Aghleb Bartegi

Effect of Endocrine Disruptor Pesticides: A Review

Endocrine disrupting chemicals (EDC) are compounds that alter the normal functioning of the endocrine system of both wildlife and humans. A huge number of chemicals have been identified as endocrine disruptors, among them several pesticides. Pesticides are used to kill unwanted organisms in crops, public areas, homes and gardens, and parasites in medicine. Human are exposed to pesticides due to their occupations or through dietary and environmental exposure (water, soil, air). For several years, there have been enquiries about the impact of environmental factors on the occurrence of human pathologies. This paper reviews the current knowledge of the potential impacts of endocrine disruptor pesticides on human health.

TNF-α and its inhibitors in cancer

Tumor necrosis factor (TNF)-α is implicated in the same time in apoptosis and in cell proliferation. TNF-α not only acts as pro-inflammatory cytokine conducing to wide spectrum of human diseases including inflammatory diseases, but can also induce tumor development. The molecular mechanisms of TNF-α functions have been intensively investigated. In this review we covered TNF-α, the molecule, its signaling pathway, and its therapeutic functions. We provide a particular insight in its paradoxical role in tumor promotion and in its use as anti-tumor agent. This review considers also the recent findings regarding TNF-α inhibitors, their pharmacokinetics, and their pharmacodynamics. Six TNF-α inhibitors have been considered here: Infliximab, Adalimumab, Golimumab, CDP870, CDP571, Etanercept, and Thalidomide. We discussed the clinical relevance of their functions in treatment of several diseases such as advanced inflammatory rheumatic and bowel disease, with a focus in cancer treatment. Targeting TNF-α by these drugs has many side effects like malignancies development, and the long-term sequels are not very well explored. Their efficacy and their safety were discussed, underscoring the necessity of close patients monitoring and of their caution use.

A role for 5,6‐epoxyeicosatrienoic acid in calcium entry by de novo conformational coupling in human platelets

A major pathway for Ca2+ entry in non‐excitable cells is activated following depletion of intracellular Ca2+ stores. A de novo conformational coupling between elements in the plasma membrane (PM) and Ca2+ stores has been proposed as the most likely mechanism to activate this capacitative Ca2+ entry (CCE) in several cell types, including platelets. Here we report that a cytochrome P450 metabolite, 5,6‐EET, might be a component of the de novo conformational coupling in human platelets. In these cells, 5,6‐EET induces divalent cation entry without having any detectable effect on Ca2+ store depletion. 5,6‐EET‐induced Ca2+ entry was sensitive to the CCE blockers 2‐APB, lanthanum, SKF‐96365 and nickel and impaired by incubation with anti‐hTRPC1 antibody. Ca2+ entry stimulated by low concentrations of thapsigargin, which selectively depletes the dense tubular system and induces EET production, was impaired by the cytochrome P450 inhibitor 17‐ODYA, which has no effect on CCE mediated by depletion of the acidic stores using 2,5‐di‐(tert‐butyl)‐1,4‐hydroquinone. We have found that 5,6‐EET‐induced Ca2+ entry requires basal levels of H2O2, which might maintain a redox state favourable for this event. Finally, our results indicate that 5,6‐EET induces the activation of tyrosine kinase proteins and the reorganization of the actin cytoskeleton, which might provide a support for the transport of portions of the Ca2+ store towards the PM to facilitate de novo coupling between IP3R type II and hTRPC1 detected by coimmunoprecipitation. We propose that the involvement of 5,6‐EET in TG‐induced coupling between IP3R type II and hTRPC1 and subsequently CCE is compatible with the de novo conformational coupling in human platelets.

Biological Analysis of Endocrine-Disrupting Compounds in Tunisian Sewage Treatment Plants

Endocrin-disrupting compounds (EDCs) are frequently found in wastewater treatment plants (WWTPs). So far, research has been mainly focused on the detection of estrogenic compounds and very little work has been carried out on other receptors activators. In this study, we used reporter cell lines, which allow detecting the activity of estrogen (ERα), androgen (AR), pregnane X (PXR), glucocorticoid (GR), progesterone (PR), mineralocorticoid (MR), and aryl hydrocarbon (AhR) receptors, to characterise the endocrine-disrupting profile of the aqueous, suspended particulate matter, and sludge fractions from three Tunisian WWTPs. The aqueous fraction exhibited estrogenic and androgenic activities. Suspended particulate matter and sludge extracts showed estrogenic, aryl hydrocarbon and pregnane X receptor activities. No GR, MR, or PR (ant) agonistic activity was detected in the samples, suggesting that environmental compounds present in sewage might have a limited spectrum of activity. By performing competition experiments with recombinant ERα, we demonstrated that the estrogenic activity detected in the aqueous fraction was due to EDCs with a strong affinity for ERα. Conversely, in the sludge fraction, it was linked to the presence of EDCs with weak affinity. Moreover, by using different incubation times, we determined that the EDCs present in suspended particulate matter and sludge, which can activate AhR, are metabolically labile compounds. Finally, we showed in this study that environmental compounds are mainly ER, AR, PXR, and AhR activators. Concerning AR and PXR ligands, we do not to know the nature of the molecules. Concerning ER and AhR compounds, competition experiments with recombinant receptor and analysis at different times of exposure of the AhR activation gave some indications of the compound’s nature that need to be confirmed by chemical analysis.

Olive tree wood phenolic compounds with human platelet antiaggregant properties

Oleuropein and (+)-cycloolivil are natural polyphenolic compounds with a significant radical scavenging activity present in olive tree. We have investigated the antiaggregant effects of oleuropein and (+)-cycloolivil isolated from an ethyl acetate extract of olive tree wood. Oleuropein and (+)-cycloolivil reduced the ability of thrombin to stimulate platelet aggregation. Both compounds reduced thrombin-evoked Ca(2+) release and entry to a similar extent to hydroxytyrosol. This effect was greater in platelets from patients with type 2 diabetes mellitus than in controls. Thrombin-, thapsigargin- and 2,5-di-(tert-butyl)-1,4-hydroquinone (TBHQ)-evoked protein tyrosine phosphorylation, which is involved in Ca(2+) signalling and platelet aggregation, is inhibited by oleuropein and (+)-cycloolivil. oleuropein and (+)-cycloolivil are natural oxygen radical scavengers that reduce thrombin-induced protein tyrosine phosphorylation, Ca(2+) signalling and platelet aggregation. These observations suggest that oleuropein and (+)-cycloolivil may prevent thrombotic complications associated to platelet hyperaggregability and be the base for the development of antiaggregant therapeutic strategies.

Attenuated store-operated divalent cation entry and association between STIM1, Orai1, hTRPC1 and hTRPC6 in platelets from type 2 diabetic patients

Agonist-evoked Ca(2+) entry has been reported to be enhanced in platelets from type 2 diabetic patients, which results in altered platelet responsiveness and cardiovascular complications. The present study is aimed to investigate whether store-operated divalent cation entry, a major Ca(2+) entry pathway, is altered in platelets from diabetic patients. Store-operated divalent cation entry was estimated by determination of Mn(2+) entry. Association between STIM1, Orai1, hTRPC1 and hTRPC6 was detected by co-immunoprecipitation and Western blotting. In the presence of specific purinergic and serotoninergic receptor antagonists Mn(2+) entry, induced by thapsigargin (TG), was reduced in platelets from diabetic donors as compared to healthy controls. Treatment with TG or the agonist thrombin enhanced co-immunoprecipitation of STIM1 with Orai1, hTRPC1 and hTRPC6 in platelets from healthy donors, a response that was significantly reduced in platelets from diabetic patients. Our results indicate that store-operated divalent cation entry is reduced in platelets from type 2 diabetic subjects, which is likely mediated by impairment of the association of STIM1 with the channel subunits Orai1, hTRPC1 and hTRPC6 and might be involved in the pathogenesis of the altered platelet responsiveness observed in diabetic patients.

Endocrine Disrupting Chemicals and Human Health Risk Assessment: A Critical Review

Concerns over the threats posed by a large number of molecules, collectively termed as endocrine disrupting compounds (EDCs) and generally known to alter and disrupt hormone systems and physiological functions, have often been expressed in academic and scholarly debates. From the perspective of classical toxicology, EDCs have genomic mechanisms of actions and exert agonistic or antagonistic effects on steroid receptors. They are also able to alter reproductive function by binding to estrogen or androgen receptors, and the neuroendocrine system by binding to the thyroid receptor. Recently, EDCs have been shown to have equally complex nongenomic mechanisms, altering steroid synthesis or steroid metabolism. As environmental contaminants, these molecules proved disruptively harmful for many wildlife species, particularly those from or depending on the aquatic ecosystem. An increasingly growing body of research has voiced further concerns that human populations are not immune from the dangers of EDCs. Studies from this line of research caution that EDCs can alter hormonal balance and that a whole range of breast and prostate cancers, endometriosis, cryptorchidism, and hypospadias have been linked to exposure to EDCs. This particular area has raised a lot of controversy and the literature on this subject often presents opposing, and sometimes conflicting, perceptions and perspectives. Accordingly, the authors aimed to contribute to the committed academic search for better appreciation of the topic. They first discuss the major natural and synthetic chemicals with endocrine disrupting properties to which humans and wildlife may be exposed. They then describe the key endocrine mechanisms of action and conclude by addressing the main observed effects in human and wildlife populations.

Homocysteine induces caspase activation by endoplasmic reticulum stress in platelets from type 2 diabetics and healthy donors

Diabetes mellitus is a disease characterised by hyperglycaemia and associated with several cardiovascular disorders, including angiopathy and platelet hyperactivity, which are major causes of morbidity and mortality in type 2 diabetes mellitus. In type 2 diabetic patients, homocysteine levels are significantly increased compared with healthy subjects. Hyperhomocysteinaemia is an independent risk factor for macro- and microangiopathy and mortality. The present study is aimed to investigate the effect of homocysteine on platelet apoptosis. Changes in cytosolic or intraluminal free Ca(2+) concentration were determined by fluorimetry. Caspase activity and phosphorylation of the eukaryotic initiation factor 2alpha (eIF2alpha) were explored by Western blot. Our results indicate that homocysteine releases Ca(2+) from agonist sensitive stores, enhances eIF2alpha phosphorylation at Ser(51) and activates caspase-3 and -9 independently of extracellular Ca(2+). Homocysteine induced activation of caspase-3 and -9 was abolished by salubrinal, an agent that prevents endoplasmic reticulum (ER) stress-induced apoptosis. Homocysteine-induced platelet effects were significantly greater in type 2 diabetics than in healthy subjects. These findings demonstrate that homocysteine induces ER stress-mediated apoptosis in human platelets, an event that is enhanced in type 2 diabetic patients, which might be involved in the pathogenesis of cardiovascular complications associated with type 2 diabetes mellitus.

Golimumab and malignancies: true or false association?

Malignancy is one of the comorbidities linked to golimumab, a biological TNF-α blocker. In this systematic review and meta-analysis, we searched different databases and analyzed original publications to elucidate the remaining open question about the real association of malignancies with golimumab therapy. The most frequent cancer in patients treated with golimumab, in association or not with methotrexate, is the lung adenocarcinoma. However, lymphoma is not very commonly represented in these patients. We show that there is no major and evident risk of malignancies associated with golimumab in current scientific literature. An increased risk of malignancies may be associated with golimumab, but this warrants further clinical confirmation. Also, this risk mentioned in different studies must be taken with caution because of number of limits and biases.

Monitoring Endocrine Disrupter Compounds in the Tunisian Hamdoun River using In Vitro Bioassays

Anthropogenic chemicals occurring in the environment, namely endocrine-disrupting chemicals (EDCs), have generated growing concern over their potential adverse effects on human wildlife health and ecosystem processes. This interest resulted particularly from their abilities to mimic the effect of endogenous hormones. In this study, we used stable transfected reporter cell lines to investigate the endocrine-disrupting profile of water as well as sediment samples. Samples are collected from up- and downstream of an industrial wastewater discharge point at the Hamdoun River in the vicinity of an industrial zone located at the center of Tunisia. The analysis of estrogen, androgen, and xenobiotic (pregnane X and dioxin) ligands receptors expressed by chimeric cell lines indicated that while the water and sediment samples from upstream sites have lower levels of estrogenic activity, those from downstream exhibited stronger estrogenic, aryl hydrocarbon receptor (AhR), and Pregnane X Receptor (PXR) activities. Moreover, collected samples have shown hormonal activity in terms of all tested receptors except the androgenic ones. In vitro recombinant estrogen receptor competitive binding assays revealed that while the estrogenic activities of the downstream water sample compounds had a strong affinity for estrogen receptor α (ERα), those present in the sediment samples showed a weaker one. These findings were consolidated by subsequent chemical analysis (high-performance liquid chromatography with UV detectors). Our results indicate that the water and sediment discharges at the Hamdoun River represent a major sink for EDCs from natural and industrial effluents, particularly those of the textile industry, with pernicious potential to disrupt normal endocrine functions.