Biology subjects

Heiger-Bernays, W.

Publications and source records attributed to Heiger-Bernays, W..

4 recordsLinked to original sources

bioRxiv2021

Predicting the Effects of Per- and Polyfluoroalkyl Substance Mixtures on Peroxisome Proliferator-Activated Receptor Alpha Activity in Vitro

Human exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous, with mixtures of PFAS detected in drinking water, food, household dust, and other exposure sources. Animal toxicity studies and human epidemiology indicate that PFAS may act through shared mechanisms including activation of peroxisome proliferator activated receptor (PPAR). However, the effect of PFAS mixtures on human relevant molecular initiating events remains an important data gap in the PFAS literature. Here, we tested the ability of modeling approaches to predict the effect of diverse PPAR ligands on receptor activity using Cos7 cells transiently transfected with a full length human PPAR (hPPAR) expression construct and a peroxisome proliferator response element-driven luciferase reporter. Cells were treated for 24 hours with two full hPPAR agonists (pemafibrate and GW7647), a full and a partial hPPAR agonist (pemafibrate and mono(2-ethylhexyl) phthalate), or a full hPPAR agonist and a competitive antagonist (pemafibrate and GW6471). Receptor activity was modeled with three additive approaches: effect summation, relative potency factors (RPF), and generalized concentration addition (GCA). While RPF and GCA accurately predicted activity for mixtures of full hPPAR agonists, only GCA predicted activity for full and partial hPPAR agonists and a full agonist and antagonist. We then generated concentration response curves for seven PFAS, which were well-fit with three-parameter Hill functions. The four perfluorinated carboxylic acids (PFCA) tended to act as full hPPAR agonists while the three perfluorinated sulfonic acids (PFSA) tended to act as partial agonists that varied in efficacy between 28-67% of the full agonist, positive control level. GCA and RPF performed equally well at predicting the effects of mixtures with three PFCAs, but only GCA predicted experimental activity with mixtures of PFSAs and a mixture of PFCAs and PFSAs at ratios found in the general population. We conclude that of the three approaches, GCA most accurately models the effect of PFAS mixtures on hPPAR activity in vitro. HighlightsO_LIPerfluorinated carboxylic acids are full human PPAR agonists C_LIO_LIPerfluorinated sulfonic acids are partial human PPAR agonists C_LIO_LIGCA predicts human PPAR activity for mixtures of full and partial agonists C_LIO_LIGCA predicts human PPAR activity for mixtures of agonists and competitive antagonists C_LIO_LIGCA accurately predicts human PPAR activity in response to PFAS mixtures C_LI

pharmacology and toxicology↗

bioRxiv2021

Perfluorooctanoic Acid Induces Liver and Serum Dyslipidemia in Humanized PPARα Mice Fed an American Diet

Per- and polyfluoroalkyl substances (PFAS) are pervasive in the environment resulting in nearly universal detection in people. Human serum PFAS concentrations are strongly associated with increased serum low-density lipoprotein cholesterol (LDL-C), and growing evidence suggests an association with serum triacylglycerides (TG). Here, we tested the hypothesis that perfluorooctanoic acid (PFOA) dysregulates liver and serum triacylglycerides in human peroxisome proliferator activated receptor (hPPAR)-expressing mice fed an American diet. Mice were exposed to PFOA (3.3 mg/l) in drinking water for 6 weeks resulting in a serum concentration of 48 {+/-} 9 g/ml. In male and female hPPAR mice, PFOA increased total liver TG and TG substituted with saturated and monounsaturated fatty acids. Lack of expression of hPPAR alone also increased total liver TG, and PFOA treatment had little effect on liver TG in null mice. In hPPAR mice, PFOA neither significantly increased nor decreased serum TG; however, there was a modest increase in TG associated with very low-density cholesterol particles in both sexes. Across studies, a non-monotonic effect of PFOA on serum TG is evident, with the serum PFOA concentration in this study falling near the "null point" between increasing and decreasing serum TG. Intriguingly, in female PPAR null mice, PFOA significantly increased serum TG, with a similar trend in males. PFOA also modified fatty acid and TG homeostasis-related gene expression in liver, in a hPPAR-dependent manner, but not in adipose. The results reveal the importance of context (serum concentration and genotype) in determining the effect of PFOA on lipid homeostasis.

pharmacology and toxicology↗

bioRxiv2020

Predicting the activation of the androgen receptor by mixtures of ligands using Generalized Concentration Addition

Concentration/dose addition (CA) is widely used for compounds that act by similar mechanisms. But, CA cannot make predictions for mixtures of full and partial agonists for effect levels above that of the least efficacious component. As partial agonists are common, we developed Generalized Concentration Addition (GCA), which has been successfully applied to systems in which ligands compete for a single binding site. Here, we applied a pharmacodynamic model for a system with two binding sites, the androgen receptor (AR). AR acts according to the classic homodimer activation model: each cytoplasmic AR protein binds ligand, undergoes a conformational change that relieves inhibition of dimerization, and binds to DNA response elements as a dimer. We generated individual dose-response data for full (dihydroxytestosterone, BMS564929) and partial (TFM-4AS-1) agonists and a competitive antagonist (MDV3100) using reporter data generated in the MDA-kb2 cell line. We used the Schild method to estimate the binding affinity of AR for MDV3100. Data for individual compounds fit the AR pharmacodynamic model well. The partial agonist had agonistic effects at low effect levels and antagonistic effects at high levels, as predicted by pharmacological theory. The GCA model fit the empirical mixtures data--full/full agonist, full/partial agonist and full agonist/antagonist--as well or better than relative potency factors (a special case of CA) or effect summation. The ability of generalized concentration addition to predict the activity of mixtures of different types of androgen receptor ligands is important as a number of environmental compounds act as partial AR agonists or antagonists.

pharmacology and toxicology↗

bioRxiv2020

Perfluorooctanoic acid activates multiple nuclear receptor pathways and skews expression of genes regulating cholesterol homeostasis in liver of humanized PPARα mice fed an American diet

Humans are exposed to per- and polyfluoroalkyl substances (PFAS) in their drinking water, food, air, dust in their homes, and by direct use of consumer products. Increased concentrations of serum total cholesterol and low density lipoprotein cholesterol are among the endpoints best supported by epidemiology. The objectives of this study were to generate a new model for examining PFAS-induced dyslipidemia and to conduct molecular studies to better define mechanism(s) of action. We tested the hypothesis that PFOA exposure at a human-relevant level dysregulates expression of genes controlling cholesterol homeostasis in livers of mice expressing human PPAR (hPPAR). Female and male hPPAR and PPAR null mice were fed a diet based on the "What we eat in America" analysis and exposed to perfluorooctanoic acid (PFOA) in drinking water (8 {micro}M) for 6 weeks. This resulted in a serum PFOA concentration of 48 g/ml. PFOA increased liver mass, which was associated with histologically-evident lipid accumulation. PFOA induced PPAR and constitutive androstane receptor target gene expression in liver. Expression of genes in four pathways regulating cholesterol homeostasis were also measured. PFOA decreased expression of Hmgcr in a PPAR-dependent manner. PFOA decreased expression of Ldlr and Cyp7a1 in a PPAR-independent manner. Apob expression was not changed. Gene expression in females appeared to be more sensitive to PFOA exposure than in males. This novel study design (hPPAR mice, American diet, long term exposure) generated new insight on the effects of PFOA on cholesterol regulation in the liver and the role of hPPAR.

pharmacology and toxicology↗