Exposure to DEP Modifies the Human Umbilical Artery Vascular Resistance Contributing to Hypertension in Pregnancy.

Hypertensive disorders in pregnancy (HDP) are the most prevalent diseases during pregnancy. In addition to the already identified risk factors, exposure to environmental contaminants has been also considered a new one. Phthalates, which are classified as priority environmental pollutants due to their ubiquitousness and endocrine disrupting properties, have been implicated in HDP in some epidemiological studies. Nevertheless, phthalates' vascular impacts still need to be clarified. Thus, we aimed to understand the connection between phthalates exposure and the occurrence of gestational hypertension, as well as the pathway involved in the pathological vascular effects. We investigated diethyl phthalate's (DEP) effect on the vascular reactivity of the human umbilical arteries (HUAs) from normotensive and hypertensive pregnant women. Both DEP's nongenomic (within minutes effect) and genomic (24 h exposure to DEP) actions were evaluated, as well as the contribution of cyclic guanosine monophosphate and Ca2+ channel pathways. The results show that short-term exposure to DEP interferes with serotonin and histamine receptors, while after prolonged exposure, DEP seems to share the same vasorelaxant mechanism as estrogens, through the NO/sGC/cGMP/PKG signaling pathway, and to interfere with the L-type Ca2+ channels. Thus, the vascular effect induced by DEP is similar to that observed in HUA from hypertensive pregnancies, demonstrating that the development of HDP may be a consequence of DEP exposure.

Adverse cardiovascular effects of long-term exposure to diethyl phthalate in the rat aorta.

Phthalates are classified as priority environmental pollutants, since they are ubiquitous in the environment, have endocrine disrupting properties and can contribute to impaired health. Used primarily in personal care products and excipients for pharmaceuticals, diethyl phthalate (DEP) is a short-chain alkyl phthalate that has been linked to decreased blood pressure, glucose tolerance, and increased gestational weight gain in humans, while in animals it has been associated with atherosclerosis and metabolic syndrome. Although all these findings are related to risk factors or cardiovascular diseases, DEP's vascular impacts still need to be clarified. Thus, performing ex vivo and in vitro experiments, we aimed to understand the vascular DEP effects in rat. To evaluate the vascular contractility of rat aorta exposed to different doses of DEP (0.001-1000 µM), an organs bath was used; and resorting to a cell line of the rat aorta vascular smooth muscle, electrophysiology experiments were performed to analyse the effects of a rapid (within minutes with no genomic effects) and a long-term (24 h with genomic effects) exposure of DEP on the L-type Ca2+ current (ICa,L), and the expression of several genes related with the vascular function. For the first time, vascular electrophysiological properties of an EDC were analysed after a long-term genomic exposure. The results show a hormetic response of DEP, inducing a Ca2+ current inhibition of the rat aorta, which may be responsible for impaired cardiovascular electrical health. Thus, these findings contribute to a greater scientific knowledge about DEP's effects in the cardiovascular system, specifically its implications in the development of electrical disturbances like arrhythmias and its possible mechanisms.

The Effects of Bisphenol A on Human Male Infertility: A Review of Current Epidemiological Studies.

Endocrine disruptor chemicals (EDCs) can have a harmful effect on the human body's endocrine system and thus adversely affect the development, reproduction, neurological, cardiovascular, and immune systems and metabolism in humans and wildlife. According to the World Health Organization, EDCs are mostly man-made and found ubiquitously in our daily lives, notably in pesticides, metals, and additives or contaminants in food and personal care products. Human exposure occurs through ingestion, inhalation, and dermal contact. Bisphenol A (BPA) is a proven EDC capable of mimicking or blocking receptors and altering hormone concentrations and metabolism. Although consumed in low doses, it can stimulate cellular responses and affect the body's functions. In humans, exposure to BPA has been correlated with the onset or development of several diseases. This literature review aimed to verify the effects of BPA on human male infertility using the most recently published literature. Thus, this review allowed us to conclude that this compound seems to have harmful effects on human male fertility, causing changes in hormonal and semen characteristics. However, these conclusions lack more robust and reproducible scientific studies. Even so, and since male infertility prevalence is increasing, preventive measures must be taken to ensure male fertility.

The Relationship between Phthalates and Diabetes: A Review.

Since the beginning of their production, in the 1930s, phthalates have been widely used in the plastics industry to provide durability and elasticity to polymers that would otherwise be rigid, or as solvents in hygiene and cosmetic products. Taking into account their wide range of applications, it is easy to understand why their use has been increasing over the years, making them ubiquitous in the environment. This way, all living organisms are easily exposed to these compounds, which have already been classified as endocrine disruptor compounds (EDC), affecting hormone homeostasis. Along with this increase in phthalate-containing products, the incidence of several metabolic diseases has also been rising, namely diabetes. That said, and considering that factors such as obesity and genetics are not enough to explain this substantial increase, it has been proposed that the exposure to environmental contaminants may also be a risk factor for diabetes. Thus, the aim of this work is to review whether there is an association between the exposure to phthalates and the development of the several forms of diabetes mellitus, during pregnancy, childhood, and adulthood.

Phthalates' exposure leads to an increasing concern on cardiovascular health.

Being an essential component in the plastics industry, phthalates are ubiquitous in the environment and in everyday life. They are considered environmental contaminants that have been classified as endocrine-disrupting compounds. Despite di-2-ethylhexyl phthalate (DEHP) being the most common plasticizer and the most studied to date, there are many others that, in addition to being widely used in the plastic, are also applied in the medical and pharmaceutical industries and cosmetics. Due to their wide use, phthalates are easily absorbed by the human body where they can disrupt the endocrine system by binding to molecular targets and interfering with hormonal homeostasis. Thus, phthalates exposure has been implicated in the development of several diseases in different age groups. Collecting information from the most recent available literature, this review aims to relate human phthalates' exposure with the development of cardiovascular diseases throughout all ages. Overall, most of the studies presented demonstrated an association between phthalates and several cardiovascular diseases, either from prenatal or postnatal exposure, affecting foetuses, infants, children, young and older adults. However, the mechanisms underlying these effects remain poorly explored. Thus, considering the cardiovascular diseases incidence worldwide and the constant human exposure to phthalates, this topic should be extensively studied to understand the mechanisms involved.

Triclosan and Its Consequences on the Reproductive, Cardiovascular and Thyroid Levels.

Hygiene is essential to avoid diseases, and this is thanks to daily cleaning and disinfection habits. Currently, there are numerous commercial products containing antimicrobial agents, and although they are efficient in disinfecting, it is still not known the effect of the constant use of these products on human health. In fact, a massive use of disinfectants has been observed due to COVID-19, but the possible adverse effects are not yet known. Triclosan is one of the antimicrobial agents used in cosmetic products, toothpaste, and disinfectants. This compound is an endocrine disruptor, which means it can interfere with hormonal function, with its estrogenic and androgenic activity having already been stated. Even if the use of triclosan is well-regulated, with the maximum allowed concentration in the European Union of 0.3% (m/m), its effects on human health are still uncertain. Studies in animals and humans suggest the possibility of harmful health outcomes, particularly for the reproductive system, and in a less extent for the cardiovascular and thyroid functions. Thus, the purpose of this review was to analyse the possible implications of the massive use of triclosan, mainly on the reproductive and cardiovascular systems and on the thyroid function, both in animals and humans.

Vascular Response of Tetrabromobisphenol a in Rat Aorta: Calcium Channels Inhibition and Potassium Channels Activation.

Tetrabromobisphenol A (TBBPA) is a flame retardant widely used to reduce flammability. It is an endocrine disruptor, and due to constant human exposure, some concerns have been raised regarding its impact on human health. Studies showed that TBBPA affects oxidative stress, cell proliferation and intracellular calcium levels. However, the vascular consequences of TBBPA exposure are still relatively unexplored. Hence, this work aimed to analyse TBBPA effects on rat aortic smooth muscle and its action mechanisms. Through an ex vivo approach, Wistar rat aortas were used in an organ bath to evaluate the vascular effect of TBBPA (0.01-100 µM). Additionally, TBBPA's mode of action was studied through calcium and potassium channel inhibitors. Resorting to in vitro studies, A7r5 cells were used to analyse L-Type voltage-gated calcium channel (VGCC) activity through the whole-cell configuration of the patch clamp technique, and the mRNA expression of proteins and ion channels involved in vascular contractility. The results showed vasorelaxation of rat aorta induced by TBBPA exposure, involving the inactivation of L-Type VGCC and activation of potassium channels, and the modulation of mRNA expression of L-type calcium and large-conductance calcium 1.1 and the BKCa 1.1 α- and ß1 -subunit channels, soluble guanylyl cyclase and protein Kinase G.

Pathways involved in the human vascular Tetrabromobisphenol A response: Calcium and potassium channels and nitric oxide donors.

Tetrabromobisphenol A (TBBPA) is a flame retardant that can contaminate the environment and human being, acting as an endocrine disruptor. Several studies propose a correlation between TBBPA exposure and adverse health outcomes, however, at vascular level TBBPA effects are still poorly understood. Thus, considering that the vascular tonus is regulated by vasoactive substances (serotonin and histamine) which are involved in some pathological processes, this work aimed to analyse the direct effects and the 24 h exposure of TBBPA on the human umbilical artery (HUA) and to investigate its signalling pathway. Using organ bath technique, endothelium-denuded HUA rings were contracted with serotonin (5-HT, 1 µM), histamine (His, 10 µM) and potassium chloride (KCl, 60 mM), and the exposure (0-24 h) of different concentrations of TBBPA (1, 10 and 50 µM) were evaluated. Besides, the vascular mode of action of TBBPA was studied through the analysis of cyclic guanosine monophosphate and calcium channels activity, pathways involved in relaxation and contraction of HUA, respectively. Our results demonstrated that the direct effects of TBBPA induce a vasorelaxation of HUA. The maximum relaxant effect was observed at 100 µM of TBBPA with 63.74%, 64.24% and 30.05%, for 5-HT-, His- or KCl-contracted arteries respectively. The 24 h TBBPA exposure altered the vasorelaxant response pattern of sodium nitroprusside and nifedipine. This effect is due to the involvement of TBBPA with the NO/sGC/cGMP/PKG pathway and the interference in calcium influx. Furthermore, using the real-time quantitative polymerase chain reaction, TBBPA clearly modulates L-type calcium and large-conductance Ca2+ 1.1 α- and ß1 -subunit channels, and soluble guanylyl cyclase and protein Kinase G. So, at vascular level TBBPA induces changes in HUA after TBBPA exposure.

In Vitro Model for Ischemic Stroke: Functional Analysis of Vascular Smooth Muscle Cells.

The Neurovascular Unit (NVU) is formed by vascular and neural cells controlling the cerebral hyperaemia. All the components are anatomically and functionally linked to each other, resulting in a highly efficient regulation of the cerebral blood flow, which, when interrupted, can lead to stroke. An ischemic stroke (IS) is the most common type of stroke with high rates of morbidity, mortality and disability. Therefore, it is of extreme importance to protect the functional and structural integrity of the NVU in patients with IS, understanding the mechanisms involved and how it affects each component of the NVU. Thus, the aim of this work is to analyse how the vascular smooth muscle cells from the rat middle cerebral artery function/react after an ischemic event. To mimic this event, primary cortical cultures were challenged to oxygen and glucose deprivation (OGD) for 4 h and 6 h, and the smooth muscle cells (SMCs) contractility was analysed after exposure to different media previously conditioned by the cortical cultures upon reperfusion. The results show a dual effect on the SMCs response to the vasorelaxant agent, only for cells exposed to the reperfusion media conditioned by neuron-glia cultures challenged by OGD, leading to increased relaxation of the SMCs for OGD 4 h, whereas for OGD 6 h the effect is reversed leading to contraction of the SMCs. These differences demonstrate that the astrocytes mediate the vasoactive response of vascular smooth muscle by releasing factors into the reperfusion medium, and the hypoxia time is fundamental for a beneficial/harmful response by the vascular smooth muscle.

Health toxicity effects of brominated flame retardants: From environmental to human exposure.

Hexabromocyclododecane (HBCD) and Tetrabromobisphenol A (TBBP-A) are brominated flame retardants widely used in variety of industrial and consumer products (e.g., automobiles, electronics, furniture, textiles and plastics) to reduce flammability. HBCD and TBBPA can also contaminate the environment, mainly water, dust, air and soil, from which human exposure occurs. This constant exposure has raised some concerns against human health. These compounds can act as endocrine disruptors, a property that gives them the ability to interfere with hormonal function and quantity, when HBCD and TBBPA bind target tissues in the body. Studies in human and animals suggest a correlation between HBCD and TBBPA exposure and adverse health outcomes, namely thyroid disorders, neurobehavior and development disorders, reproductive health, immunological, oncological and cardiovascular diseases. However, in humans these effects are still poorly understood, once only a few data evaluated the human health effects. Thus, the purpose of this review is to present the toxicity effects of HBCD and TBBPA and how these compounds affect the environment and health, resorting to data and knowledge of 255 published papers from 1979 to 2020.

Phthalates Implications in the Cardiovascular System.

Today's sedentary lifestyle and eating habits have been implicated as some of the causes of the increased incidence of several diseases, including cancer and cardiovascular diseases. However, environmental pollutants have also been identified as another possible cause for this increase in recent decades. The constant human exposure to plastics has been raising attention regarding human health, particularly when it comes to phthalates. These are plasticizers used in the manufacture of industrial and consumer products, such as PVC (Polyvinyl Chloride) plastics and personal care products, with endocrine-disrupting properties, as they can bind molecular targets in the body and interfere with hormonal function. Since these compounds are not covalently bound to the plastic, they are easily released into the environment during their manufacture, use, or disposal, leading to increased human exposure and enhancing health risks. In fact, some studies have related phthalate exposure with cardiovascular health, having already shown a positive association with the development of hypertension and atherosclerosis in adults and some cardiometabolic risk factors in children and adolescents. Therefore, the main purpose of this review is to present and relate the most recent studies concerning the implications of phthalates effects on the cardiovascular system.

Vascular mechanisms of testosterone: The non-genomic point of view.

Testosterone (T) is the predominant endogenous androgen in the bloodstream. At the vascular level, T presents genomic and non-genomic effects, and both effects may overlap. The genomic actions assume that androgens can freely cross the plasma membrane of target cells and bind to nuclear androgen receptors, inducing gene transcription and protein synthesis. The non-genomic effects have a more rapid onset and may be related to the interaction with protein/receptor/ion channels of the plasma membrane. The key T effect at the vascular level is vasorelaxation, which is primarily due to its rapid effect. Thus, the main purpose of this review is to discuss the T non-genomic effects at the vascular level and the molecular pathways involved in its vasodilator effect observed in in vivo and in vitro studies. In this sense, the nuclear receptor activation, the influence of vascular endothelium and the activation or inhibition of ion channels (potassium and calcium channels, respectively) will be reviewed regarding all the data that corroborated or not. Moreover, this review also provides a brief update on the association of T with the risk factors for cardiovascular diseases, namely metabolic syndrome, type 2 diabetes mellitus, obesity, atherosclerosis, dyslipidaemia, and hypertension. In summary, in this paper we consider the non-genomic vascular mode of action of androgen in physiological conditions and the main risk factors for cardiovascular diseases.

Vascular Pathways of Testosterone: Clinical Implications.

Cardiovascular diseases (CVD) are one of the leading causes of death worldwide. Testosterone (T) is an important sex hormone that triggers several genomic and non-genomic pathways, leading to improvements of several cardiovascular risk factors and quality of life in men. At the vascular level, the key effect of T is the vasorelaxation. This review discusses the molecular pathways and clinical implications of T in the vascular system. Firstly, the mechanisms involved in the T vasodilator effect will be presented. Then, it will be discussed the association of T with the main risks for CVD, namely metabolic syndrome, type 2 diabetes mellitus, obesity, atherosclerosis, dyslipidaemia and hypertension. Several studies have shown a correlation between low T levels and an increased prevalence of several CVD. These observations suggest that T has beneficial effects on the cardiovascular system and that testosterone replacement therapy may become a therapeutic reality for some of these disorders. Graphical abstract .

Inhibition of L-type calcium channels by Bisphenol A in rat aorta smooth muscle.

Bisphenol A (BPA) is an endocrine disrupting chemical used on a wide range in industry. This compound has been used in the production of polycarbonate plastics and epoxy resins. For this reason and their global use, BPA is one of the most common environmental chemicals to which humans are exposed. This exposure can cause several adverse health outcomes, including at the cardiovascular level. The regulation of ion channels in vascular smooth muscle is pivotal and important for vasoreactivity, and changes in their flux can be involved in the pathophysiology of some cardiovascular diseases. This study aims to analyse in rat aorta whether the vasorelaxant effect of BPA is mediated by L-type Ca2+ channels inhibition. Using male Wistar rat aorta artery rings in the organ bath we analysed the contractility, and to study the activity of calcium current in A7r5 cells we used the whole cell configuration of Patch Clamp technique. Regarding the contractility experiences we observed that in both NA and KCl contraction, BPA caused a rapid and concentration-dependent relaxation. The electrophysiology experiments showed that BPA inhibited the basal and BAY K8644-stimulated whole-cell L-type Ca2+ channel (W-CLTCC) currents, indicating that this drug blocks the L-type Ca2+ channels. Our results suggest that BPA inhibits the W-CLTCC, leading to the relaxation of vascular smooth muscle.

How is the human umbilical artery regulated?

The purpose of this review is to present an update of the main mechanisms involved in the physiological regulation of contraction and relaxation of the human umbilical artery (HUA) smooth muscle cells. A literature review was performed based on the analysis of papers available on PubMed. The most important and relevant studies regarding the regulation of the HUA are presented in this article. The vascular smooth muscle is a highly specialized structure, whose main function is to regulate the vascular tonus. This is controlled by a balance between the cellular signaling pathways that mediate contraction and relaxation. The cells responsible for the contractile property of this muscle are the smooth muscle cells (SMC), and an excellent source of these cells is the HUA, involved in fetoplacental circulation. Since the umbilical blood vessels are not innervated, the HUA tonus is modulated by vasoactive substances that regulate the contractile process. The main vasoactive substances that induce contraction are serotonin, histamine, thromboxane, bradykinin, endothelin 1 and prostaglandin F2α, that are linked to the activation of proteins Gq and Gi/0 . On the other hand, the main vasorelaxation mechanisms are the activation of adenyl and guanil cyclases, potassium channels and the inhibition of calcium channels. The SMC from the HUA allow the study of different cellular mechanisms and their functions. Therefore, these cells are an important tool to study the mechanisms regulating the contractility of this artery, allowing to detect potential therapeutic targets to treat HUA disorders (gestational hypertension and pre-eclampsia).

Pre-Eclampsia and Eclampsia: An Update on the Pharmacological Treatment Applied in Portugal.

Pre-eclampsia and eclampsia are two hypertensive disorders of pregnancy, considered major causes of maternal and perinatal death worldwide. Pre-eclampsia is a multisystemic disease characterized by the development of hypertension after 20 weeks of gestation, with the presence of proteinuria or, in its absence, of signs or symptoms indicative of target organ injury. Eclampsia represents the consequence of brain injuries caused by pre-eclampsia. The correct diagnosis and classification of the disease are essential, since the therapies for the mild and severe forms of pre-eclampsia are different. Thus, this review aims to describe the most advisable antepartum pharmacotherapy for pre-eclampsia and eclampsia applied in Portugal and based on several national and international available guidelines. Slow-release nifedipine is the most recommended drug for mild pre-eclampsia, and labetalol is the drug of choice for the severe form of the disease. Magnesium sulfate is used to prevent seizures caused by eclampsia. Corticosteroids are used for fetal lung maturation. Overall, the pharmacological prevention of these diseases is limited to low-dose aspirin, so it is important to establish the safest and most effective available treatment.

Photoprotection of ultraviolet-B filters: Updated review of endocrine disrupting properties.

The Ultraviolet (UV) radiation is emitted by the sun and is part of the electromagnetic spectrum. There are three types of UV rays (UV-A, UV-B and UV-C), however only UV-A and UV-B have biologic effects in humans, with UV-B radiation being primarily responsible for these effects. Among the measures of photoprotection advised by the health authorities, the topical application of sunscreens (containing UV-B filters) is the preferred worldwide. Currently, octylmethoxycinnamate (OMC) is the most commonly used UV-B filter in sunscreens. Their application has proven to be effective in preventing burns, but its efficiency against melanoma continues under intense controversy. Studies have shown that OMC behaves like an endocrine disruptor, altering the normal functioning of organisms. However, few studies have evaluated their multiple hormonal activities. Some studies suggest that the OMC exerts an estrogenic, anti-androgenic, anti-progestenic and anti-thyroid activity. But, through what mechanisms? In humans, few studies were performed, and some questions remain unclear. Thus, the purpose of this review is to present the multiple hormonal activities established for the OMC, making a critical analysis and relationship between the effects in cells, animals and humans.

Cardiovascular Response of Rat Aorta to Di-(2-ethylhexyl) Phthalate (DEHP) Exposure.

Phthalates are one of the main constituents of plastic, reaching up to 40% of the total plastic weight, and their main function is to impart flexibility/elasticity to polymers that would otherwise be rigid. Phthalates are known as endocrine disruptors, since they can interfere with hormone homeostasis. Regarding the cardiovascular system, it was already shown the effects of di-(2-ethylhexyl) phthalate (DEHP) exposure with significant changes in several calcium-handling proteins and an increase in the blood pressure of mice offspring, suggesting that DEHP leads to vasocontraction. However, the mechanisms involved were not elucidated yet. The aim of this study is to analyse the involvement of calcium channels in the effects induced by DEHP on vascular smooth muscle cells. Endothelium-denuded aorta artery rings were prepared from male Wistar rats and incubated in an organ bath, and the whole-cell configuration of Patch Clamp technique was used to measure the activity of L-type Ca2+ channels (LTCC) in A7r5 cells. Overall, DEHP caused relaxation on KCl-induced contraction at higher concentrations and inhibited the basal and BAY K8644-stimulated calcium current, indicating that this drug blocks LTCC. These results suggest that DEHP induces relaxation on vascular smooth muscle cells due to the inhibition of calcium channels.

Genomic and Nongenomic Effects of Mifepristone at the Cardiovascular Level: A Review.

Mifepristone (RU 486) is a compound that is structurally related to steroid hormones, which is derived from the estrane progestins. This compound strongly binds the progesterone and glucocorticoid receptor and, to a lesser extent, the androgen receptor. This compound has its effects through different signaling pathways, related to genomic and nongenomic effects. The genomic effect involves the activation or blockage of nuclear or intracellular receptor, that in this case the progesterone, glucocorticoid, and androgen receptors. On the contrary, the nongenomic effect of mifepristone is independent of the activation of these receptors. Regarding the nongenomic, several authors observed that mifepristone induces higher uterine artery blood flow probably due to the decrease in serum nitric oxide level. Moreover, recently it has been demonstrated that mifepristone induces relaxation, and this effect is independent of the endothelium and due to the activation of the calcium channels. The main side effects associated with this pathway are hemorrhage and inhibition of platelet aggregation that can lead to hypovolemia or to hypotension. Concerning the genomic effect, this drug blocks progesterone, androgens, and glucocorticoids receptors and also activates the progesterone receptor and their respective effects. The most frequently reported adverse effects of mifepristone are nausea, vomiting, hypovolemia, hypotension, amenorrhea, and infertility. The main purpose of this review is to describe the genomic and nongenomic effects of mifepristone at vascular level and describe some pathologies in which mifepristone is used as a treatment.

The effects of phthalates in the cardiovascular and reproductive systems: A review.

Every year millions of tons of plastic are produced around the world and humans are increasingly exposed to them. This constant exposure to plastics has raised some concerns against human health, particularly when it comes to phthalates. These compounds have endocrine-disrupting properties, as they have the ability to bind molecular targets in the body and interfere with hormonal function and quantity. The main use of phthalates is to give flexibility to polyvinyl chloride (PVC) polymers. Phthalates are found in a variety of industrial and consumer products, and as they are not covalently bound to the plastic, phthalates contaminate the environment from which human exposure occurs. Studies in human and animal populations suggest a correlation between phthalate exposure and adverse health outcomes, particularly at the reproductive and cardiovascular systems, however there is much less information about the phthalate toxicity of the later. Thus, the main purpose of this review is to present the studies relating the effects already stated of phthalates on the cardiovascular and reproductive systems, and also present the link between these two systems.