Bisphenol A Exposure Disrupts Genomic Imprinting in the Mouse

Exposure to endocrine disruptors is associated with developmental defects. One compound of concern, to which humans are widely exposed, is bisphenol A (BPA). In model organisms, BPA exposure is linked to metabolic disorders, infertility, cancer, and behavior anomalies. Recently, BPA exposure has been linked to DNA methylation changes, indicating that epigenetic mechanisms may be relevant. We investigated effects of exposure on genomic imprinting in the mouse as imprinted genes are regulated by differential DNA methylation and aberrant imprinting disrupts fetal, placental, and postnatal development. Through allele-specific and quantitative real-time PCR analysis, we demonstrated that maternal BPA exposure during late stages of oocyte development and early stages of embryonic development significantly disrupted imprinted gene expression in embryonic day (E) 9.5 and 12.5 embryos and placentas. The affected genes included Snrpn, Ube3a, Igf2, Kcnq1ot1, Cdkn1c, and Ascl2; mutations and aberrant regulation of these genes are associated with imprinting disorders in humans. Furthermore, the majority of affected genes were expressed abnormally in the placenta. DNA methylation studies showed that BPA exposure significantly altered the methylation levels of differentially methylated regions (DMRs) including the Snrpn imprinting control region (ICR) and Igf2 DMR1. Moreover, exposure significantly reduced genome-wide methylation levels in the placenta, but not the embryo. Histological and immunohistochemical examinations revealed that these epigenetic defects were associated with abnormal placental development. In contrast to this early exposure paradigm, exposure outside of the epigenetic reprogramming window did not cause significant imprinting perturbations. Our data suggest that early exposure to common environmental compounds has the potential to disrupt fetal and postnatal health through epigenetic changes in the embryo and abnormal development of the placenta.     

基因改造家兔在动脉粥样硬化研究中的应用

目前应用转基因和基因敲除小鼠的研究工作几乎成为各种国际高水平学术刊物的主流,而基因改造的家兔由于其独有的特点,在心血管研究中占有重要地位。本文从基因改造小鼠的最新研究进展着手,分析了基因修饰小鼠在动脉粥样硬化研究中的局限性,进而阐明基因改造家兔用于动脉粥样研究的优越性及研究近况。文章分析表明基因改造家兔技术及其应用必将在生物医学研究中发挥重要作用。     

Urotensin II Promotes Atherosclerosis in Cholesterol-Fed Rabbits

Urotensin II (UII) is a vasoactive peptide composed of 11 amino acids that has been implicated to contribute to the development of cardiovascular disease. The purpose of this study was to investigate whether UII affects the development of atherosclerosis in cholesterol-fed rabbits. UII was infused for 16 weeks through an osmotic mini-pump into male Japanese White rabbits fed on a high-cholesterol diet. Plasma lipids and body weight were measured every 4 weeks. Aortic atherosclerotic lesions along with cellular components, collagen fibers, matrix metalloproteinase-1 and -9 were examined. Moreover, vulnerability index of atherosclerotic plaques was evaluated. UII infusion significantly increased atherosclerotic lesions within the entire aorta by 21% over the control (P = 0.013). Atherosclerotic lesions were increased by 24% in the aortic arch (P = 0.005), 11% in the thoracic aorta (P = 0.054) and 18% in the abdominal aorta (P = 0.035). These increases occurred without changes in plasma levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides or body weight. Immunohistochemical staining revealed that macrophages and matrix metalloproteinase-9 were significantly enhanced by 2.2-fold and 1.6-fold in UII group. In vitro studies demonstrated that UII up-regulated the expression of vascular cell adhesion protein-1 and intercellular adhesion molecule-1 in human umbilical vein endothelial cells, which was inhibited by the UII receptor antagonist urantide. In conclusion, our results showed that UII promotes the development of atherosclerotic lesions and destabilizes atherosclerotic plaques in cholesterol-fed rabbits.     

Bisphenol A Exposure and Asthma Development in School-Age Children: A Longitudinal Study

Background

Although the effect of bisphenol A on various health outcomes has been extensively examined, few studies have investigated its effect on asthma.

Objective

We hypothesized that exposure to bisphenol A in school-age children was associated with wheezing and asthma.

Methods

Participants included 127 children aged 7–8 years without a previous asthma diagnosis in an elementary school in Seoul, Korea. Three surveys were conducted, each 2 years apart. Bisphenol A concentration was measured at the baseline survey, and PC₂₀, which is defined as the methacholine concentration that induces a decrease in FEV₁ of 20% from baseline, was measured at every survey. Associations between bisphenol A concentration at 7–8 years of age and wheezing, asthma, and PC₂₀ at ages up to 11–12 years were examined using generalized estimating equations, a marginal Cox regression model, and a linear mixed model.

Results

The log-transformed creatinine-adjusted urinary bisphenol A concentration at 7–8 years was positively associated with wheezing (odds ratio, 2.48; 95% confidence interval, 1.15–5.31; P = .02) and asthma (hazard ratio, 2.13; 95% confidence interval, 1.51–3.00; P<.001) at ages up to 11–12 years. Bisphenol A was also negatively associated with PC₂₀ (ß = −2.33; P = .02). When stratified by sex, the association between bisphenol A and asthma remained significant only in girls (hazard ratio, 2.45; 95% confidence interval, 2.18–2.76; P<.001).

Conclusion

Increased urinary bisphenol A concentrations at 7–8 years old were positively associated with wheezing and asthma and negatively associated with PC₂₀ at ages up to 11–12 years.     

Intermittent Cold Exposure Enhances Fat Accumulation in Mice

Due to its high energy consuming characteristics, brown adipose tissue (BAT) has been suggested as a key player in energy metabolism. Cold exposure is a physiological activator of BAT. Intermittent cold exposure (ICE), unlike persistent exposure, is clinically feasible. The main objective of this study was to investigate whether ICE reduces adiposity in C57BL/6 mice. Surprisingly, we found that ICE actually increased adiposity despite enhancing Ucp1 expression in BAT and inducing beige adipocytes in subcutaneous white adipose tissue. ICE did not alter basal systemic insulin sensitivity, but it increased liver triglyceride content and secretion rate as well as blood triglyceride levels. Gene profiling further demonstrated that ICE, despite suppressing lipogenic gene expression in white adipose tissue and liver during cold exposure, enhanced lipogenesis between the exposure periods. Together, our results indicate that despite enhancing BAT recruitment, ICE in mice increases fat accumulation by stimulating de novo lipogenesis.     

妊娠期和哺乳期双酚A暴露对幼年子代小鼠焦虑和抑郁行为的影响

双酚A(bisphenol-A,BPA)对脑和行为发育的低剂量效应已引起广泛关注。本研究分别于妊娠最后2周和分娩后前2周母鼠灌胃BPA(0.4和4 mg/kg.d),然后以旷场、高架十字迷宫、明暗箱、镜子迷宫、强迫游泳和被动回避箱等模型,分别测试幼年期(生后21～28 d)子代小鼠的行为,探讨围生期不同阶段的BPA暴露对幼年仔鼠自发活动、探究、焦虑、抑郁和被动回避记忆等行为的影响。结果表明,围生期不同阶段的BPA暴露对这些行为的影响不同,主要表现为:妊娠期BPA暴露促进幼年仔鼠的活动性,减弱其焦虑状态,提高雄性仔鼠的探究能力,促进雌性仔鼠的被动回避记忆;哺乳期BPA暴露减少幼年仔鼠的活动性,但对其焦虑行为的影响相对较弱,不影响仔鼠的探究能力和被动回避记忆;而妊娠期和哺乳期BPA暴露均加剧幼年仔鼠的抑郁行为。以上结果提示,妊娠期和哺乳期BPA暴露均可影响幼年仔鼠的焦虑、抑郁、被动回避记忆等多种行为,而妊娠期可能是BPA影响的更敏感时期。     

Developmental Exposure to Bisphenol A: Interaction with Endogenous Estradiol During Pregnancy in Mice

Individual variability in endogenous hormones can confound theinterpretation of effects of developmental exposure to endocrinedisrupting chemicals. In single-birth species, such as humans,there are many sources of variability in fetal sex hormone levels,such as birth order or race. In litter-bearing species a sourceof fetal variability in serum levels of estradiol and testosteroneis the sex of adjacent fetuses due to fetus-to-fetus steroidtransport (called the intrauterine position phenomenon or IUP).Distinct phenotypes of reproductive physiology and behaviorare due to IUP in house mice and other litter-bearing animals.We review here the effects of background levels of sex steroidsin fetuses due to IUP in an experiment in which pregnant micewere exposed to an environmentally relevant low dose of theestrogen-mimicking chemical, bisphenol A. Bisphenol A is themonomer used to make polycarbonate plastic products (such asbaby bottles), the resin lining of food and beverage cans, dentalsealants, and a host of other products. Fetal exposure via themother to bisphenol A increased the rate of postnatal growthin males and females and also advanced the timing of pubertyin females. However, the greatest response to bisphenol A occurredin males and females with the highest background levels of endogenousestradiol during fetal life due to their IUP, while fetuseswith the lowest endogenous levels of estradiol showed no responseto maternal bisphenol A treatment. This finding suggests thatestrogen-mimicking chemicals interact with endogenous estrogenin altering the course of development.     

动脉粥样硬化模型-大耳白家兔脑血管在体成像

动脉粥样硬化是中老年人的常见病,对人类的健康危害很大。应用激光扫描共聚焦显微镜,在不同刺激药物作用下对动脉粥样硬化大耳白家兔的脑血管形态进行了活体的实时动态观察。从脑血管的荧光图像和血管横截面的荧光强度分布可获取正常与异常状态血管内血流状态的相关形态学和流变学参数,从而提供对血管的阻塞状况以及形成机理进行研究的重要信息。     

High Intake of Dietary Sugar Enhances Bisphenol A (BPA) Disruption and Reveals Ribosome-Mediated Pathways of Toxicity

Bisphenol A (BPA) is an organic compound to which human populations are ubiquitously exposed. Epidemiological data suggest BPA exposure might be associated with higher rates of diabetes and reproductive anomalies. Health concerns also include transgenerational consequences, but these mechanisms are crudely defined. Similarly, little is known about synergistic interactions between BPA and other substances. Here we show that acute and chronic exposure to BPA causes genome-wide modulation of several functionally coherent genetic pathways in the fruit fly Drosophila melanogaster. In particular, BPA exposure causes massive downregulation of testis-specific genes and upregulation of ribosome-associated genes widely expressed across tissues. In addition, it causes the modulation of transposable elements that are specific to the ribosomal DNA loci, suggesting that nucleolar stress might contribute to BPA toxicity. The upregulation of ribosome-associated genes and the impairment of testis-specific gene expression are significantly enhanced upon BPA exposure with a high-sugar diet. Our results suggest that BPA and dietary sugar might functionally interact, with consequences to regulatory programs in both reproductive and somatic tissues.     

Egg Cortisol Exposure Enhances Fearfulness in Larvae and Juvenile Rainbow Trout

We investigated the effects of an early boost of cortisol exposure in rainbow trout (Oncorhynchus mykiss) eggs during fertilisation on subsequent behavioural responses when exposed to a sudden stimulus in larvae and juveniles. At 55 d post‐fertilisation (dpf), treatment had no effect on high accelerations occurring after a sudden event. At 146 dpf, these high accelerations were more frequent in cortisol‐treated fish than in controls. At 146 dpf also, swimming activity was increased in cortisol‐treated fish both before and after the sudden stimulus. This study underlines the important behavioural modifications in both larvae and juveniles, linked to a change in the surrounding environment of the embryo. Indeed, fish exposed to cortisol as eggs showed a higher level of fearfulness later in life. Our findings are of major interest for stress management in an aquaculture context and also allow for a better understanding of the long‐lasting effects of a permanent and/or acute stress – mediated by cortisol – that could be encountered by females, affecting population's life history trajectory.     

Endogenous Androgen Deficiency Enhances Diet-Induced Hypercholesterolemia and Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

BackgroundDespite numerous clinical and animal studies, the role of sex steroid hormones on lipoprotein metabolism and atherosclerosis remain controversial.ObjectiveWe sought to determine the effects of endogenous estrogen and testosterone on lipoprotein levels and atherosclerosis using mice fed a low-fat diet with no added cholesterol.MethodsMale and female low-density lipoprotein receptor-deficient mice were fed an open stock low-fat diet (10% of kcals from fat) for 2, 4, or 17 weeks. Ovariectomy, orchidectomy, or sham surgeries were performed to evaluate the effects of the presence or absence of endogenous hormones on lipid levels, lipoprotein distribution, and atherosclerosis development.ResultsFemale mice fed the study diet for 17 weeks had a marked increase in levels of total cholesterol, triglycerides, apolipoprotein-B containing lipoproteins, and atherosclerosis compared with male mice. Surprisingly, ovariectomy in female mice had no effect on any of these parameters. In contrast, castration of male mice markedly increased total cholesterol concentrations, triglycerides, apolipoprotein B-containing lipoproteins, and atherosclerotic lesion formation compared with male and female mice.ConclusionsThese data suggest that endogenous androgens protect against diet-induced increases in cholesterol concentrations, formation of proatherogenic lipoproteins, and atherosclerotic lesions formation. Conversely orchidectomy, which decreases androgen concentrations, promotes increases in cholesterol concentrations, proatherogenic lipoprotein formation, and atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice in response to a low-fat diet.     

Exposure to Biomass Smoke Extract Enhances Fibronectin Release from Fibroblasts

COPD induced following biomass smoke exposure has been reported to be associated with a more fibrotic phenotype than cigarette smoke induced COPD. This study aimed to investigate if biomass smoke induced extracellular matrix (ECM) protein production from primary human lung fibroblasts in vitro. Primary human lung fibroblasts (n = 5–10) were stimulated in vitro for up to 72 hours with increasing concentrations of biomass smoke extract (BME) or cigarette smoke extract (CSE) prior to being assessed for deposition of ECM proteins, cytokine release, and activation of intracellular signalling molecules. Deposition of the ECM proteins perlecan and fibronectin was upregulated by both CSE (p<0.05) and BME (p<0.05). The release of the neutrophilic chemokine IL-8 was also enhanced by BME. ERK1/2 phosphorylation was significantly upregulated by BME (p<0.05). Chemical inhibition of ERK signalling molecules partially attenuated these effects (p<0.05). Stimulation with endotoxin had no effect. This study demonstrated that BME had similar effects to CSE in vitro and had the capacity to directly induce fibrosis by upregulating production of ECM proteins. The mechanisms by which both biomass and cigarette smoke exposure cause lung damage may be similar.     

Exposure to Odors of Rivals Enhances Sexual Motivation in Male Giant Pandas

Males will alter their mating behavior to cope with the presence of their competitors. Even exposure to odors from potential competitors can greatly increase male ejaculate expenditure in a variety of animals including insects, fishes, birds and rodents. Major efforts have been made to examine males'' plastic responses to sperm competition and its fitness benefits. However, the effects of competitor absence on male''s sexual motivation and behaviors remain unclear, which has been proposed to be one of the causes for the poor sexual performance of some captive mammals. This study revealed that sexual motivation can be greatly enhanced in captive male giant pandas (Ailuropoda melanoleuca) by exposure to chemosensory cues from either one or three conspecifics males. It had been shown that potential rivals'' odors increased males'' chemosensory investigation behavior, as well as their observing, following and sniffing behaviors towards estrous females. Behaviors changed regardless of the number of rivals (one or three). Our results demonstrate the effects of potential competition on male giant pandas'' sexual motivation and behavioral coping strategy. We anticipate that our research will provide a fresh insight into the mechanisms underlying poor sexual performance in male captive mammals, and valuable information for the practical management and ex situ conservation of endangered species.