Endocrine disruption of vitamin D activity by perfluoro-octanoic acid (PFOA)

Abstract

Perfluoroalkyl substances (PFAS) are a class of compounds used in industry and consumer products. Perfluorooctanoic acid (PFOA) is the predominant form in human samples and has been shown to induce severe health consequences, such as neonatal mortality, neurotoxicity, and immunotoxicity. Toxicological studies indicate that PFAS accumulate in bone tissues and cause altered bone development. Epidemiological studies have reported an inverse relationship between PFAS and bone health, however the associated mechanisms are still unexplored. Here, we present computational, in silico and in vitro evidence supporting the interference of PFOA on vitamin D (VD). First, PFOA competes with calcitriol on the same binding site of the VD receptor, leading to an alteration of the structural flexibility and a 10% reduction by surface plasmon resonance analysis. Second, this interference leads to an altered response of VD-responsive genes in two cellular targets of this hormone, osteoblasts and epithelial cells of the colorectal tract. Third, mineralization in human osteoblasts is reduced upon coincubation of PFOA with VD. Finally, in a small cohort of young healthy men, PTH levels were higher in the exposed group, but VD levels were comparable. Altogether these results provide the first evidence of endocrine disruption by PFOA on VD pathway by competition on its receptor and subsequent inhibition of VD-responsive genes in target cells.

Associations of Maternal Serum Perfluoroalkyl Substances Concentrations with Early Adolescent Bone Mineral Content and Density: The Health Outcomes and Measures of the Environment (HOME) Study

“…2016 ). PFOA competes with 1,25-dihydroxyvitamin D on the same binding site of the vitamin D receptor, leading to altered response of vitamin D–related genes in osteoblasts ( Di Nisio et al. 2020b ).…”

“…2020b ). In human osteoblast cells, coexposure to PFOA significantly reduced 1,25-dihydroxyvitamin D associated mineralization ( Di Nisio et al. 2020b ).…”

Legacy and Emerging Per- and Polyfluoroalkyl Substances: Analytical Techniques, Environmental Fate, and Health Effects

“…Analyses of dry bone and bone marrow from cadavers have shown that PFNA, but not PFOA or PFOS, was present in bone [194]. Another recent study provides evidence that PFOA disrupts vitamin D activity through binding to the vitamin D receptor, which may indicate a mechanism involved in the effects of PFOA on bone mineralization [199].…”

Environmental Factors That Affect Parathyroid Hormone and Calcitonin Levels

“…Exposure to persistent organochlorine compounds (p,p′-diphenyldichloroethene (p,p′-DDE) and polychlorinated biphenyls (PCBs)) did not affect PTH levels [ 132 , 250 ]. Exposure to perfluoroalkyl substances (PFAS) led to an increase in PTH levels [ 251 ]. Di Nisio et al suggested that perfluoro-octanoic acid (PFOA) binds to vitamin D receptors, causing reduced 1,25(OH)D activity, which in turn increases PTH levels [ 251 ].…”

“…Exposure to perfluoroalkyl substances (PFAS) led to an increase in PTH levels [ 251 ]. Di Nisio et al suggested that perfluoro-octanoic acid (PFOA) binds to vitamin D receptors, causing reduced 1,25(OH)D activity, which in turn increases PTH levels [ 251 ]. Fluoride exposure increases PTH levels [ 252 ].…”