6PPDQ Exposure Induces Mammary Developmental Damage through Mitochondrial Dysfunction Mediated by the p38 MAPK Signaling Pathway

Abstract

N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPDQ), the primary oxidative metabolite of rubber antioxidant N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD), is an emerging global contaminant with multiorgan toxicity and has been detected in human breast milk and urine. Its mammary toxicity and molecular mechanisms remain poorly defined. Here, we integrated network toxicology, transcriptomics, and in vivo/in vitro validation to investigate 6PPDQ triggered mammary toxicity during adolescent exposure in mice. Network toxicology screened core targets and identified the MAPK signaling pathway as a key regulatory axis. Adolescent 6PPDQ exposure decreased mammary gland weight and length, induced pathological lesions, inhibited epithelial proliferation, and disrupted apoptotic homeostasis. Further assays confirmed that 6PPDQ caused mitochondrial dysfunction, oxidative stress, and inflammation. Mechanistically, 6PPDQ mediated mammary injury through p38 MAPK cascade activation, and p38 inhibition alleviated such adverse effects. This study elucidates a distinct p38 MAPK-dependent mechanism driving 6PPDQ-related developmental mammary toxicity, advancing the mechanistic understanding of health risks posed by rubber-derived quinone contaminants.