ABSTRACT
INTRODUCTION: Sexual dimorphism significantly influences cancer incidence and prognosis. Notably, females exhibit a lower risk and favorable prognosis for non-reproductive cancers compared to males, a pattern observable beyond the scope of risk behaviors such as alcohol consumption and smoking. Colorectal cancer, ranking third in global prevalence and second in mortality, disproportionately affects men. Sex steroid hormones, particularly estrogens and androgens, play crucial roles in cancer progression, considering epidemiological in vivo and in vitro, in general estrogens imparting a protective effect in females and androgens correlating with an increasing risk of colorectal cancer development. MAIN BODY: The hormonal impact on immune response is mediated by receptor interactions, resulting in heightened inflammation, modulation of NF-kB, and fostering an environment conducive to cancer progression and metastasis. These molecules also influence the enteric nervous system, that is a pivotal in neuromodulator release and intestinal neuron stimulation, also contributes to cancer development, as evidenced by nerve infiltration into tumors. Microbiota diversity further intersects with immune, hormonal, and neural mechanisms, influencing colorectal cancer dynamics. A comprehensive understanding of hormonal influences on colorectal cancer progression, coupled with the complex interplay between immune responses, microbiota diversity and neurotransmitter imbalances, underpins the development of more targeted and effective therapies. CONCLUSIONS: Estrogens mitigate colorectal cancer risk by modulating anti-tumor immune responses, enhancing microbial diversity, and curbing the pro-tumor actions of the sympathetic and enteric nervous systems. Conversely, androgens escalate tumor growth by dampening anti-tumor immune activity, reducing microbial diversity, and facilitating the release of tumor-promoting factors by the nervous system. These findings hold significant potential for the strategic purposing of drugs to fine-tune the extensive impacts of sex hormones within the tumor microenvironment, promising advancements in colorectal cancer therapies.
Subject(s)
Colorectal Neoplasms , Sex Characteristics , Humans , Colorectal Neoplasms/metabolism , Animals , Female , Gonadal Steroid Hormones/metabolism , Gonadal Steroid Hormones/physiology , MaleABSTRACT
Introduction: Worldwide, breast cancer is the most important cancer in incidence and prevalence in women. Different risk factors interact to increase the probability of developing it. Biological agents such as helminth parasites, particularly their excretory/secretory antigens, may play a significant role in tumor development. Helminths and their antigens have been recognized as inducers or promoters of cancer due to their ability to regulate the host's immune response. Previously in our laboratory, we demonstrated that chronic infection by Toxocara canis increases the size of mammary tumors, affecting the systemic response to the parasite. However, the parasite does not invade the tumor, and we decided to study if the excretion/secretion of antigens from Toxocara canis (EST) can affect the progression of mammary tumors or the pathophysiology of cancer which is metastasis. Thus, this study aimed to determine whether excretion/secretion T. canis antigens, injected directly into the tumor, affect tumor growth and metastasis. Methods: We evaluated these parameters through the monitoring of the intra-tumoral immune response. Results: Mice injected intratumorally with EST did not show changes in the size and weight of the tumors; although the tumors showed an increased microvasculature, they did develop increased micro and macro-metastasis in the lung. The analysis of the immune tumor microenvironment revealed that EST antigens did not modulate the proportion of immune cells in the tumor, spleen, or peripheral lymph nodes. Macroscopic and microscopic analyses of the lungs showed increased metastasis in the EST-treated animals compared to controls, accompanied by an increase in VEGF systemic levels. Discussion: Thus, these findings showed that intra-tumoral injection of T. canis EST antigens promote lung metastasis through modulation of the tumor immune microenvironment.
Subject(s)
Breast Neoplasms , Parasites , Toxocara canis , Toxocariasis , Humans , Female , Animals , Mice , Antigens, Helminth , Injections, Intralesional , Lung , Tumor MicroenvironmentABSTRACT
BACKGROUND: Toxocara canis (T. canis) is a helminth parasite of zoonotic and veterinary health significance that causes the disease known as Toxocariasis. This disease has been associated with conditions of poverty, especially in tropical climate zones throughout the world. Although it rarely causes important clinical manifestations, T. canis can lead to blindness, meningoencephalitis, or other nervous manifestations in humans. Moreover, some studies show its importance in the development of tumor growth, which have been associated with the parasite's ability to modulate the host's immune response. While different studies have evaluated the immune response during this disease, currently, there are no studies where the infection is analyzed from the perspective of sexual dimorphism. METHODS: To evaluate sex differences in susceptibility, we analyzed lesions and parasite loads in lung and liver at 7 days post-infection. In addition, immune cell subpopulations were analyzed in spleen, mesenteric and peripheral lymph nodes. Finally, the production of cytokines and specific antibodies were determined in the serum. Statical analyses were performed using a Two-way ANOVA and a post-hoc Bonferroni multiple comparison test. RESULTS: Female rats had a higher number of larvae in the liver, while male rats had them in the lungs. The percentages of immune cells were evaluated, and in most cases, no significant differences were observed. Regarding the cytokines production, infection can generate a decrease in Th1 such as IL-1ß in both sexes and IL-6 only in females. In the case of Th2, IL-4 increases only in infected males and IL-5 increases in males while decreasing in females due to the effect of infection. IL-10 also decreases in both sexes as a consequence of the infection, and TGF-ß only in females. Finally, the infection generates the production of antibodies against the parasite, however, their quantity is lower in females. CONCLUSIONS: This study demonstrates that T. canis infection is dimorphic and affects females more than males. This is due to a polarization of the inadequate immune response, which is reflected as a higher parasite load in this sex.
Subject(s)
Toxocara canis , Toxocariasis , Humans , Female , Rats , Male , Animals , Toxocariasis/parasitology , Toxocariasis/pathology , Toxocara canis/physiology , Sex Characteristics , Cytokines , ImmunityABSTRACT
Although the modulation of immunity by exercise has been a long-studied paradigm, the molecular pathways connecting the two are still not fully understood. Regular moderate aerobic exercise is associated with improved health and directly impacts the immune system by changing the proportion of cell subpopulations, their function, and interleukin production. The endocannabinoid system has gained importance as an immune modulator, affected by moderate aerobic promoting the production of endocannabinoids, which are ligands of the cannabinoid receptors (CBRs) expressed on the surface of all immune cells. Our group previously reported a reduction of lymphocytic populations in the spleen of chronically exercised rats, accompanied by an increase in CBR expression. Given the complex and compartmentalized nature of the immune system, we decided to study the effects of chronic exercise on the proportion of peripheral blood mononuclear cells, serum interleukins, and the expression of CBRs on these cells. Overall, our results indicate that chronic exercise decreases the proportion of T helper and Tγδ cells but increases the expression of cannabinoids (CBR1) on T helper and natural killer cells, and the production of interleukins, including IL-1ß, interferon-gamma, tumor necrosis factor-alpha, IL-10, and IL-4, suggesting higher reactivity and efficiency from the immune system conferred by exercise.
Subject(s)
Cytokines , Leukocytes, Mononuclear , Rats , Animals , Cytokines/metabolism , Interleukins/metabolism , Killer Cells, Natural , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Breast cancer treatment failure is related to low response rates, high costs, and long-term toxicities. Thus, it is necessary to find less toxic, cheaper, and more effective treatments. In situ administration ensures drug delivery to tumor cells and decreases systemic toxic effects. The androstene-3ß, 17α-diol (α-AED) reduces breast tumor cell proliferation and is an ideal candidate to treat mammary tumors. This study aims to identify the in vitro and in vivo effects of α-AED on a triple-negative mammary tumor model. An in vitro biphasic steroid effect was observed in mouse and human mammary tumor cells treated with α-AED. In this sense, cells treated with higher doses (100 and 200 µM) showed an antiproliferative effect. The α-AED administrated intratumorally reduced average tumor weight and increased the percentage of natural killer cells (NK), plasmatic, and plasmablast cells in mice tumors. Of note, VEGF levels in all α-AED-treated tumors was lower than in the control and vehicle groups. The tumor in situ increased response was reflected systemically by higher anti-4T1 IgG concentration in serum from α-AED-treated mice, but no other associated systemic changes were detected. The reduction in tumor size for the local injection of α-AED is associated with the anti-proliferative effect of this steroid, and the lower local levels of VEGF may be related to the imperceptible macroscopic metastasis in α-AED-treated mice. The above suggests that α-AED may be used in clinical studies to prove its efficacy as an alternative breast tumor treatment or in conjunction with already established therapies.
Subject(s)
Breast Neoplasms , Lung Neoplasms , Androstenes , Animals , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Humans , Immunoglobulin G , Lung Neoplasms/drug therapy , Mice , Models, Theoretical , Vascular Endothelial Growth Factor AABSTRACT
Phthalates and bisphenols are ubiquitous environmental pollutants with the ability to perturb different systems. Specifically, they can alter the endocrine system, and this is why they are also known as endocrine-disrupting compounds (EDCs). Interestingly, they are related to the development and progression of breast cancer (BC), but the threshold concentrations at which they trigger that are not well established. OBJECTIVES: The aim of this study was to compare the concentration measures of parent EDCs in three groups of women (without BC, with BC, and BC survivors) from two urban populations in Mexico, to establish a possible association between EDCs and this disease. We consider the measure of the parent compounds would reflect the individual's exposure. METHODS: The levels of di-ethyl-hexyl-phthalate (DEHP), butyl-benzyl-phthalate (BBP), di-n-butyl phthalate (DBP) and di-ethyl-phthalate (DEP), bisphenol A (BPA) and bisphenol S (BPS) were determined by gas chromatograph-mass spectrometry in 102 subjects, including 37 women without any pathological disease, 46 patients with BC and 19 women survivals of BC of Mexico and Toluca City. RESULTS: All phthalates were detected in 100% of women, two of them were significantly higher in patients with different BC subtypes in Mexico City. Differential increases were observed mainly in the serum concentration of phthalates in women with BC compared to women without disease between Mexico and Toluca City. In addition, when performing an analysis of the concentrations of phthalates by molecular type of BC, DEP and BBP were found mainly in aggressive and poorly differentiated types of BC. It should be noted that female BC survivors treated with anti-hormonal therapy showed lower levels of BBP than patients with BC. BPA and BPS were found in most samples from Mexico City. However, BPS was undetectable in women from Toluca City. DISCUSSION: The results of our study support the hypothesis of a positive association between exposure to phthalates and BC incidence.
Subject(s)
Breast Neoplasms , Endocrine Disruptors , Phthalic Acids , Benzhydryl Compounds/analysis , Breast Neoplasms/epidemiology , Environmental Exposure/analysis , Female , Humans , Phenols , Phthalic Acids/analysis , Plasticizers/analysis , SurvivorsABSTRACT
Breast cancer (BC) metastasis represents the main physiopathology leading to poor prognosis and death. Bisphenol A (BPA) is a pollutant, classified as an endocrine-disrupting chemical compound with estrogenic properties, their exposure in the early stages of neonatal life leads to an increase in the size and weight of breast tumors and induces cellular changes in the tumoral immune microenvironment where cytokines play a key role. Thus, we used female BALB/c mice exposed neonatally to a single dose of BPA. Once mice reached sexual maturity, a mammary tumor was induced, injecting 4T1 cells in situ. After 25 days of injection, we evaluated endocrine alterations, cytokine expression, tissue alterations denoted by macro or micro-metastasis in the lung, and cell infiltration induced by metastasis. We found that BPA neonatal treatment did not show significant endocrine alterations. Noteworthy, BPA led to an augmented rate of metastasis to the lung associated with higher intratumoral expression of IL-1ß, IL-6, IFN-γ, TNF-α, and VEGF. Our data suggest that cytokines are key players in the induction of BC metastasis and that BPA (an environmental pollutant) should be considered as a risk factor in the clinical history of patients as a possible inductor of BC metastasis.
Subject(s)
Breast Neoplasms , Endocrine Disruptors , Lung Neoplasms , Animals , Benzhydryl Compounds/toxicity , Cytokines , Endocrine Disruptors/toxicity , Female , Humans , Lung Neoplasms/chemically induced , Mice , Models, Theoretical , Phenols , Tumor MicroenvironmentABSTRACT
The interaction of the nervous, immune, and endocrine systems is crucial in maintaining homeostasis in vertebrates, and vital in mammals. The spleen is a key organ that regulates the neuroimmunoendocrine system. The Taenia crassiceps mouse system is an excellent experimental model to study the complex host-parasite relationship, particularly sex-associated susceptibility to infection. The present study aimed to determine the changes in neurotransmitters, cytokines, sex steroids, and sex-steroid receptors in the spleen of cysticercus-infected male and female mice and whole parasite counts. We found that parasite load was higher in females in comparison to male mice. The levels of the neurotransmitter epinephrine were significantly decreased in infected male animals. The expression of IL-2 and IL-4 in the spleen was markedly increased in infected mice; however, the expression of Interleukin (IL)-10 and interferon (IFN)-γ decreased. We also observed sex-associated differences between non-infected and infected mice. Interestingly, the data show that estradiol levels increased in infected males but decreased in females. Our studies provide evidence that infection leads to changes in neuroimmunoendocrine molecules in the spleen, and these changes are dimorphic and impact the establishment, growth, and reproduction of T. crassiceps. Our findings support the critical role of the neuroimmunoendocrine network in determining sex-associated susceptibility to the helminth parasite.
ABSTRACT
Public concern has emerged about the effects of endocrine-disrupting compounds (EDCs) on neuropsychiatric disorders. Preclinical evidence suggests that exposure to EDCs is associated with the development of major depressive disorder (MDD) and could result in neural degeneration. The interaction of EDCs with hormonal receptors is the best-described mechanism of their biological activity. However, the dysregulation of the hypothalamic-pituitary-gonadal adrenal axis has been reported and linked to neurological disorders. At a worldwide level and in Mexico, the incidence of MDD has recently been increasing. Of note, in Mexico, there are no clinical associations on blood levels of EDCs and the incidence of the MDD. Methodology: Thus, we quantified for the first time the serum levels of parent compounds of two bisphenols and four phthalates in patients with MDD. The levels of di-ethyl-hexyl-phthalate (DEHP), butyl-benzyl-phthalate (BBP), di-n-butyl phthalate (DBP), and di-ethyl-phthalate (DEP), bisphenol A (BPA), and bisphenol S (BPS) in men and women with or without MDD were determined with a gas chromatograph-mass spectrometer. Results/conclusion: We found significant differences between concentrations of BBP between controls and patients with MDD. Interestingly, the serum levels of this compound have a dysmorphic behavior, being much higher in women (~500 ng/mL) than in men (≤10 ng/mL). We did not observe significant changes in the serum concentrations of the other phthalates or bisphenols tested, neither when comparing healthy and sick subjects nor when they were compared by gender. The results point out that BBP has a critical impact on the etiology of MDD disorder in Mexican patients, specifically in women.
Subject(s)
Depressive Disorder, Major , Endocrine Disruptors , Phthalic Acids , Depressive Disorder, Major/epidemiology , Dibutyl Phthalate , Endocrine Disruptors/toxicity , Environmental Exposure/statistics & numerical data , Environmental Pollution/statistics & numerical data , Female , Humans , Male , Phthalic Acids/toxicityABSTRACT
We previously reported that the Trichinella nematode showed higher parasite loads in one gender than another, but also the parasite molting rate decreased when it was cultivated in the presence of progesterone. In this study we explored the hypothesis that the direct effect of progesterone on Trichinella spiralis could be mediated by a steroid-binding parasite protein. We sequenced, cloned and amplified the Cyt-domain of the progesterone receptor membrane component-2 of Trichinella spiralis (PGRMC2-Ts). Furthermore, we expressed the protein and developed an antibody to perform confocal microscopy and flow cytometry. The expression of the PGRMC2-Ts protein was exclusively detected at the oocyte and the parasite's cuticle in cross-sections of the parasite, and this expression was confirmed by western blot and flow cytometry. Molecular modeling studies and computer docking for the PGRMC2-Ts protein showed that it is potentially able to bind to progesterone, estradiol, testosterone, and dihydrotestosterone with different affinities. Furthermore, phylogenetic analysis demonstrated that T. spiralis PGRMC2 is related to a steroid-binding protein of another platyhelminth. Progesterone probably acts upon Trichinella spiralis oocytes by binding to PGRMC2-Ts. Our data showed that the PGRMC2-Ts protein is present in the parasite's oocytes, a development step that is crucial for the life cycle of the parasite. Indeed, this research might have implications in the field of host-parasite co-evolution and the sex-associated susceptibility to this infection. In a more practical matter, these results may contribute to the design of new drugs with anti-parasite effects.
Subject(s)
Parasites , Trichinella spiralis , Trichinellosis , Animals , Helminth Proteins , Oocytes , Phylogeny , Progesterone , Trichinella spiralis/genetics , Trichinellosis/veterinaryABSTRACT
Toxoplasmosis is a zoonotic disease caused by the apicomplexa protozoan parasite Toxoplasma gondii. This disease is a health burden, mainly in pregnant women and immunocompromised individuals. Dehydroepiandrosterone (DHEA) has proved to be an important molecule that could drive resistance against a variety of infections, including intracellular parasites such as Plasmodium falciparum and Trypanozoma cruzi, among others. However, to date, the role of DHEA on T. gondii has not been explored. Here, we demonstrated for the first time the toxoplasmicidal effect of DHEA on extracellular tachyzoites. Ultrastructural analysis of treated parasites showed that DHEA alters the cytoskeleton structures, leading to the loss of the organelle structure and organization as well as the loss of the cellular shape. In vitro treatment with DHEA reduces the viability of extracellular tachyzoites and the passive invasion process. Two-dimensional (2D) SDS-PAGE analysis revealed that in the presence of the hormone, a progesterone receptor membrane component (PGRMC) with a cytochrome b5 family heme/steroid binding domain-containing protein was expressed, while the expression of proteins that are essential for motility and virulence was highly reduced. Finally, in vivo DHEA treatment induced a reduction of parasitic load in male, but not in female mice.
ABSTRACT
Phthalates are endocrine disrupting compounds (EDCs) used as plasticizers in a wide array of daily-use products, from flooring and automotive parts to medical devices and are even present in the children�s toys. Since these compounds are not covalently bound other molecules, they leach from these synthetic products, causing a high level of human exposure to them. EDCs exert several endocrine effects, most typically, reduced biosynthesis of the male hormone, testosterone and disturbances in estrogen, androgen, PPAR-gamma and AhR that control complex immunoendocrine regulatory networks. Besides impacting the developmental processes and long-term adverse effects, since cells of the immune system express endocrine receptors, and synthetize and respond to several hormones and other endocrine ligands, phthalates also cause dysregulation of immune system.
Subject(s)
Endocrine System/drug effects , Environmental Pollutants/toxicity , Immune System/drug effects , Phthalic Acids/toxicity , Environmental Exposure/adverse effects , HumansABSTRACT
Breast cancer is one of the most common malignancies and the second leading cause of death in women. Despite efforts for its early detection, its worldwide incidence continues to increase. Thus, identification of risk factors for its development and new targets for its therapy are of vital importance. Environmental pollutants derived from human activity have been associated with predisposition to the development of cancer. Bisphenol A (BPA) is an endocrine disruptor compound (EDC) widely used in the manufacture of polycarbonates, and it has affinity for the estrogen receptor (ER). Scientific evidence has proposed an association between increased incidence of breast cancer and BPA exposure at lower doses. Among worldwide concerns with BPA exposure, different industries proceeded to replace BPA with analogs such as bisphenol S (BPS), which is now employed in products labelled as BPA-free. Nevertheless, recent studies exhibit that its exposure results in altered mammary gland development and morphogenesis; and promotes breast cancer cell proliferation. Of note, most of the effects of both BPA and BPS have been performed in estrogen-dependent breast cancer models. However, gaps in knowledge still exist on the roles and mechanisms that both compounds, specifically BPS, may play in cancer initiation and development in hormone-dependent and other types of breast cancer. Thus, the aim of the present study was to deepen the understanding of biological targets modulated by these ubiquitous pollutants in different breast cancer cell lines, representing two scenarios of this pathology: hormone-dependent and hormone-independent breast cancer. Results point out that both compounds induced proliferation in ER positive cells, not showing this effect in the ER-negative breast cancer cells. Different targets modified at the proteomic level in both breast cancer scenarios were also identified. Stem cell markers (eg. CD44) and invasion proteins (eg. MMP-14) were importantly increased by BPA and BPS in ER-positive breast cancer cells. In contrast, growth factors and associated receptors such as EGFR and TGF-ß were induced by BPS in the ER-negative breast cancer cells; both pollutants induced an increase of vascular endothelial growth factor (VEGF) protein secretion. This finding suggests that the use of BPS must be considered with more caution than BPA, since it can act independently of the presence of the hormonal receptor. These findings show new evidence that BPA and BPS exposure can contribute to breast cancer development and progression. Our results suggest that both BPA and BPS must be considered equally as outstanding risk factors for this pathology.
Subject(s)
Breast Neoplasms , Environmental Pollutants , Benzhydryl Compounds/toxicity , Breast Neoplasms/chemically induced , Environmental Pollutants/toxicity , Female , Humans , Phenols , Phenotype , Proteomics , Sulfones , Vascular Endothelial Growth Factor AABSTRACT
Taiep rat is a myelin mutant with a progressive motor syndrome characterized by tremor, ataxia, immobility episodes, epilepsy and paralysis of the hindlimbs. Taiep had an initial hypomyelination followed by a progressive demyelination associated with an increased expression of some interleukins and their receptors. The pathology correlated with an increase in nitric oxide activity and lipoperoxidation. In base of the above evidences taiep rat is an appropriate model to study neuroimmune interactions. The aim of this study was to analyze the immune responses in male taiep rats after acute infection with Trichinella spiralis. Our results show that there is an important decrease in the number of intestinal larvae in the taiep rat with respect to Sprague-Dawley control rats. We also found differences in the percentage of innate and adaptive immune cell profile in the mesenteric lymphatic nodes and the spleen that correlated with the demyelination process that took place on taiep subjects. Finally, a clear pro-inflammatory cytokine pattern was seen on infected taiep rats, that could be responsible of the decrement in the number of larvae number. These results sustain the theory that neuroimmune interaction is a fundamental process capable of modulating the immune response, particularly against the parasite Trichinella spiralis in an animal model of progressive demyelination due to tubulinopathy, that could be an important mechanism for the clinical course of autoimmune diseases associated with parasite infection.
Subject(s)
Myelin Sheath/genetics , Myelin Sheath/metabolism , Trichinella spiralis/pathogenicity , Animals , Demyelinating Diseases/pathology , Disease Models, Animal , Male , Parasites , Rats , Rats, Mutant Strains/immunology , Rats, Sprague-Dawley/genetics , Rats, Sprague-Dawley/immunology , Tremor/pathology , Trichinella spiralis/metabolismABSTRACT
BACKGROUND: As a result of human socioeconomic activity, industrial wastes have increased distressingly. Plastic pollution is globally distributed across the world due to its properties of buoyancy and durability. A big health hazard is the sorption of toxicants to plastic while traveling through the environment. Two broad classes of plastic-related chemicals are of critical concern for human health-bisphenols and phthalates. Bisphenol A (BPA) is an endocrine-disruptor compound (EDC) with estrogenic activity. It is used in the production of materials that are used daily. The endocrine modulating activity of BPA and its effects on reproductive health has been widely studied. BPA also has effects on the immune system; however, they are poorly investigated and the available data are inconclusive. Phthalates are also EDCs used as plasticizers in a wide array of daily-use products. Since these compounds are not covalently bound to the plastic matrix, they easily leach out from it, leading to high human exposure. These compounds exert several cell effects through modulating different endocrine pathways, such as estrogen, androgen, peroxisome proliferator-activated receptor gamma, and arylhydrocarbon receptor pathways. The exposure to both classes of plastic derivatives during critical periods has detrimental effects on human health. METHODS: In this review, we have compiled the most important of their perinatal effects on the function of the immune system and their relationship to the development of different types of cancer. RESULTS/CONCLUSION: The administration of bisphenols and phthalates during critical stages of development affects important immune system components, and the immune function; which might be related to the development of different diseases including cancer.
Subject(s)
Endocrine Disruptors , Neoplasms , Child , Endocrine Disruptors/toxicity , Female , Humans , Immune System , Microplastics , Plastics , PregnancyABSTRACT
Worldwide, breast cancer is the most important type of cancer in women with regard to incidence and prevalence. Several risk factors interact to increase the probability of breast cancer development. Biological environmental contaminants such as infectious agents play a significant role in tumor development, and helminths have been recognized as cancer enhancers or inducers due to their ability to regulate the host immune response. Toxocara canis is a zoonotic and cosmopolite nematode with immuno-regulatory abilities. T. canis infection has been related to T helper type-2 cell (Th2 or type 2) and regulatory responses. Type 2 and regulatory immune responses may favor the development of comorbidities that are usually controlled or eliminated through a type 1 response such as cancer. The aim of this study was to determine whether T. canis infection alters mammary tumor growth through modulation of the immune response. Infected mice developed larger tumors. Tumor immune cell milieu analysis revealed that infection reduced the proportions of CD8+ lymphocytes and increased the proportions of F4/80+ macrophages and CD19+ B cells. These changes were accompanied by a type 2 local response represented by increased amounts of IL-4 and VEGF and a regulatory microenvironment associated with higher IL-10 levels. Thus, this study demonstrates that T. canis infection enhances tumor development and suggests that this is through modulation of the tumor immune microenvironment.
ABSTRACT
AIMS: Industrial growth has increased the exposure to endocrine disruptor compounds (EDCs) in all organisms. Bisphenol A (BPA), an EDC, has been demonstrated to be involved in the susceptibility to parasite infections. However, few studies have analysed this connection in more depth. The aim of this study was to determine whether early BPA exposure in female mice affects the systemic immune response and the susceptibility to Taenia crassiceps infection. METHODS AND RESULTS: BALB/c mice were exposed to BPA at post-natal day 3. At 6 weeks of age, they were inoculated with T crassiceps larvae and, 2 weeks later, were euthanized. The number of parasites was quantified. By flow cytometry, in the spleen, the peripheral and mesenteric lymph nodes, the different innate and adaptive immune cell modulation was analysed, and RT-PCR cytokine expression was also evaluated. BPA induced a reduction of 40% in parasite load. BPA treatment modulated some lineages of the innate immune response and caused slight changes in cells belonging to the adaptive immune response. Additionally, BPA enhanced the type 2 cytokine profile. CONCLUSION: Neonatal BPA treatment in female mice affects not only the percentage of different immune cells but also their ex vivo cytokine gene expression, decreasing T crassiceps cysticercosis susceptibility.
Subject(s)
Anthelmintics/therapeutic use , Benzhydryl Compounds/therapeutic use , Cysticercosis/prevention & control , Phenols/therapeutic use , Taenia/immunology , Animals , Cysticercosis/immunology , Cysticercosis/parasitology , Cytokines/metabolism , Female , Lymph Nodes , Mice , Mice, Inbred BALB C , Parasite Load , Spleen/immunology , Taeniasis/immunology , Taeniasis/prevention & controlABSTRACT
Bisphenol A, a very widespread environmental pollutant and endocrine disruptor compound, can interact with several steroid receptors, particularly with estrogen ones. In different studies, it has observed that the endocrine disruption during critical periods of development can trigger alterations in the immune response during the adult life. Male Wistar rats were exposed indirectly to BPA at a dose of 250 µg/kg day during the perinatal period (from day 5 of pregnancy until day 21 postnatal), At the 60 days of age, the adulthood, animals were infected with larvated eggs of the Toxocara canis, and were sacrificed at 7 days post-infection. Parasitic loads in the lung and in the liver were analyzed by artificial digestion. Furthermore, immune cell subpopulations (macrophages, NK cells, Tγδ, total T cells, T helper, T cytotoxic, and B lymphocytes) present in spleen, peripheral and mesenteric lymph nodes were analyzed by flow cytometry. The expression of Th1 and Th2 cytokines at the splenic level was determined by real-time quantitative PCR. Finally, the titers of specific antibodies against to the parasite were analyzed by ELISA. The BPA treatment administrated in the perinatally stage favors a significant increase of the percentage of Toxocara canis larvae in the lungs and liver in the adulthood. Additionally, the exposure to this compound caused a dramatically decrease in the production of specific antibodies against to this parasite, downregulating together Th2 cytokines (IL-4, IL-5 and IL-13), meanwhile upregulated Th1 cytokines (IFN-γ and TNF-α). Perinatal exposure to BPA affects the performance of the immune response during adult life, modifying both cytokines and antibodies production by these cells, which favors the susceptibility to infections, specifically toxocariosis.
Subject(s)
Parasites , Toxocara canis , Adult , Animals , Benzhydryl Compounds/toxicity , Female , Humans , Male , Phenols , Pregnancy , Rats , Rats, WistarABSTRACT
The impact of performing exercise on the immune system presents contrasting effects on health when performed at different intensities. In addition, the consequences of performing chronic exercise have not been sufficiently studied in contrast to the effects of acute bouts of exercise. The porpoise of this work was to determine the effect that a popular exercise regimen (chronic/moderate/aerobic exercise) has on the proportion of different immune cell subsets, their function and if it affects the cannabinoid system with potentially functional implications on the immune system. A marked increase in several immune cell subsets and their expression of cannabinoid receptors was expected, as well as an enhanced proliferative and cytotoxic activity by total splenocytes in exercised animals. For this study male Wistar rats performed treadmill running 5 times a week for a period of 10 weeks, at moderate intensity. Our results showed a significant decrease in lymphocyte subpopulations (CD4+, Tγδ, and CD45 RA+ cells) and an increase in the cannabinoid receptors expression in those same cell. Although functional assays did not reveal any variation in total immunoglobulin production or NK cells cytotoxic activity, proliferative capability of total splenocytes increased in trained rats. Our results further support the notion that exercise affects the immunological system and extends the description of underlying mechanisms mediating such effects. Altogether, our results contribute to the understanding of the benefits of exercise on the practitioner´s general health.