Novel Insights on 6:6 Perfluoroalkyl Phosphonic Acid-Induced Melanin Synthesis Disorders Leading to Pigmentation in Tadpoles

As one emerging PFAS, 6:6 PFPiAinduced pigmentation byup-regulating MITF, which is activated by damaging the retinal function,disrupting the circadian rhythm and binding with 6:6 PFPiA. As alternatives to traditional per- and polyfluoroalkylsubstances,perfluoroalkyl phosphonic acids (PFPiAs) are widely present in aquaticenvironments and can potentially harm aquatic organisms. Pigmentationaffects the probability of aquatic organisms being preyed on and servesas an important toxic endpoint of development, but little is knownabout the impacts of PFPiAs on the development of aquatic organisms.In this study, Xenopus laevis embryoswere exposed to 6:6 PFPiA (1, 10, and 100 nM) for 14 days. The developedtadpoles exhibited evident pigmentation with increased melanin particlesize and density on the skin. Pathological and behavioral experimentsrevealed that the retinal layers became thinner, reducing the photosensitivityand disturbing the circadian rhythm of the tadpoles. Compared to thecontrol group, the exposed tadpoles showed higher levels but lesschanges of melanin throughout the light/dark cycle, as well as distinctoxidative damage. Consequently, the expression level of microphthalmia-associatedtranscription factor (MITF), a key factor inducing melanin synthesis,increased significantly. Molecular docking analysis suggested that6:6 PFPiA forms strong interactions in the binding pocket of MITF,implying that it could activate MITF directly. The activation of MITFultimately promotes melanin synthesis, resulting in pigmentation ontadpoles.

Automated summary

As an alternative to traditional per- and polyfluoroalkyl substances (PFAS), perfluoroalkyl phosphonic acids (PFPiAs) can induce pigmentation in Xenopus laevis tadpoles by up-regulating MITF and damaging retinal function, disrupting circadian rhythm. The exposure to 6:6 PFPiA resulted in evident pigmentation, thinner retinal layers, reduced photosensitivity, disturbed circadian rhythm, higher and relatively stable levels of melanin throughout the light/dark cycle, distinct oxidative damage, and significantly increased expression of MITF. Molecular docking analysis suggested that 6:6 PFPiA can directly activate MITF by forming strong interactions in its binding pocket.