Estrogen Metabolism-Associated CYP2D6 and IL6-174G/C Polymorphisms in Schistosoma haematobium Infection.

Schistosoma haematobium is a human blood fluke causing a chronic infection called urogenital schistosomiasis. Squamous cell carcinoma of the urinary bladder (SCC) constitutes chronic sequelae of this infection, and S. haematobium infection is accounted as a risk factor for this type of cancer. This infection is considered a neglected tropical disease and is endemic in numerous countries in Africa and the Middle East. Schistosome eggs produce catechol-estrogens. These estrogenic molecules are metabolized to active quinones that induce modifications in DNA. The cytochrome P450 (CYP) enzymes are a superfamily of mono-oxygenases involved in estrogen biosynthesis and metabolism, the generation of DNA damaging procarcinogens, and the response to anti-estrogen therapies. IL6 Interleukin-6 (IL-6) is a pleiotropic cytokine expressed in various tissues. This cytokine is largely expressed in the female urogenital tract as well as reproductive organs. Very high or very low levels of IL-6 are associated with estrogen metabolism imbalance. In the present study, we investigated the polymorphic variants in the CYP2D6 gene and the C-174G promoter polymorphism of the IL-6 gene on S. haematobium-infected children patients from Guine Bissau. CYP2D6 inactivated alleles (28.5%) and IL6G-174C (13.3%) variants were frequent in S. haematobium-infected patients when compared to previously studied healthy populations (4.5% and 0.05%, respectively). Here we discuss our recent findings on these polymorphisms and whether they can be predictive markers of schistosome infection and/or represent potential biomarkers for urogenital schistosomiasis associated bladder cancer and infertility.

Wound healing and cancer progression in Opisthorchis viverrini associated cholangiocarcinoma.

Infection with the human liver fluke Opisthorchis viverrini induces cancer of the bile ducts, cholangiocarcinoma (CCA). It was shown previously that O. viverrini-secreted proteins accelerate wound resolution in human cholangiocytes. Recombinant Ov-GRN-1 (O. viverrini-derived gene encoding granulin-like growth factor) induced angiogenesis and accelerated mouse wound healing. Given the striking similarities of wound healing and cancer progression, here we discuss the major implications of this finding for an infection-induced cancer of major public health significance in the developing world.

Schistosoma haematobium in Guinea-Bissau: unacknowledged morbidity due to a particularly neglected parasite in a particularly neglected country.

Schistosomiasis is the major neglected tropical helminthic disease worldwide. Current knowledge on the epidemiology of schistosomiasis in Guinea-Bissau is scarce and regarding to the absence of Schistosoma haematobium (S.h.). Therefore, a pilot study was undertaken to assess the prevalence and morbidity due to S.h. infection in randomly selected 90 children and adolescents aged 6 to 15 years. Prevalence of S.h. infection was 20.00 % (18/90). Microhematuria was observed in 61.11 % (11/18) of S.h.-egg-excreting vs. 37.50 % (27/72) of non-S.h.-egg-excreting children p ≤ 0.01. Body mass index (BMI) was less than 15 kg/m(2) in 52/90 (57.78 %) of all children and adolescents, but this proportion increased to 66.67 % (12/18) in S.h.-infected children who were more frequently stunted and wasted than in non-infected children. The mean weight-for-age Z score (WAZ) was reduced in S.h. infected as compared to non-infected children (-1.48 ± 1.08 SD vs. -0.80 ± 1.11 SD; p ≤ 0.01). To our knowledge, this is the first epidemiologic report on S. haematobium infection in Guinea-Bissau since 22 years. Even in this relatively small study sample, it appears that S. haematobium, besides the well-known symptoms such as hematuria, leads to significant, albeit commonly unacknowledged morbidity such as stunting and wasting. These observations underscore the notion that this vulnerable but neglected population urgently needs to be targeted for implementation of measures for treatment and control.

Ultrasonography of gallbladder abnormalities due to schistosomiasis.

After malaria, schistosomiasis remains the most important tropical parasitic disease in large parts of the world. Schistosomiasis has recently re-emerged in Southern Europe. Intestinal schistosomiasis is caused by most Schistosoma (S.) spp. pathogenic to humans and leads to chronic inflammation and fibrosis of the colon as well as to liver fibrosis. Gallbladder abnormalities usually occur in patients with advanced hepatic portal fibrosis due to Schistosoma mansoni infection. Occasionally, gallbladder abnormalities have been seen also in children and occurring without associated overt liver abnormalities.The specific S. mansoni-induced gallbladder abnormalities detectable by ultrasound include typical hyperechogenic wall thickening with external gallbladder wall protuberances. The luminal wall surface is smooth. The condition is usually clinically silent although some cases of symptomatic cholecystitis have been described. The ultrasonographic Murphy response is negative. Gallbladder contractility is impaired but sludge and calculi occur rarely. Contrary to other trematodes such as liver flukes, S. mansoni does not obstruct the biliary tract. Advanced gallbladder fibrosis is unlikely to reverse after therapy.

Schistosomiasis and Infertility: What Do We Know?

There is increasing attention on the complex interactions occurring between schistosome parasites and their hosts. However, little is known about the occurrence, epidemiology, and mechanisms of schistosomiasis-associated infertility. In this article, we argue that an in-depth understanding of the interplay between parasites and the host endocrine system may significantly enhance current knowledge of infertility in infected individuals. We discuss the basic hormonal mechanisms that may lead to the discovery of entirely novel anthelmintic interventions against schistosomiasis.

Imbalance of Steroid Hormones in Hamsters Infected with Schistosoma mansoni.

OBJECTIVE: Schistosomiasis is a debilitating disease that affects 200 million people worldwide. Schistosoma haematobium and Schistosoma mansoni are the major causative agents of this disease. Cancer-association and infertility-association in Schistosoma haematobium infection have already been described and it is known that the parasite produces a catechol-estrogen molecule that induces a hormonal imbalance in the host. METHODS: In order to better understand the relation of hormonal imbalance in experimental Schistosoma mansoni infection, we investigated a serum panel of steroid hormones in Schistosoma mansoni infected hamsters. RESULTS: We found a decrease in the serum levels of Estradiol (E2), Testosterone and Progesterone in infected females and an increase of Testosterone and a decrease in Progesterone in infected males in comparison with controls. CONCLUSION: These results indicate that S. mansoni alters the levels of steroid hormones in infected males and females and it will increase the repertoire of data about the host-parasite molecular interplay and its relation with the endocrine system.

Fasciola Hepatica Extract Induces Cell Death of Mammalian Cells.

BACKGROUND: Fascioliasis is a neglected tropical disease that affects poor people from poor and developing countries. In the world, it has been estimated that at least 2.6 million people are affected with this disease. The International agency for Research on Cancer, states that O. viverrini and C. sinensis, also liver flukes, are considered as definitive causes of cholangiocarcinoma. However, fascioliasis caused by F. hepatica has not been associated with cancer to date. There are not any known causative associations between this parasite and liver cancer (cholangiocarcinoma). METHODS: Chine Hamster Ovary (CHO) cells were treated with F. hepatica extracts and cell proliferation was assessed by using the indirect method for estimating cell number based on the mitochondrial activity with MTS cell proliferation reagent. We observed unexpected death of these cells when treated with F. hepatica extracts. RESULTS: We now hypothesize that this parasite could be used as a medically-important trematode pathogen in cancer therapy.

Halting Schistosoma haematobium - associated bladder cancer.

BACKGROUND: At present schistosomiasis is endemic in 78 countries affecting more than 260 million people. Schistosomiasis haematobia alone affects more than 112 millions. MATERIAL AND METHODS: We performed a computerized search of Pubmed database with keywords: bladder cancer cost and schistosomiasis mass treatment. RESULTS: Bladder cancer is an important sequelae of this infection. In low-resource countries, where this disease is endemic, individuals inflicted with bladder cancer have very limited access to treatment and death is most probably certain. CONCLUSION: Mass treatment with praziquantel is an easy, safe and inexpensive treatment that could save the lives of thousands and reduce the morbidity of millions.

Parasites in Forensic Science: a historic perspective

Parasites show a great potential to Forensic Science. Forensic Science is the application of any science and methodology to the legal system. The forensic scientist collects and analyses the physical evidence and produce a report of the results to the court. A parasite is an organism that lives at the expense of another and they exist in any ecosystem. Parasites are the cause of many important diseases. The forensic scientists can use the parasites to identify a crime scene, to determine the murder weapon or simply identify an individual. The applications for parasites in the Forensic Science can be many and more studies should be made in Forensic Parasitology. The most important parasites in Forensic Science are helminths specifically schistosomes. Through history there are many cases where schistosomes were described in autopsies and it was related to the cause of death. Here we review the applications of parasites in Forensic Science and its importance to the forensic scientist.

Angiogenesis in Schistosoma haematobium-associated urinary bladder cancer.

Schistosoma haematobium, a parasitic flatworm that infects more than 100 million people, mostly in the developing world, is the causative agent of urogenital schistosomiasis, and is associated with a high incidence of squamous cell carcinoma (SCC) of the bladder. During infection, eggs are deposited in the bladder causing an intense inflammatory reaction. Angiogenesis is defined as the formation of new blood vessels from preexisting ones and is recognized as a key event in cell proliferation and carcinogenesis and spread of malignant lesions. A growing amount of evidence points to angiogenesis playing a key role in schistosomiasis-associated bladder cancer. Thus, identifying biomarkers of this process plays an important role in the study of cancer. Here, we review recent findings on the role of angiogenesis in bladder cancer and the growth factors that induce and assist in their development, particularly SCC of the bladder associated to urogenital schistosomiasis.

Endothelial Progenitor Cells in Breast Cancer.

Recent evidences demonstrated the importance of bone marrow derived Endothelial Progenitor Cells (EPC), in the contribution to postnatal physiological and pathological neovascularization, and in tumor growth and angiogenesis. These cells are recruited undifferentiated, in response to systemic or chemoatractive signals, such as Vascular Endothelial Growth Factor (VEGF), they lodge in the growing or lesioned tissue and differentiate into endothelial cells in response to local stimuli and cell-cell interactions. The extent and the significance of the EPCs contribution for the growing of most tumors, including those of the breast, are still not fully defined. We analyzed the peripheral blood of breast cancer patients and found that they have circulating EPCs. We also found an association between expression of AC133+Kdr+ and VEGF plasma levels in these patients. Strategies to impair the mobilization and incorporation of EPCs into breast tumors may contribute to halt the growth of these tumors.

Progesterone in Breast Cancer Angiogenesis.

The involvement of steroid hormones in breast carcinogenesis is well established. Recent evidence suggests that angiogenesis can be regulated by hormones. Both oestrogen and progesterone have been implicated in the angiogenic process of hormone-dependent cancers, such as breast cancer. Vascular Endothelial Growth Factor (VEGF) is a growth factor involved in angiogenesis in breast cancer that is up-regulated by estrogens. In our study we evaluated the role of progesterone in the expression of this angiogenic growth factor commonly up-regulated in breast cancer. Our findings indicate that progesterone activates an angiogenic pathway involving VEGF stimulation. The elucidation of specific angiogenic pathways promoted by progesterone can raise new therapeutic targets at least in a subset of breast cancers responsive to progesterone.

Bladder cancer and urinary Schistosomiasis in Angola.

Schistosomiasis haematobia is among the most prevalent parasitosis in Angola. The pathology is characterized by serious and irreversible lesions in the urogenital tract induced by chronic infection with the parasite that can eventually lead to squamous cell carcinoma of the bladder. Considering the frequency and severe morbidity observed, even in younger ages, the purpose of this study was to assess the prevalence and morbidity of S. haematobium infection in Angola. A baseline survey was conducted between November 2007 and February 2008. A randomly sample of 300 inhabitants aged 15 to 75 years old participated in this study. Prevalence of S. haematobium infection was 71.7 % (215/300). Infection was higher in females (56.3 %) but no significant difference was found in prevalence and intensity between gender and age groups. The predominant selfreported symptoms were dysuria (91.2 %), hypogastralgia (88.7 %) and haematuria (87.1%) and these symptoms were strongly associated with S. haematobium infection (p<0.05). Ultrasound and cystoscopy examinations performed in a sub-sample of 29 individuals revealed pathological conditions at the urinary tract in all examined. Considering the high prevalence of S. haematobium infections in Angola and schistosomiasis-associated bladder cancer, our results indicate that this population should be targeted for follow up and implementation of measures for treatment and control of schistosomiasis.

The role of estrogens and estrogen receptor signaling pathways in cancer and infertility: the case of schistosomes.

Schistosoma haematobium, a parasitic flatworm that infects more than 100 million people, mostly in the developing world, is the causative agent of urogenital schistosomiasis, and is associated with a high incidence of squamous cell carcinoma (SCC) of the bladder. Schistosomiasis haematobia also appears to negatively influence fertility, and is particularly associated with female infertility. Given that estrogens and estrogen receptors are key players in human reproduction, we speculate that schistosome estrogen-like molecules may contribute to infertility through hormonal imbalances. Here, we review recent findings on the role of estrogens and estrogen receptors on both carcinogenesis and infertility associated with urogenital schistosomiasis and discuss the basic hormonal mechanisms that might be common in cancer and infertility.

Schistosome and liver fluke derived catechol-estrogens and helminth associated cancers.

Infection with helminth parasites remains a persistent public health problem in developing countries. Three of these pathogens, the liver flukes Clonorchis sinensis, Opisthorchis viverrini and the blood fluke Schistosoma haematobium, are of particular concern due to their classification as Group 1 carcinogens: infection with these worms is carcinogenic. Using liquid chromatography-mass spectrometry (LC-MS/MS) approaches, we identified steroid hormone like (e.g., oxysterol-like, catechol estrogen quinone-like, etc.) metabolites and related DNA-adducts, apparently of parasite origin, in developmental stages including eggs of S. haematobium, in urine of people with urogenital schistosomiasis, and in the adult stage of O. viverrini. Since these kinds of sterol derivatives are metabolized to active quinones that can modify DNA, which in other contexts can lead to breast and other cancers, helminth parasite associated sterols might induce tumor-like phenotypes in the target cells susceptible to helminth parasite associated cancers, i.e., urothelial cells of the bladder in the case of urogenital schistosomiasis and the bile duct epithelia or cholangiocytes, in the case of O. viverrini and C. sinensis. Indeed we postulate that helminth induced cancers originate from parasite estrogen-host epithelial/urothelial cell chromosomal DNA adducts, and here we review recent findings that support this conjecture.

Urinary estrogen metabolites and self-reported infertility in women infected with Schistosoma haematobium.

BACKGROUND: Schistosomiasis is a neglected tropical disease, endemic in 76 countries, that afflicts more than 240 million people. The impact of schistosomiasis on infertility may be underestimated according to recent literature. Extracts of Schistosoma haematobium include estrogen-like metabolites termed catechol-estrogens that down regulate estrogen receptors alpha and beta in estrogen responsive cells. In addition, schistosome derived catechol-estrogens induce genotoxicity that result in estrogen-DNA adducts. These catechol estrogens and the catechol-estrogen-DNA adducts can be isolated from sera of people infected with S. haematobium. The aim of this study was to study infertility in females infected with S. haematobium and its association with the presence of schistosome-derived catechol-estrogens. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional study was undertaken of female residents of a region in Bengo province, Angola, endemic for schistosomiasis haematobia. Ninety-three women and girls, aged from two (parents interviewed) to 94 years were interviewed on present and previous urinary, urogenital and gynecological symptoms and complaints. Urine was collected from the participants for egg-based parasitological assessment of schistosome infection, and for liquid chromatography diode array detection electron spray ionization mass spectrometry (LC/UV-DAD/ESI-MSn) to investigate estrogen metabolites in the urine. Novel estrogen-like metabolites, potentially of schistosome origin, were detected in the urine of participants who were positive for eggs of S. haematobium, but not detected in urines negative for S. haematobium eggs. The catechol-estrogens/ DNA adducts were significantly associated with schistosomiasis (OR 3.35; 95% CI 2.32-4.84; P≤0.001). In addition, presence of these metabolites was positively associated with infertility (OR 4.33; 95% CI 1.13-16.70; P≤0.05). CONCLUSIONS/SIGNIFICANCE: Estrogen metabolites occur widely in diverse metabolic pathways. In view of the statistically significant association between catechol-estrogens/ DNA adducts and self-reported infertility, we propose that an estrogen-DNA adduct mediated pathway in S. haematobium-induced ovarian hormonal deregulation could be involved. In addition, the catechol-estrogens/ DNA adducts described here represent potential biomarkers for schistosomiasis haematobia.

Carcinogenic ability of Schistosoma haematobium possibly through oncogenic mutation of KRAS gene.

Schistosoma haematobium is a parasitic flatworm that infects millions of people, mostly in the developing world, and is associated with high incidence of bladder cancer, although why is not clear. Previously, we have used CD-1 mice to show that Schistosoma haematobium total antigen (Sh) has a carcinogenic ability. Sh intravesically instillation induced the development of several urothelial lesions, namely nodular hyperplasia and dysplasia (LGIUN-Low Grade Intra-Urothelial Neoplasia) after 40 weeks of treatment. These results suggested that Sh induce urothelium malignization. Bladder carcinoma frequently harbours gene mutations that constitutively activate the receptor tyrosine kinase-Ras pathway for this reason we studied activating mutations in KRAS gene. Twenty percent of the bladders with dysplasia presented a KRAS mutation in codon 12 of exon 2. We concluded from these results that the parasite extract of S. haematobium has carcinogenic ability possibly through oncogenic mutation of KRAS gene.

Tumour-like phenotypes in urothelial cells after exposure to antigens from eggs of Schistosoma haematobium: an oestrogen-DNA adducts mediated pathway?

Chronic infection with the blood fluke, Schistosoma haematobium, is associated with squamous cell carcinoma of the bladder. Previously, it has been shown that soluble extracts of mixed sex adult S. haematobium worms (SWAP) are tumourigenic, both in vitro and in vivo. In addition, oestrogen-related molecules in SWAP of S. haematobium down-regulate oestrogen receptors (ERs) alpha and beta in oestrogen responsive cells. Moreover, schistosome oestrogens occur in sera of persons with schistosomiasis haematobia and repress transcription of ERs in urothelial cells. Given that eggs of S. haematobium are the developmental stage directly responsible for urogenital disease during schistosomiasis haematobia, we suspected that soluble antigens from S. haematobium eggs exhibit similar or more potent tumorigenic capacity. Here we investigated the tumorigenic potential of soluble egg antigens (Sh-SEA) of S. haematobium and the endocrine system in favouring parasitism by schistosomes. The findings confirmed that 6.25µg/ml of Sh-SEA was enough to stimulate cell proliferation, reduce apoptosis and increase oxidative stress of Sh-SEA-exposed urothelial cells. In addition, genotoxic effects of Sh-SEA on these cells were determined by using alkaline single-cell gel electrophoresis (Comet). Furthermore, Liquid Chromatography Diode Array Detection Electron Spray Ionisation Mass Spectrometry indicated the presence of catechol-oestrogens in S. haematobium SEA. A prospective oestrogen-DNA adduct mediated pathway in S. haematobium egg induced bladder cancer is also discussed.