PPARα genotype impacts bone quality and perfluorooctanoic acid-induced effects

Per-and polyfluoroalkyl substances (PFAS) are significant environmental contaminants that cause a number of adverse human health effects. Studies increasingly link exposure to PFAS with disruptions in osteoblast and osteoclast differentiation and function, reduced bone mineral density (BMD), and negative impacts on skeletal structure. In vivo studies on the effects of PFAS on bone health remain limited, with none investigating the impacts in mice expressing human peroxisome proliferator activated receptor α (PPARα). Given PFAS’s ability to interact with the peroxisome proliferator activated receptor family and their importance in bone health, we present work investigating the effects of perfluorooctanoic acid (PFOA) exposure and PPARα genotype (mouse, human or null) on bone quality across two exposure periods (6 and 14 weeks) in mice fed a human relevant diet. In both exposure scenarios, the serum PFOA concentrations were ≈ 50 μg/mL, similar to a highly exposed fluorochemical worker. We began by establishing the liver phenotype across exposures and genotypes. Across genotypes and exposure timing, PFOA increased liver to body weight ratios, but the contribution of increased triglycerides was reduced at 14 weeks. Exposure to PFOA increased hepatic PPARα-dependent gene expression ( Acox ) in both sexes and exposure periods, but only in mPPARα mice. The effect of PFOA on hepatic CAR- and PXR-dependent gene expression ( Cyp2b10 and Cyp3a11 , respectively) was more complex; with sex-, genotype-, and exposure timing-dependent differences. Trabecular and cortical bone parameters were not impacted by PFOA treatment, but genotype was a significant factor across sexes and exposure periods. mPPARα mice had higher trabecular tissue mineral density at 9 and 20 weeks of age than hPPARα mice, but the lower trabecular bone volume evident at 9 weeks of age resolved at 20 weeks of age. mPPARα mice had higher cortical tissue mineral density and bone volume than hPPARα and PPARα null mice. Analysis of serum markers of osteoblast and osteoclast activity following 14 weeks of exposure to PFOA revealed a PPARα-dependent decrease in PINP but no effect on CTX. Our results reveal the importance of PPARα genotype for bone quality parameters and emerging evidence of the effect of PFOA on osteoblast activity. Given the unusual mouse bone quality model (sv/129 background), this work underscores the need for future in vivo research shifts to investigate the effects of PFAS on in bone quality.