RESUMO
P-glycoprotein (P-gp, encoded by the ABCB1 gene) and breast cancer resistance protein (BCRP/ABCG2) are efflux multidrug resistance (MDR) transporters localized at the syncytiotrophoblast barrier of the placenta and protect the conceptus from drug and toxin exposure throughout pregnancy. Infection is an important modulator of MDR expression and function. This review comprehensively examines the effect of infection on the MDR transporters, P-gp and BCRP in the placenta. Infection PAMPs such as bacterial lipopolysaccharide (LPS) and viral polyinosinic-polycytidylic acid (poly I:C) and single-stranded (ss)RNA, as well as infection with Zika virus (ZIKV), Plasmodium berghei ANKA (modeling malaria in pregnancy - MiP) and polymicrobial infection of intrauterine tissues (chorioamnionitis) all modulate placental P-gp and BCRP at the levels of mRNA, protein and or function; with specific responses varying according to gestational age, trophoblast type and species (human vs. mice). Furthermore, we describe the expression and localization profile of Toll-like receptor (TLR) proteins of the innate immune system at the maternal-fetal interface, aiming to better understand how infective agents modulate placental MDR. We also highlight important gaps in the field and propose future research directions. We conclude that alterations in placental MDR expression and function induced by infective agents may not only alter the intrauterine biodistribution of important MDR substrates such as drugs, toxins, hormones, cytokines, chemokines and waste metabolites, but also impact normal placentation and adversely affect pregnancy outcome and maternal/neonatal health.
Assuntos
Infecção por Zika virus , Zika virus , Gravidez , Feminino , Humanos , Camundongos , Animais , Placenta/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Distribuição Tecidual , Proteínas de Neoplasias/genética , Resistência a Múltiplos Medicamentos , Proteínas de Membrana Transportadoras/metabolismoRESUMO
Limited information is available about the effect of mid-pregnancy viral infections on the placental expression of efflux transporters and offspring behavior. We hypothesized that maternal exposure to polyinosinic-polycytidylic acid [poly(I:C)], a synthetic double-stranded RNA viral mimic, would impair placental cell turnover, the expression of selected ABC transporters and adult offspring behavior. C57BL/6 mice were administered poly(I:C) (10 mg/Kg;ip) or vehicle at gestational day (GD) 13.5 (mid-pregnancy). Dams were euthanized for blood collection 4 h after injection, fetal and placental collection at GD18.5 or allowed to deliver spontaneously at term. At GD 13.5, poly(I:C) induced an acute pro-inflammatory response characterized by an increase in maternal plasma levels of IL-6, CXCL-1 and CCL-2/MCP-1. At GD 18.5, poly(I:C) decreased cell proliferation/death in the labyrinthine and increased cell death in the junctional zones, characterizing a disruption of placental cell turnover. Abca1 and Abcg1 immunolabelling was decreased in the labyrinthine zone, whereas Abca1, Abcg1 and breast cancer resistance transporter (Bcrp) expression increased in the junctional zone. Moreover, adult offspring showed motor and cognitive impairments in the Rotarod and T-water maze tests. These results indicate that viral infection during mid-pregnancy may disrupt relevant placental efflux transporters, as well as placental cell turnover and offspring behavior in adult life.
Assuntos
Transportadores de Cassetes de Ligação de ATP , Disfunção Cognitiva , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Disfunção Cognitiva/metabolismo , Feminino , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Neoplasias/metabolismo , Placenta/metabolismo , Poli I-C/farmacologia , GravidezRESUMO
Bacterial infection alters placental ABC transporters expression. These transporters provide fetal protection against circulating xenobiotics and environmental toxins present in maternal blood. We hypothesized that lipopolysaccharide (LPS-bacterial mimic) alters the yolk sac morphology and expression of key ABC transporters in a gestational-age dependent manner. Yolk sac samples from C57BL/6 mice were obtained at gestational ages (GD) 15.5 and GD18.5, 4 or 24 h after LPS exposure (150ug/kg; n = 8/group). Samples underwent morphometrical, qPCR and immunohistochemistry analysis. The volumetric proportions of the histological components of the yolk sac did not change in response to LPS. LPS increased Abcg2 expression at GD15.5, after 4 h of treatment (p < 0.05). No changes in Abca1, Abcb1a/b, Abcg1, Glut1, Snat1, Il-1ß, Ccl2 and Mif were observed. Il-6 and Cxcl1 were undetectable in the yolk sac throughout pregnancy. Abca1, breast cancer resistance protein (Bcrp, encoded by Abcg2) and P-glycoprotein (P-gp/ Abcb1a/b) were localized in the endodermal (uterine-facing) epithelium and to a lesser extent in the mesothelium (amnion-facing), whereas Abca1 was also localized to the endothelium of the yolk sac blood vessels. LPS increased the labeling area and intensity of Bcrp in the yolk sac's mesothelial cells at GD15.5 (4 h), whereas at GD18.5, the area of Bcrp labeling in the mesothelium (4 and 24 h) was decreased (p < 0.05). Bacterial infection has the potential to change yolk sac barrier function by affecting Bcrp and Abcg2 expression in a gestational-age dependent-manner. These changes may alter fetal exposure to xenobiotics and toxic substances present in the maternal circulation and in the uterine cavity.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Lipopolissacarídeos/farmacologia , Saco Vitelino/efeitos dos fármacos , Animais , Feminino , Idade Gestacional , Camundongos Endogâmicos C57BL , Gravidez , Saco Vitelino/metabolismoRESUMO
Malaria in Pregnancy (MiP) is characterized by placental accumulation of Plasmodium-infected erythrocytes, intrauterine growth restriction (IUGR) and preterm delivery (PTD). Placental ATP-binding cassette (ABC) transporters mediate the efflux of nutrients, cytokines and xenobiotics. The expression and activity of these transporters are highly responsive to infection. We hypothesized that MiP would perturb the expression of placental ABC transporters, promoting PTD. Peripheral blood, spleens, livers and placentas of pregnant mice, infected with Plasmodium berghei ANKA on gestational day (GD) 13.5, were collected and analyzed on GD18.5. The primary consequences of human MiP, including IUGR, PTD (20%) and placental inflammation, were recapitulated in our mouse model. Electron microscopy revealed attenuated presence of labyrinthine microvilli and dilated spongiotrophoblasts -granular endoplasmic reticulum cisternae. Additionally, a decrease in placental Abca1 (ABCA1), Abcb1b (P-glycoprotein), Abcb9 and Abcg2 (BCRP) expression was observed in MiP mice. In conclusion, MiP associated with PTD impairs placental ABC transporters' expression, potentially modulating placental nutrient, environmental toxin and xenobiotic biodistribution within the fetal compartment, and may, at some degree, be involved with pregnancy outcome in MiP.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Malária/complicações , Trabalho de Parto Prematuro/imunologia , Placenta/patologia , Plasmodium berghei/imunologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Malária/imunologia , Malária/parasitologia , Troca Materno-Fetal/imunologia , Camundongos , Nutrientes/metabolismo , Trabalho de Parto Prematuro/parasitologia , Trabalho de Parto Prematuro/patologia , Placenta/metabolismo , Gravidez , Xenobióticos/metabolismoRESUMO
Zika virus (ZIKV) is associated with brain development abnormalities such as primary microcephaly, a severe reduction in brain growth. Here we demonstrated in vivo the impact of congenital ZIKV infection in blood vessel development, a crucial step in organogenesis. ZIKV was injected intravenously in the pregnant type 2 interferon (IFN)-deficient mouse at embryonic day (E) 12.5. The embryos were collected at E15.5 and postnatal day (P)2. Immunohistochemistry for cortical progenitors and neuronal markers at E15.5 showed the reduction of both populations as a result of ZIKV infection. Using confocal 3D imaging, we found that ZIKV infected brain sections displayed a reduction in the vasculature density and vessel branching compared to mocks at E15.5; altogether, cortical vessels presented a comparatively immature pattern in the infected tissue. These impaired vascular patterns were also apparent in the placenta and retina. Moreover, proteomic analysis has shown that angiogenesis proteins are deregulated in the infected brains compared to controls. At P2, the cortical size and brain weight were reduced in comparison to mock-infected animals. In sum, our results indicate that ZIKV impairs angiogenesis in addition to neurogenesis during development. The vasculature defects represent a limitation for general brain growth but also could regulate neurogenesis directly.
Assuntos
Neovascularização Fisiológica , Infecção por Zika virus/congênito , Zika virus/fisiologia , Animais , Vasos Sanguíneos/patologia , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Encéfalo/virologia , Modelos Animais de Doenças , Embrião de Mamíferos/patologia , Embrião de Mamíferos/virologia , Células Endoteliais/patologia , Células Endoteliais/virologia , Feminino , Camundongos Endogâmicos C57BL , Neurogênese , Tamanho do Órgão , Infecção por Zika virus/patologia , Infecção por Zika virus/virologiaRESUMO
Rapid Ecological Assessment protocols are important tools for the training of postgraduate students, as well as the collection of data on poorly-known and protected areas with the potential for the preservation of water supplies for urban areas. The objective of this study was to perform a survey of water quality and diversity of benthic macroinvertebrates in two sub-basins at the Mata do Junco Wildlife Refuge in the Brazilian state of Sergipe. The collection of data in the field, laboratory processing, and the interpretation and discussion of data were conducted in groups by students from two postgraduate programmes in Ecology and Conservation (UFMG and UFS), personnel of the state environment agency (SEMARH), school teachers from the local town of Capela, and members of the reserve's voluntary fire brigade. The results of the assessment were organised, analysed, and presented at the reserve headquarters in the form of posters, for the development of environmental education activities with pupils from local schools, as well as contributing to a SEMARH seminar. Samples were characterised by distinct taxonomic compositions and diversity, as confirmed by MDS and additive partitioning of diversity analyses. The gravel substrate presented the lower mean taxonomic richness in each sampling unit (α1 = 28%), while the average difference among samples (ß1 diversity) was elevated for both substrates (39% for leaf litter, 41% for gravel), reflecting the pronounced variation among samples, even adjacent ones within the same stream. Diversity between streams was lower in the case of leaf litter in comparison with gravel (ß2 = 21 and 31%, respectively). A total of 57 fish specimens were collected with a predominance of individuals of the orders Characiformes (62%) and Perciformes (21%). This rapid ecological assessment confirmed the importance of the conservation unit and emphasised the need for its continuation, given its importance for the maintenance of water quality and its other ecological services, such as the conservation of the region's aquatic biodiversity and providing the local town of Capela (circa 20,000 inhabitants) with its water supply, the Mata do Junco being its only source.
Protocolos de avaliação ecológica rápida são ferramentas importantes para treinamento de pós-graduandos e levantamento de informações em áreas pouco conhecidas. O objetivo deste estudo foi realizar um levantamento de qualidade de água e diversidade de macroinvertebrados bentônicos em duas sub-bacias em uma área protegida. Atividades de campo, processamento em laboratório, interpretação e discussão de dados foram realizados em grupos com a participação de representantes dos Programas de Pós-graduação em Ecologia da UFMG e da UFS, SEMARH, professores do município de Capela e "brigada voluntária de incêndio" do Refúgio de Vida Silvestre (RVS) Mata do Junco em Sergipe. Os resultados foram sintetizados, analisados e disponibilizados na Unidade de Conservação (UC) RVS Mata do Junco na forma de banners de divulgação, atividades de educação ambiental com alunos de escolas locais e em um seminário de recursos hídricos no estado de Sergipe. As amostras de fundo apresentaram composições taxonômicas e diversidade diferentes, como mostraram as análises de ordenação MDS e de partição aditiva da diversidade. O substrato cascalho apresentou menor riqueza taxonômica média em cada unidade amostral (α1 = 28%) e a diferença média entre amostragens (diversidade ß1) foi elevada nos dois casos (39% em folhiço, 41% em cascalho), indicando a alta variação que há entre amostras espacialmente próximas em um mesmo riacho. A diversidade entre riachos foi menor em folhiço do que em cascalho (ß2 = 21 e 31%, respectivamente). Foram capturados 57 peixes, com predomínio de Characiformes (62%) e Perciformes (21%). Esta avaliação ecológica rápida corrobora a importância da criação e manutenção desta unidade de conservação, a fim de manter a boa qualidade de suas águas e serviços ecológicos, destacando-se a conservação da biodiversidade aquática e o abastecimento do município de Capela, com cerca de 20 mil habitantes que têm no RVS Mata do Junco seu único manancial de abastecimento de água.
Assuntos
Animais , Qualidade da Água , Perciformes/classificação , Fauna Bentônica/classificação , Reservas Naturais , Áreas Protegidas , Biodiversidade , Caraciformes/classificaçãoRESUMO
We established a Website which allowed clinical dermatology cases to be submitted, with digital images, through a simple online form. The case could then be managed within the public health service. A database containing 6000 drug interactions was also available on the Website to help clinical management. The Website was tested by 10 junior doctors, who examined dermatology patients, filled in the electronic form with their clinical observations and descriptions, and forwarded digital images. Five dermatologists then evaluated the 71 cases stored on the Website. The agreement between the virtual evaluation and the definitive diagnosis (on face-to-face examination) was 95%. The Website could be used in national health strategies, as a tool for promoting voluntary medical attendance, and for multicentre epidemiological surveillance.