Mechanistic insights into bisphenol A–induced systemic toxicodynamics: haematopoietic injury and hepatic ERα–AP-1-associated mitochondrial and metabolic reprogramming in freshwater perch

• BPA triggers erythrocytic, haematological changes and multiorgan toxicity in perch • BPA-induced ERα upregulation and AP-1 activation abrogate hepatic IGF1 signaling • BPA inhibition of PDK1 prompted TCA cycle and mitochondrial OXPHOS components • BPA inhibits p-AMPKα, PPARα, CPT1 but promotes FASN and HMGCR expression • A high serum lipid profile, hepatotoxicity, and fatty liver depict metabolic disruption Given the exceptionally high environmental prevalence of bisphenol A (BPA) in rapidly industrializing regions and its sustained production growth in Southern Asia, this study provides mechanistic insights into how chronic, environmentally relevant BPA exposure (1, 10, and 100 µg/L) disrupts haematopoietic integrity and hepatic endocrine-metabolic homeostasis in climbing perch ( Anabas testudineus ). While it could promote robust changes in erythrocytic cytoplasmic, nuclear abnormalities, and haematological parameters, BPA-induced renal and splenic lesions reveal haematopoietic stress. Hepatic assessments revealed an estrogen receptor (ERα/ERβ) imbalance in BPA-treated groups, consistent with heightened TLR4/MAPK (p38, JNK)-mediated AP-1 activation, increased inflammatory markers (TNF-α, IL-1β, PTGS2), and nitrite load. Crucially, BPA-mediated metabolic disruption involved impaired growth hormone receptor (GHR) expression and attenuated JAK2/STAT5 signalling, driving a sharp decline in hepatic IGF1 expression, which in turn led to inhibition of AKT/ERK1/2 signalling, GSK-3β activation, and subsequent reduction in HIF-1α and HSP90 levels. Although chronic exposure modulated TCA and OXPHOS components, reduced TFAM expression suggested compromised mitochondrial biogenesis. Concurrent NOX4 upregulation, ROS accumulation, and diminished antioxidant defence indices triggered lipid peroxidation and protein carbonyls, exacerbating the oxidative stress response. Furthermore, BPA inhibited the p-AMPKα/SIRT1 and PPARα/CPT1α pathways while upregulating lipogenic markers (FASN, HMGCR), thereby driving fatty liver disease (macrovesicular steatosis). Integration of Pearson's correlation and protein–protein interaction analyses confirmed interconnected hubs spanning ER modulation, inflammation, the HIF-1α axis, oxidative stress, energy sensors, and lipid metabolism. Collectively, these findings reveal the systemic toxicity of low-dose BPA, establishing A. testudineus as a critical sentinel for aquatic ecotoxicology and informing South Asian environmental regulatory frameworks.