Microalgal resilience under Bisphenol A exposure: Dynamic metabolic reprogramming, deoxynucleotide pool imbalance and DNA damage management

Bisphenol A (BPA), an endocrine-disrupting chemical prevalent in aquatic environments due to wastewater discharge and plastic leaching, exerts chronic stress on primary producers. Although its toxicity to microalgae has been documented, a time-resolved, mechanistic understanding of their acclimation and recovery from acute BPA stress—particularly the interplay among cell-cycle control, nucleotide metabolism, and genome integrity—remains limited. In this study, we employed an integrated flow cytometry and multi-omics approach to elucidate the temporal response of the marine microalga Tetraselmis chuii to acute BPA exposure at its half-inhibition concentration. A biphasic response pattern was observed, consisting of an initial phase of acute toxicity (Days 0–2) marked by growth inhibition, DNA replication arrest, oxidative stress, and physiological disturbances, followed by a stepwise recovery phase (Days 2–10), during which all measured physiological parameters were normalized. Multi-omics profiling conducted at Days 1, 5, and 10 revealed a dynamic acclimation strategy. At Day 1, cells upregulated components of the mitochondrial electron transport chain and activated the SOD-GPX-GSR antioxidant system, supported by a reconfigured tricarboxylic acid (TCA) cycle via the IDH-NADPH-GSH axis to meet energy demands and mitigate oxidative stress. This transitioned into an energy-conserving state through reduced respiratory activity during Days 5–10. Concurrently, nucleotide metabolism was remodeled, shifting from de novo pyrimidine synthesis toward salvage pathways while maintaining de novo purine biosynthesis. A sustained imbalance in the deoxyribonucleotide triphosphate (dNTP) pool, specifically an elevated dATP/dTTP ratio, was associated with S-phase arrest, a potential strategy to prevent mutagenic DNA replication under stress. A phased DNA damage response (DDR) was concurrently activated, involving early upregulation of the damage sensor DDB1 and downregulation of the replication initiator MCM6 , followed by induction of repair factors ( RPA1 , PRI2 , LIG1 ), and late-stage expression of the error-prone DNA polymerase POLD1 . These findings unveil a multilayered resilience strategy in which T. chuii prioritizes survival over proliferation by dynamically balancing energy allocation, redox homeostasis, and genomic integrity, thereby providing a mechanistic framework for microalgal persistence under chronic pollutant stress.