Phthalate exposure induces inflammatory signaling and alters mitochondrial respiration in marine mammal and human cells

ABSTRACT Phthalate plasticizers are contaminants of emerging concern that interfere with the synthesis, secretion, and transport of hormones and receptors, altering the immune response and energy balance. Phthalate metabolites have been detected in marine mammals globally, and while studies on phthalate toxicity in marine mammals are beginning to emerge, a comprehensive understanding of the cellular response to these compounds remains elusive. Here, we investigated the transcriptional and bioenergetic responses to mono-ethylhexyl phthalate (MEHP), the active metabolite of di(2-ethylhexyl) phthalate (DEHP), in primary dermal derived from northern elephant seals ( Mirounga angustirostris ), common dolphins ( Delphinus delphis ), and humans. MEHP exposure did not induce cytotoxicity in any species, but triggered distinct, species-specific changes in gene expression and mitochondrial metabolism. Human cells showed the greatest transcriptional response to MEHP, upregulating detoxification, antioxidant, and inflammatory genes, and downregulating lipid metabolism pathways. Although mitochondrial respiration declined only at the highest dose, sustained extracellular acidification rates and increased glycolytic gene expression indicate a metabolic shift toward glycolysis. In contrast, elephant seal cells upregulated antioxidant and immune genes while maintaining mitochondrial respiration until the highest MEHP dose, alongside increased expression of genes involved in oxidative phosphorylation, the TCA cycle, and mitochondrial dynamics, suggesting a delayed shift to glycolysis and a potential evolutionary adaptation to sustain mitochondrial function during energy-demanding conditions such as breath-hold diving. Dolphin cells exhibited fewer transcriptional changes, which were enriched for hormone signaling and mitotic pathways, and showed dose-dependent declines in both oxygen consumption and extracellular acidification rates, even at the lowest MEHP concentration, alongside upregulation of stress and hypoxia-related genes. Together, these findings highlight distinct cellular strategies for coping with phthalate exposure and likely species-specific susceptibility to toxicant-induced stress. This study provides new insights into how marine mammals respond to plastic-derived contaminants at the cellular level, reinforcing the need for species-specific ecotoxicological risk assessments.