Lam, E. K. | Search bioRxiv

bioRxiv2026

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

This study investigated the transcriptional and bioenergetic responses to monoethylhexyl phthalate (MEHP) in primary fibroblasts derived from northern elephant seals (Mirounga angustirostris), common dolphins (Delphinus delphis), and humans, using RNA-seq, extracellular flux assays, and high-resolution microscopy of the mitochondrial reticulum. MEHP exposure did not induce cytotoxicity but triggered species-specific changes in gene expression and mitochondrial metabolism and morphology. Human cells showed the greatest transcriptional response, upregulating genes involved in detoxification, antioxidant, and inflammation while downregulating lipid metabolism pathways. The highest dose also decreased mitochondrial respiration and increased mitochondrial fragmentation, triggering a metabolic shift toward glycolysis. Elephant seal cells showed delayed glycolytic shifts, maintaining mitochondrial respiration and upregulating antioxidant, immune, and metabolic pathway genes through the highest dose. Despite mitochondrial fragmentation, they upregulated mitochondrial fusion/fission and trafficking genes. Dolphin cells exhibited the fewest changes in gene expression, mostly in hormone signaling and mitotic pathways. They showed dose-dependent declines in both respiration and glycolytic rates, even at the lowest concentration, yet maintained mitochondrial structural integrity while upregulating stress- and hypoxia-induced genes. These distinct strategies highlight species-specific susceptibility to toxicant-induced stress, offering new insights into how marine mammals respond to plastic-derived contaminants and reinforcing the need for species-specific ecotoxicological risk assessments.

physiology↗

bioRxiv2021

Repeated stimulation of the HPA axis alters white blood cell counts without increasing oxidative stress or inflammatory cytokines in fasting elephant seal pups

The hypothalamic-pituitary-adrenal (HPA) axis controls the release of glucocorticoids, which regulate immune and inflammatory function by modulating cytokines, white blood cells (WBCs), and oxidative stress via glucocorticoid receptor (GR) signaling. Although the response to HPA activation is well characterized in many species, little is known about the impacts of HPA activation during extreme physiological conditions in marine mammals. Hence, we challenged 18 simultaneously fasting and developing elephant seal pups with daily intramuscular injections of adrenocorticotropin (ACTH), a GR antagonist (RU486), or a combination (ACTH+RU486) for four days (4d). We collected blood at baseline, two hours (2h), and 4d after the beginning of treatment. ACTH and ACTH+RU486 elevated serum aldosterone and cortisol at 2h, with effects diminishing at 4d. RU486 alone induced a compensatory increase in aldosterone, but not cortisol, at 4d. ACTH decreased neutrophils at 2h while decreasing lymphocytes and increasing neutrophil:lymphocyte ratio at 4d. These effects were abolished by RU486. Despite alterations in WBCs, there was no effect of ACTH or RU486 on transforming growth factor-{beta} or interleukin-6 levels; however, both cytokines decreased with the 4-d fasting progression. Similarly, ACTH did not impact protein oxidation, lipid peroxidation, or antioxidant enzymes, but plasma isoprostanes and catalase activity decreased while glutathione peroxidase increased with fasting progression. These data demonstrate differential acute (2h) and chronic (4d) modulatory effects of HPA activation on WBCs and that the chronic effect is mediated, at least in part, by GR. These results also underscore elephant seals resistance to potential oxidative stress derived from repeated HPA activation. Summary statementMany species experience oxidative stress and inflammation after repeated activation of the hypothalamic-pituitary-adrenal axis. We show that simultaneously fasting and developing elephant seals are resistant to repeated hypothalamic-pituitary-adrenal axis activation.

physiology↗