Environmentally relevant concentrations of 2,3,7,8-TCDD induced inhibition of multicellular alternative splicing and transcriptional dysregulation.

Alternative splicing (AS), found in approximately 95 % of human genes, significantly amplifies protein diversity and is implicated in disease pathogenesis when dysregulated. However, the precise involvement of AS in the toxic mechanisms induced by TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) remains incompletely elucidated. This study conducted a thorough global AS analysis in six human cell lines following TCDD exposure. Our findings revealed that environmentally relevant concentration (0.1 nM) of TCDD significantly suppressed AS events in all cell types, notably inhibiting diverse splicing events and reducing transcript diversity, potentially attributed to modifications in the splicing patterns of the inhibitory factor family, particularly hnRNP. And we identified 151 genes with substantial AS alterations shared among these cell types, particularly enriched in immune and metabolic pathways. Moreover, TCDD induced cell-specific changes in splicing patterns and transcript levels, with increased sensitivity notably in THP-1 monocyte, potentially linked to aberrant expression of pivotal genes within the spliceosome pathway (DDX5, EFTUD2, PUF60, RBM25, SRSF1, and CRNKL1). This study extends our understanding of disrupted alternative splicing and its relation to the multisystem toxicity of TCDD. It sheds light on how environmental toxins affect post-transcriptional regulatory processes, offering a fresh perspective for toxicology and disease etiology investigations.

Chlorinated Polycyclic Aromatic Hydrocarbons Induce Immunosuppression in THP-1 Macrophages Characterized by Disrupted Amino Acid Metabolism.

Frequent chlorinated polycyclic aromatic hydrocarbon (Cl-PAH) occurrence in environmental samples and emerging detection in human serum have warned of their underestimated risks. Studies showed that some Cl-PAHs exhibit dioxin-like properties, implying immunotoxic potential but lacking direct evidence and specific mechanisms. Here, we integrated a high-content screening (HCS) system and high-resolution mass spectrometry to investigate the immune dysfunction and metabolic disruption induced by Cl-PAHs and their parent PAHs (PPAHs) in THP-1 macrophages. Both 9-chloroanthracene and 2,7-dichlorofluorene exerted clear immunosuppression on THP-1 mφs, while their PPAHs exhibited different immune disturbances. Interestingly, Cl-PAH/PPAHs induced complex alterations in the multicytokine/chemokine network, including biphasic alterations with initial inhibition and later enhancement. Furthermore, the protein-protein interaction results revealed that inflammatory cytokines are the core of this complicated network regulation. Connecting immune phenotypes and metabolomics, amino acid metabolism reprogramming was identified as a potential cause of Cl-PAH/PAH-induced immunotoxicity. Phytosphingosine and l-kynurenine were proposed as candidate immunosuppression biomarkers upon Cl-PAH exposure. This article provides direct immunotoxicity evidence of Cl-PAHs without activating AhR for the first time and discusses the contribution of metabolites to Cl-PAH/PPAH-induced immune responses in macrophages, highlighting the potential of developing new methods based on immunometabolism mechanisms for toxic risk evaluation of environmental chemicals.

Ethyl 2-[4-(1,3-benzothiazol-2-yl)-anilino]acetate.

In the title compound, C(17)H(16)N(2)O(2)S, the dihedral angle between the benzothia-zole ring system and the benzene ring is 1.20 (2)°. The substituted amino substituent is in an extended conformation with an N-C-C-O torsion angle of 179.4 (3)°. In the crystal structure, pairs of mol-ecules are connected by inter-molecular N-H⋯O and weak C-H⋯O hydrogen bonds, forming centrosymmetric dimers.

2-{[4-(1,3-Benzothia-zol-2-yl)phen-yl](meth-yl)amino}acetic acid.

In the title compound, C(16)H(14)N(2)O(2)S, the dihedral angle between the benzothia-zole ring system and benzene ring is 3.11 (2)°. In the crystal structure, inter-molecular O-H⋯N hydrogen bonds link mol-ecules into chains along [100] and these chains are, in turn, linked into a three-dimensional network via weak inter-molecular C-H⋯O hydrogen bonds.

Bis(benzothia-zol-2-ylmeth-yl)amine.

In the title compound, C(16)H(13)N(3)S(2), the dihedral angle between the two benzothia-zole ring systems is 20.41 (2)°. In the crystal structure, inter-molecular N-H⋯N hydrogen bonds link mol-ecules into a chain along the b axis. The packing is further stabilized by C-H⋯π stacking inter-actions involving the two benzothia-zole ring systems.

N-(2-Amino-ethyl)-5-(dimethyl-amino)naphthalene-1-sulfonamide.

In the title compound, C(14)H(19)N(3)O(2)S, the N atom of the dimethyl-amino group and the S atom are displaced by 0.078 (2) and 0.084 (2) Å, respectively, from the naphthalene ring plane. The 2-amino-ethyl group has a coiled conformation with an N-C-C-NH(2) torsion angle of 53.6 (4)°. In the crystal structure, inter-molecular N-H⋯N and weak C-H⋯O hydrogen bonds link mol-ecules into chains along [001].