. Acetylation of histone and non-histone proteins, induction of apoptotic-related proteins and de-phosphorylation of focal adhesion kinase were confirmed in treated mice. CONCLUSIONS/SIGNIFICANCE: These results suggested that intrinsic apoptotic pathway may involve in anti-tumor growth effects of HTPB in lung cancer cells. HTPB significantly suppresses tumor metastasis partly through inhibition of integrin-β1/FAK/MMP/RhoA/F-actin pathways. We have provided convincing preclinical evidence that HTPB is a potent HDAC targeted inhibitor and is thus a promising candidate for lung cancer chemotherapy

Additive cardiotoxicity of a bisphenol mixture in zebrafish embryos: The involvement of calcium channel and pump

Bisphenol A (BPA) and its analogs, such as bisphenol F (BPF), bisphenol AF (BPAF), and bisphenol B (BPB), are often simultaneously detected in environmental and human specimens. Thus, assessing the toxicity of bisphenol (BP) mixtures is more relevant than assessing that of each BP type. Here, we found that BPs, individually or in a mixture, concentration-dependently and additively increased the mortality of zebrafish embryos (ZFEs) at 96 h post fertilization (hpf) and induced bradycardia (i.e., reduced heart rate) at 48 hpf, indicating their cardiotoxic potency. BPAF was the most potent, followed by BPB, BPA, and BPF. We then explored the mechanism underlying BP-induced bradycardia in ZFEs. Although BPs increased the mRNA expression of the estrogen-responsive gene, treatment with the estrogen receptor inhibitor ICI 182780 did not prevent BP-induced bradycardia. Because they did not change cardiomyocyte counts or heart development–related gene expression, BPs might not affect cardiomyocyte development. By contrast, BPs might impair calcium homeostasis during cardiac contraction and relaxation through the downregulation of the expression of the mRNAs for the pore-forming subunit of L-type Ca2+ channel (LTCC; cacna1c) and sarco/endoplasmic reticulum Ca2+-ATPase (SERCA; atp2a2a). BPs reduced SERCA activity significantly. BPs also potentiated the cardiotoxicity induced by the LTCC blocker nisoldipine, conceivably by inhibiting SERCA activity. In conclusion, BPs additively induced bradycardia in ZFEs, possibly by impeding calcium homeostasis during cardiac contraction and relaxation. BPs also potentiated the cardiotoxicity of calcium channel blockers

A novel multitask learning algorithm for tasks with distinct chemical space: zebrafish toxicity prediction as an example

Abstract Data scarcity is one of the most critical issues impeding the development of prediction models for chemical effects. Multitask learning algorithms leveraging knowledge from relevant tasks showed potential for dealing with tasks with limited data. However, current multitask methods mainly focus on learning from datasets whose task labels are available for most of the training samples. Since datasets were generated for different purposes with distinct chemical spaces, the conventional multitask learning methods may not be suitable. This study presents a novel multitask learning method MTForestNet that can deal with data scarcity problems and learn from tasks with distinct chemical space. The MTForestNet consists of nodes of random forest classifiers organized in the form of a progressive network, where each node represents a random forest model learned from a specific task. To demonstrate the effectiveness of the MTForestNet, 48 zebrafish toxicity datasets were collected and utilized as an example. Among them, two tasks are very different from other tasks with only 1.3% common chemicals shared with other tasks. In an independent test, MTForestNet with a high area under the receiver operating characteristic curve (AUC) value of 0.911 provided superior performance over compared single-task and multitask methods. The overall toxicity derived from the developed models of zebrafish toxicity is well correlated with the experimentally determined overall toxicity. In addition, the outputs from the developed models of zebrafish toxicity can be utilized as features to boost the prediction of developmental toxicity. The developed models are effective for predicting zebrafish toxicity and the proposed MTForestNet is expected to be useful for tasks with distinct chemical space that can be applied in other tasks. Scieific contribution A novel multitask learning algorithm MTForestNet was proposed to address the challenges of developing models using datasets with distinct chemical space that is a common issue of cheminformatics tasks. As an example, zebrafish toxicity prediction models were developed using the proposed MTForestNet which provide superior performance over conventional single-task and multitask learning methods. In addition, the developed zebrafish toxicity prediction models can reduce animal testing

Metal-Based Nanoparticles and the Immune System: Activation, Inflammation, and Potential Applications

Nanomaterials, including metal-based nanoparticles, are used for various biological and medical applications. However, metals affect immune functions in many animal species including humans. Different physical and chemical properties induce different cellular responses, such as cellular uptake and intracellular biodistribution, leading to the different immune responses. The goals of this review are to summarize and discuss the innate and adaptive immune responses triggered by metal-based nanoparticles in a variety of immune system models