Developmental exposure to environmentally relevant bisphenol A bis(diphenyl phosphate) impairs host defense and disrupts epidermal immune and barrier responses in Caenorhabditis elegans

Bisphenol A bis(diphenyl phosphate) (BDP), an emerging oligomeric organophosphate ester, has been increasingly detected in the environment. However, its effects on host defense at environmentally relevant concentrations remain unclear. Using Caenorhabditis elegans, we examined whether developmental exposure to 2, 20, or 200 ng/L BDP impaired resistance to the pathogenic bacterium Pseudomonas aeruginosa PA14 and affected related immune processes. Among the three exposure windows, continuous L1-to-adult exposure produced the broadest response profile. BDP did not markedly affect lifespan or growth but significantly shortened survival during PA14 infection at 2 and 200 ng/L. RNA-seq and qRT-PCR revealed alterations in antimicrobial gene expression involving epidermal nlp/cnc effectors, intestinal lys/spp-type genes, and the p38 MAPK and DAF-2/FOXO pathways. These changes coincided with increased intestinal permeability, disrupted antioxidant status, and mild apoptosis-associated responses. Mutant assays and genotype × exposure interaction analysis showed that the PA14-sensitive phenotype at 2 ng/L differed between wild-type and tir-1 mutant worms, whereas pmk-1, skn-1, and dbl-1 mutants retained similar susceptibility patterns. TJ356 assays further showed increased cytosolic retention of DAF-16, suggesting insufficient nuclear activation during BDP-induced PA14 susceptibility. Overall, these findings indicate that environmentally relevant BDP exposure can disrupt host immune homeostasis and weaken resistance to pathogen challenge, suggesting that such susceptibility may represent an underrecognized toxicological consequence of emerging organophosphate esters with broader ecological and health implications.