TIP RNA

Evidence indicates that the default mode network (DMN) plays a crucial role in the neuropathology of major depressive disorder (MDD). However, the neural signatures of DMN subsystems in MDD after low resistance Thought Induction Psychotherapy (TIP) remain incompletely understood. We collected functional magnetic resonance imaging data from 20 first-episode, drug-naive MDD and 20 healthy controls (HCs). The DMN was segmented into three subsystems and seed-based functional connectivity (FC) was computed. After 6-week treatment, the significantly reduced FCs with the medial temporal lobe memory subsystem in MDD at baseline were enhanced and were comparable to that in HCs. Changed Hamilton Depression Rating Scale scores were significantly related with changed FC between the posterior cingulate cortex (PCC) and the right precuneus (PCUN). Further, changed serotonin 5-hydroxytryptamine levels were significantly correlated with changed FCs between the PCC and the left PCUN, between the posterior inferior parietal lobule and the left inferior temporal gyrus, and between the retrosplenial cortex and the right inferior frontal gyrus, opercular part. Finally, the support vector machine obtained an accuracy of 67.5% to distinguish between MDD at baseline and HCs. These findings may deepen our understanding of the neural basis of the effects of TIP on DMN subsystems in MDD.

2,4,6-Trichlorophenol (TCP), 2,4,6-tribromophenol (TBP) and 2,4,6-triiodophenol (TIP) are three widely detected trihalophenolic disinfection by-products (DBPs). Previous studies have mainly focused on the carcinogenic risk and developmental toxicity of 2,4,6-trihalophenols. Very little is known about their immunotoxicity in mammals.

We investigated the effects of 2,4,6-trihalophenols on mammalian immunity using a mouse macrophage model infected with bacteria or intracellular parasites and aimed to elucidate the underlying mechanisms from an epitranscriptomic perspective. The identified mechanisms were further validated in human peripheral blood mononuclear cells (PBMCs).

The mouse macrophage cell line RAW264.7 and primary mouse peritoneal macrophages were exposed to different concentrations of TCP, TBP, and TIP. The pro-inflammatory marker Ly6C, the survival of the bacterium Escherichia coli (E. coli), and the parasite burden of Toxoplasma gondii (T. gondii) were assessed. Furthermore, the global gene expression profiling of macrophages following exposure to 2,4,6-trihalophenols was obtained through RNA-sequencing (RNA-seq). The effects of 2,4,6-trihalophenols on RNA __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__N6-methyladenosine (__-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__m6A) methyltransferases and total RNA __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__m6A levels were evaluated using Western blotting and dot blot, respectively. Transcriptome-wide __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__m6A methylome was analyzed by __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__m6A-seq. In addition, expression of __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__m6A regulators and total RNA __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__m6A levels in human PBMCs exposed to 2,4,6-trihalophenols were detected using quantitative reverse transcriptase polymerase chain reaction and dot blot, respectively.

Mouse macrophages exposed to TCP, TBP, or TIP had lower expression of the pro-inflammatory marker Ly6C, with a greater difference from control observed for TIP-exposed cells. Consistently, macrophages exposed to such DBPs, especially TIP, were susceptible to infection with the bacterium E. coli and the intracellular parasite T. gondii, indicating a compromised ability of macrophages to defend against pathogens. Intriguingly, macrophages exposed to TIP had significantly greater __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__m6A levels, which correlated with the greater expression levels of __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__m6A methyltransferases. Macrophages exposed to each of the three 2,4,6-trihalophenols exhibited transcriptome-wide redistribution of __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__m6A. In particular, the __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__m6A peaks in genes associated with immune-related pathways were altered after exposure. In addition, differences in __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__m6A were also observed in human PBMCs after exposure to 2,4,6-trihalophenols.

These findings suggest that 2,4,6-trihalophenol exposure impaired the ability of macrophages to defend against pathogens. This response might be associated with notable differences in __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__m6A after exposure. To the best of our knowledge, this study presents the first __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__m6A landscape across the transcriptome of immune cells exposed to pollutants. However, significant challenges remain in elucidating the mechanisms by which __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__m6A mediates immune dysregulation in infected macrophages after 2,4,6-trihalophenol exposure. https://doi.org/10.1289/EHP11329.