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bioRxiv2026

PM2.5 toxin benzopyrene induces life-limiting inflammation and oxidative stress in the airway by up-regulation of TRPC6 and inactivation of β2AR/CFTR signaling

Abstract2O_ST_ABSBackgroundC_ST_ABSSustained exposures to high atmospheric levels of PM2.5 at population scale are associated with increased risks for pulmonary inflammatory diseases. These are marked by activation of the TRPC6 (Transient Receptor Potential Canonical type 6) calcium channel, increased reactive oxygen species (ROS) and oxidative stress. Long term exposures are associated with reduced life span, and increased incidences of cardiovascular diseases, dementia, Parkinsons and Alzheimer disease, and increased risk of autism and autism spectrum disorders. It has been proposed that the PM2.5 toxin is benzo[a]pyrene (B[a]P) that is adsorbed to the surface of the PM2.5 particle.. But the mechanism by which B[a]P might drive pulmonary inflammatory diseases, or any other of the indications above, are not known. HypothesisB[a]P was recently reported to bind irreversibly and destructively to the {beta}2 Adrenergic Receptor ({beta}2AR) in the lung. We have therefore hypothesized that B[a]P is the adsorbed PM2.5 toxin, and that {beta}2AR is the B[a]P receptor responsible for TRPC6 activation in lung epithelial cells. ResultsTo test this hypothesis, we exposed a polarized organoid model of normal human lung epithelia, polarized lung epithelial 16HBE14o-cells, and tracheobronchial slice cultures from ferret lung to either PM2.5 or B[a]P. We found that both PM2.5 and B[a]P: (i) irreversibly activated of {beta}2AR signaling via Gi to PI3K/AKT; (ii) increased NF{kappa}B-activated release of proinflammatory cytokines through IKK{beta} activation by PI3K/AKT, which was suppressed by the PI3K inhibitor LY 294002 (iii) desensitized and destroyed the activated {beta}2AR receptor by endocytic recycling; (iv) also destroyed {beta}2ARs signalplex partner CFTR by the same process; (v) activated the CFTR-bound calcium channel protein TRPC6 due to loss of inhibitory CFTR; leading to (vi) increased cytosolic [Ca2+] concentration; (vii) increased ROS due to mitochondrial uncoupling; and (viii) increased expression of oxidative stress. Treatment with the TRPC6 inhibitor BI 749327 blocked steps (vi-viii), and preserved CFTR from endocytic loss. Treatment of tracheobronchial slice cultures of ferret lung with either PM2.5 or B[a]P resulted in increased secretion of IL-6, increased expression of TRPC6, and reduced expression of {beta}2AR and CFTR. Finally, we found that exposure of lung organoids to B[a]P significantly reduced expression of the same five microRNAs (miR-126a-3p, miR-30b-5p, miR-103a-3p, miR-26a-5p, and miR-766-3p) previously identified in sera from service members exposed to PM2.5 from burn pit emissions during deployment to Iraq and Afghanistan. ConclusionPM2.5 and the PM2.5 toxin benzo[a]pyrene (B[a]P) induce inflammation and oxidative stress in the airway by increased expression of TRPC6 and inactivation of {beta}2AR/CFTR signaling. These discoveries mark the first identification of a mechanism by which exposure to PM2.5 or the PM2.5 toxin B[a]P itself can induce inflammation and TRPC6-dependent oxidative stress in lung epithelia.

pharmacology and toxicology↗

bioRxiv2025

Optogenetic disruption of neural dynamics in the prefrontal cortex impaired spatial learning

1.Cortical neural activity is highly dynamical at several temporal scales, property that has been postulated to be critical for the emergence of specific patterns supporting cognitive operations. During spatial learning, task-associated activity patterns gradually develop in the medial prefrontal cortex (mPFC) as the subject acquires experience. If neural activity dynamics is required in the mPFC for spatial learning is still unclear. Here we show that optogenetic entrainment of neural activity the mPFC disrupted local oscillatory and single-neuron dynamics. When applied during spatial training, optogenetic entrainment impaired behavioral performance and navigation strategy progression, a hallmark of spatial learning supported by the mPFC. Also, optogenetic entrainment blocked the emergence of learning-related activity patterns such as cross-frequency coupling and firing patterns signaling efficient goal approaching. Importantly, during memory retrieval, training-stimulated mice showed impaired performance in the absence of optogenetic stimulation. This evidence show that neural activity dynamics in the mPFC is crucial for spatial learning. SignificanceCortical neural activity is highly fluctuating at several temporal scales, which has been postulated to be critical for cognitive functions. The medial prefrontal cortex (mPFC) is involved in the learning-related optimization of behavioral responses; however, it is unknown whether the dynamics of neural activity in the mPFC is required for learning. Here we found that optogenetic disruption of ongoing neural activity dynamics in the mPFC during training in a spatial memory acquisition task impaired spatial learning and hindered the emergence of learning-related activity patterns. These findings provide insight into the role of prefrontal activity dynamics in cognitive functions.

neuroscience↗