Long-Term Environmental Pyrethroid Exposure, Pregnane X Receptor, and Glucose Dyshomeostasis: Unveiling Relationship and Potential Mechanism via Integrated Approaches

Pyrethroids are extensively used in agriculture and environmental sanitation, but the associations of long-term pyrethroid exposure with glucose dyshomeostasis and the underlying mechanisms remain unclear. This repeated-measures prospective study, comprising 6160 observations (4098 participants at baseline and 2062 participants at the six-year follow-up) from the Wuhan-Zhuhai cohort, measured serum pyrethroids and glucose metabolic traits to assess the cross-sectional and longitudinal associations of pyrethroid exposure with glucose dyshomeostasis. Network toxicological analyses and gene-environment interaction analyses were integrated to identify the underlying targets and mechanisms. Cross-sectionally, multiple pyrethroids, particularly bifenthrin and fenvalerate, were positively associated with fasting plasma glucose (FPG), insulin resistance, and β-cell dysfunction. Longitudinally, serum bifenthrin and fenvalerate were associated with the annual change rate of glucose metabolic traits and an increased incident risk of type 2 diabetes. Additionally, pregnane X receptor (PXR) was predicted as a key molecular target for pyrethroid exposure-related glucose dyshomeostasis. PXR variants significantly interacted with bifenthrin exposure, with individuals carrying a high-risk PXR genotype and high bifenthrin exposure exhibiting higher FPG or lower β-cell function. This study demonstrates that long-term pyrethroid exposure is associated with glucose dyshomeostasis in the general population, with PXR activation regulating the nuclear receptor transduction pathway, potentially involved in the underlying mechanisms.