Evaluation of Placental Toxicity of Five Essential Oils and Their Potential Endocrine-Disrupting Effects.

Pregnant women may use EOs in case of morning sickness, nausea, stress management, etc. Little is known about the potential danger that EOs represent for the placenta and therefore for the pregnancy. Our aim was to explore and compare the placental toxicity and potential endocrine disrupting effects of niaouli, orange, tea tree, wintergreen and ylang-ylang EOs, and their key compounds: 4-terpineol, 1,8-cineol, limonene, methyl salicylate and benzyl salicylate. We studied the release of four hormones and the activation of P2X7 receptor in JEG-Tox human placental cells as key biomarkers for endocrine toxicity. We observed that niaouli, orange, tea tree, wintergreen and ylang-ylang EOs and their key components disrupted at least one of the studied hormones but none of them activated the P2X7 cell death receptor. The tested EOs appear then to be more hormonal modulators rather than EDCs in human placental cells. The hormonal effects observed with the key components were very different from those observed with the EOs. EOs are very complex mixtures, and it is essential to study whole EOs rather than their components individually in safety assessment.

Advancing Endocrine Disruptors via In Vitro Evaluation: Recognizing the Significance of the Organization for Economic Co-Operation and Development and United States Environmental Protection Agency Guidelines, Embracing New Assessment Methods, and the Urgent Need for a Comprehensive Battery of Tests.

Efforts are being made globally to improve the evaluation and understanding of endocrine-disrupting chemicals. Recognition of their impact on human health and the environment has stimulated attention and research in this field. Various stakeholders, including scientists, regulatory agencies, policymakers, and industry representatives, are collaborating to develop robust methodologies and guidelines for assessing these disruptors. A key aspect of these efforts is the development of standardized testing protocols and guidelines that aim to provide consistent and reliable methods for identifying and characterizing endocrine disruptors. When evaluating the potential endocrine-disrupting activity of chemicals, no single test is capable of detecting all relevant endocrine-disrupting agents. The test battery approach is designed to reduce the risk of false negative results for compounds with toxic potential. A weight-of-evidence approach is therefore necessary for endocrine disruptor evaluation. This approach considers various types of data from multiple sources, assessing the overall strength, consistency, and reliability of the evidence. OECD guidelines are highly regarded for their scientific rigor, transparency, and consensus-based development process. It is crucial to explore and develop new methodologies that can effectively evaluate the risks associated with potential endocrine disruptors. Integrating these methods into a comprehensive weight-of-evidence framework will enhance risk assessments and facilitate informed decisions regarding the regulation and management of these substances, ensuring the protection of human health and the environment from their adverse effects.

Forskolin Induces Endocrine Disturbance in Human JEG-3 Placental Cells.

Forskolin, used in folk medicine since ancient times, is now available as a dietary supplement, with an indication as a fat burner and appetite suppressant. However, the safety of forskolin is poorly documented especially for pregnant women. The question that we raised is what about the safety of forskolin in pregnant women? As the placenta, an endocrine organ, is the key organ of pregnancy, we evaluated the in vitro placental toxicity of forskolin. We focused first on the activation of a P2X7 degenerative receptor as a key biomarker for placental toxicity, and second on steroid and peptide hormonal secretion. We observed that forskolin activated P2X7 receptors and disturbed estradiol, progesterone, hPL and hyperglycosylated hCG secretion in human placental JEG-Tox cells. To the best of our knowledge, we highlighted, for the first time, that forskolin induced endocrine disturbance in placental cells. Forskolin does not appear to be a safe product for pregnant women and restrictions should be taken.

Pregnant Women and Endocrine Disruptors: Role of P2X7 Receptor and Mitochondrial Alterations in Placental Cell Disorders.

In pregnant women, the lungs, skin and placenta are exposed daily to endocrine-disrupting chemicals (EDCs). EDCs induce multiple adverse effects, not only on endocrine organs, but also on non-endocrine organs, with the P2X7 cell death receptor being potentially the common key element. Our objective was first to investigate mechanisms of EDCs toxicity in both endocrine and non-endocrine cells through P2X7 receptor activation, and second, to compare the level of activation in lung, skin and placental cells. In addition, apoptosis in placental cells was studied because the placenta is the most exposed organ to EDCs and has essential endocrine functions. A total of nine EDCs were evaluated on three human cell models. We observed that the P2X7 receptor was not activated by EDCs in lung non-endocrine cells but was activated in skin and placenta cells, with the highest activation in placenta cells. P2X7 receptor activation and apoptosis are pathways shared by all tested EDCs in endocrine placental cells. P2X7 receptor activation along with apoptosis induction could be key elements in understanding endocrine placental and skin disorders induced by EDCs.

Cocktail Effect of Endocrine Disrupting Chemicals: Application to Chlorpyrifos in Lavender Essential Oils.

Chlorpyrifos is a pesticide that is toxic to human health and has been banned for the past decade. Due to its persistent and bioaccumulative properties, chlorpyrifos is still present in soil. Pregnant women can be exposed to chlorpyrifos through drinking water and herbal products, such as essential oils (EOs), resulting in adverse effects to the mother and fetus. Our objective was to evaluate and compare the potential endocrine disrupting effects of chlorpyrifos "free" or in contaminated lavender EO. We studied the release of four hormones and the activation of the P2X7 cell death receptor in human placental JEG-Tox cells as key biomarkers of endocrine toxicity for pregnant women (hPlacentox assay). We observed that "free" chlorpyrifos disrupted placental hormones and activated the P2X7 receptor, whereas chlorpyrifos in lavender EO disrupted only the placental hormones. We confirm that chlorpyrifos can be classified as an endocrine disrupting chemical (EDC) for pregnant women and point out that its endocrine disrupting effect may not be apparent when present in lavender EOs. Our results reveal the existence of specific reverse cocktail effects that may have protective properties against EDCs.

Solvent/base effects in the selective domino synthesis of phenanthridinones that involves high-valent palladium species: experimental and theoretical studies.

The domino reaction of o-bromobenzamides 1a-m in the presence of K(2)CO(3) and the [PdCl(2)(PPh(3))(2)] catalyst granted a selective access to phenanthridinones 2 or to the new 1-carboxamide phenanthridinones 3 depending on the solvent, DMF or 1,4-dioxane, respectively. Investigations of the reaction parameters provided the first example of a direct correlation between the base dissociation and the solvent polarity on the selectivity observed. Moreover, mechanistic studies (NMR spectroscopy and ESI-MS monitoring) allowed us to characterize Pd(II) palladacycle 4 and biaryl species as common intermediates for these two domino processes. On that basis, C(sp(2))-C(sp(2)) bond formation is envisaged by generation of a Pd(IV) complex after oxidative addition of 1 into Pd(II) palladacycle 4, a rationale that is supported by DFT calculations. A general catalytic cycle is proposed to account for these observations.

Bisphenol A, Bisphenol F, and Bisphenol S: The Bad and the Ugly. Where Is the Good?

BACKGROUND: Bisphenol A (BPA), a reprotoxic and endocrine-disrupting chemical, has been substituted by alternative bisphenols such as bisphenol F (BPF) and bisphenol S (BPS) in the plastic industry. Despite their detection in placenta and amniotic fluids, the effects of bisphenols on human placental cells have not been characterized. Our objective was to explore in vitro and to compare the toxicity of BPA to its substitutes BPF and BPS to highlight their potential risks for placenta and then pregnancy. METHODS: Human placenta cells (JEG-Tox cells) were incubated with BPA, BPF, and BPS for 72 h. Cell viability, cell death, and degenerative P2X7 receptor and caspases activation, and chromatin condensation were assessed using microplate cytometry and fluorescence microscopy. RESULTS: Incubation with BPA, BPF, or BPS was associated with P2X7 receptor activation and chromatin condensation. BPA and BPF induced more caspase-1, caspase-9, and caspase-3 activation than BPS. Only BPF enhanced caspase-8 activity. CONCLUSIONS: BPA, BPF, and BPS are all toxic to human placental cells, with the P2X7 receptor being a common key element. BPA substitution by BPF and BPS does not appear to be a safe alternative for human health, particularly for pregnant women and their fetuses.

A Chemically Stable Fluorescent Mimic of Dihydroartemisinin, Artemether, and Arteether with Conserved Bioactivity and Specificity Shows High Pharmacological Relevance to the Antimalarial Drugs.

Three novel tracers designed as fluorescent surrogates of artemisinin-derived antimalarial drugs (i.e., dihydroartemisinin, artemether, arteether, and artemisone) were synthesized from dihydroartemisinin. One of these tracers, corresponding to a dihydroartemisinin/artemether/arteether mimic, showed a combination of excellent physicochemical and biological properties such as hydrolytic stability, high inhibitory potency against blood-stage parasites, similar ring-stage survival assay values than the clinical antimalarials, high cytopermeability and specific labeling of live P. falciparum cells, alkylation of heme, as well as specific covalent labeling of drug-sensitive and drug-resistant P. falciparum proteomes at physiological concentrations, consistent with a multitarget action of the drugs. Our study demonstrates that probes containing the complete structural core of clinical artemisinin derivatives can be stable in biochemical and cellular settings, and recapitulate the complex mechanisms of these frontline, yet threatened, antimalarial drugs.

Total chemical synthesis of the D2 domain of human VEGF receptor 1.

The interaction of the vascular endothelial growth factor (VEGF) with its cellular receptors exerts a central role in the regulation of angiogenesis. Among these receptors, the VEGF receptor 1 may be implicated in pathological angiogenesis. Here, we report the first total chemical synthesis of the VEGF-binding domain of the VEGF receptor 1. Aggregation issues were overcome by the use of a low-substituted resin and the stepwise introduction of pseudoproline dipeptides and Dmb-glycines. The folding of the protein was achieved by air oxidation and its biological activity was verified on ELISA-based assays.