NF-κB/NLRP3 inflammasome is associated with formaldehyde-induced reproductive and metabolic dysfunction: protective...

Environmental pollutants, including common industrial chemicals, have been associated with global declines in male reproductive health. However, the relationships with formaldehyde (F) exposure, metabolic imbalance, and testicular impairment are still unknown. This study hypothesized that subchronic formaldehyde exposure triggers the NF-κB/NLRP3 inflammasome cascade to promote both metabolic and reproductive damage and that such effects can be attenuated by the flavonoid quercettin.

In a male rat model (n = 8) of subchronic F (3% formaldehyde/day intraperitoneally at a dose of 15 mg/kg body weight for 21 days) treatment, with or without quercetin (dissolved in 5% DMSO in distilled water at doses of 25, 50, and 100 mg/kg body weight, orally), were given for 21 days along with a normal control group. After the treatment period, metabolic profiling, sperm analysis, hormonal assays, histology, and molecular investigations were determined. Data were analyzed by GraphPad Prism software (version 10.0). Normality was checked with the Shapiro-Wilk test, and one‑way ANOVA was used to compare groups, followed by Tukey's post hoc test. Statistical significance was set at p ≤ 0.05. F treatment induced significant systemic metabolic dysfunction (increased FBG and HbA1c; decreased insulin), testicular damage (decreased sperm count, viability, motility, as well as testosterone, LH, and FSH concentrations), oxidative stress (increased pro-oxidants and intracellular reactive oxygen species; decreased endogenous antioxidants), fibrosis followed by apoptosis. Mechanistically, F triggers DAMP-associated sterile inflammation via TNF-α and TLR4 to promote NF-κB and NLRP3 inflammasome activation, while repressing steroidogenic gene expression. Most F-induced alterations were dose-associated and ameliorated by quercetin co-treatment, with the highest dose (100 mg/kg) showing the most significant efficacy. The molecular docking results suggest that the binding affinities of quercetin to TNF, TLR4, NF-κB and NLRP3 may be higher than those of F.

This study provides initial evidence that formaldehyde triggers DAMP-associated sterile inflammation with disruption of metabolism and reproduction, and it also demonstrates the potential benefit of quercetin treatment as a nutraceutical against environmental aldehydes by suppressing multitarget pathways.