Gestational and Lactational Exposure to Perfluorohexanoic Acid Compromises Skeletal Muscle Regeneration in Adult Male Mice: A Preliminary Study
July 6
Legacy per- and polyfluoroalkyl substances (PFAS) have been associated with male-biased defects in tissue repair and organogenesis. Industries have largely substituted them with next-generation PFAS, including perfluorohexanoic acid (PFHxA). Zebrafish work suggests developmental PFHxA exposure disrupts myofiber patterning; however, the developmental toxicology of PFHxA on mammalian regenerative processes remains uncharacterized. Epidemiological surveys warrant such studies because PFHxA is detectable in maternal serum and breast milk. Post-mortem analyses further reveal that PFHxA partitions into skeletal muscle, with the quadriceps exhibiting particularly elevated concentrations. Given this tissue selectivity, we hypothesized that developmental PFHxA exposure would impair post-natal myogenesis and adult regenerative capacity.
Pregnant C57BL/6J dams were gavaged daily from embryonic day 0 through postnatal day (P)21 with vehicle (ddH₂O), a low (0.32 mg kg⁻¹ body weight) or a high (50 mg kg⁻¹) dose of PFHxA. This regimen increased PFHxA burden in hind-limb muscle at P1 in the high-dose group and at P21 in both exposure groups, yet levels normalized to control values by P90. Adult progeny received a standardized cardiotoxin injury to the gastrocnemius at P90. Males from both exposure groups displayed delayed fiber caliber restoration, reduced satellite-cell proliferation, and diminished maximal isometric force relative to controls, whereas females were unaffected. No significant differences were observed in bone morphometry, tendon tensile strength, or voluntary locomotor activity.
These preliminary findings indicate that PFHxA exposure during critical windows of development can induce long-lasting, male-specific deficits across multiple facets of skeletal muscle repair in a mammalian model. Expanded studies interrogating additional regenerative tissues and underlying epigenetic mechanisms are warranted.