From Hatch to Lineage: Multifaceted Toxicity of Flame Retardants and Benzo[a]pyrene in Oryzias sp.
Early-life chemical exposures can leave imprints that reverberate across the lifespan and even across generations. Using medaka species (Oryzias sp.) as a vertebrate model, weassessed two ubiquitous contaminant classes—benzo[a]pyrene (BaP) and per- and polyfluoroalkyl substances (PFAS)—to pinpoint molecular mechanisms and developmental windows of maximal vulnerability. Bulk ATAC-seq of oocytes from BaP-exposed females uncovered 24 251 loci with altered accessibility, skewing toward heterochromatinization of genes associated with the bone and neuronal development. BaP therefore appears to stabilize repressive chromatin states that could propagate transgenerational impacts of bone tissue und behavior. Developmental PFAS exposures revealed embryonic and late-larval stages of immune system development most susceptible: PFHxA and GenX respectively reduced pathogen resistance by 10 % and up to 93 %, coinciding with transcriptomic repression of T-cell differentiation genes and metabolomic signatures of mitochondrial dysfunction and disrupted glycosphingolipid metabolism. Persistent adult phenotypes—including sex-specific leukocyte depletion and long-term remodeling of fatty-acid, amino-acid, and oxidative-stress pathways—mirrored early-life metabolic fingerprints, underscoring the predictive value of acute biomarkers. Collectively, these findings show that these toxicants program lasting health outcomes. BaP reinforces repressed chromatin in germ cells, offering a mechanistic bridge to BaP-mediated transgenerational phenotypes, whereas PFAS hijack developmental checkpoints of thymic maturation to impose lifelong, sex-biased immunometabolic deficits. Integrating epigenomic profiling, and multi-omics across defined windows thus provides a blueprint for assessing chemical risk over a lifetime and across generations.