Hypercholesterolemia with consumption of PFOA-laced Western diets is dependent on strain and sex of mice

Rebholz, Sandra; Jones, T. Hugh; Herrick, Robert; Xie, Changchun; Calafat, Antònia M.; Pinney, Susan M.; Woollett, Laura A.

doi:10.1016/j.toxrep.2015.11.004

Cited by 57 publications

(64 citation statements)

References 74 publications

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“…While the decrease in Hmgcr expression would be expected to decrease serum cholesterol, reductions in Cyp7a1 and Ldlr expression would be expected in increase serum cholesterol. The downregulation of Cyp7a1 occurs more broadly across models, as we observed Cyp7a1 downregulation in both male and female SV129 mice and Rebholz et al, 2016 observed its downregulation in both sexes in both C57Bl/6J and Balb/C mice. Importantly, PFOA also downregulates Cyp7a1 expression in human hepatocytes (Behr et al 2020).…”

Section: Discussionmentioning

confidence: 50%

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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

Schlezinger

Puckett

Oliver

et al. 2020

Preprint

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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 PPARα (hPPARα). Female and male hPPARα and PPARα 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 µM) for 6 weeks. This resulted in a serum PFOA concentration of 48 μg/ml. PFOA increased liver mass, which was associated with histologically-evident lipid accumulation. PFOA induced PPARα 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 PPARα-dependent manner. PFOA decreased expression of Ldlr and Cyp7a1 in a PPARα-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 (hPPARα mice, American diet, long term exposure) generated new insight on the effects of PFOA on cholesterol regulation in the liver and the role of hPPARα.

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Section: Discussionmentioning

confidence: 50%

“…A single previous study has investigated the effects of PFAS on lipid homeostasis in female mice (Rebholz et al 2016). The results presented here corroborate the observation of sexdependent effects of PFOA on liver physiology.…”

Section: Discussionmentioning

confidence: 99%

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

Schlezinger

Puckett

Oliver

et al. 2020

Preprint

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“…Laboratory animal studies identify multiple targets for PFAA toxicity including the liver, immune system, endocrine system, male reproductive system, and developing fetus and neonate [ 31 , 38 , 39 ]. Toxicological effects are generally concordant with human epidemiology data, and recent studies suggest that dietary factors (high-fat Western human diet versus low-fat standard laboratory rodent diet) may contribute to differences in effects on lipid metabolism observed in rodents versus humans [ 40 , 41 ]. In chronic rodent carcinogenicity studies, PFOA and PFOS caused tumors while perfluorohexanoic acid (PFHxA), a six-carbon carboxylate which is more rapidly excreted, did not [ 42 ].…”

Section: Scientific Information Considered In Developing Pfaa Drinkinmentioning

confidence: 74%

Key scientific issues in developing drinking water guidelines for perfluoroalkyl acids: Contaminants of emerging concern

2017

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Perfluoroalkyl acids (PFAAs), a group of synthetic organic chemicals with industrial and commercial uses, are of current concern because of increasing awareness of their presence in drinking water and their potential to cause adverse health effects. PFAAs are distinctive among persistent, bioaccumulative, and toxic (PBT) contaminants because they are water soluble and do not break down in the environment. This commentary discusses scientific and risk assessment issues that impact the development of drinking water guidelines for PFAAs, including choice of toxicological endpoints, uncertainty factors, and exposure assumptions used as their basis. In experimental animals, PFAAs cause toxicity to the liver, the immune, endocrine, and male reproductive systems, and the developing fetus and neonate. Low-dose effects include persistent delays in mammary gland development (perfluorooctanoic acid; PFOA) and suppression of immune response (perfluorooctane sulfonate; PFOS). In humans, even general population level exposures to some PFAAs are associated with health effects such as increased serum lipids and liver enzymes, decreased vaccine response, and decreased birth weight. Ongoing exposures to even relatively low drinking water concentrations of long-chain PFAAs substantially increase human body burdens, which remain elevated for many years after exposure ends. Notably, infants are a sensitive subpopulation for PFAA’s developmental effects and receive higher exposures than adults from the same drinking water source. This information, as well as emerging data from future studies, should be considered in the development of health-protective and scientifically sound guidelines for PFAAs in drinking water.

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“…Rodents treated with APFO over 14 days showed decreased serum lipids at PFOA levels between 20 000 and 51 000 ng/ml in rats and 10 000–14 000 ng/ml in mice ( Loveless et al , 2006 ). A study of C57BL/6 and BALB/c mice fed a high cholesterol and fat diet containing PFOA, found elevated hypercholesterolemia (primarily HDL) ( Rebholz et al , 2016 ) but this was not supported by a study of humanized ApoE*3.Leiden.CETP mice ( Westerterp et al , 2006 ), in which a Western diet containing APFO resulted in decreased plasma non-HDL cholesterol and triglycerides ( Princen et al , 2016 ). Hypolipidemia was not observed in cynomolgus monkeys with repeated oral administration of APFO over six months ( Butenhoff et al , 2002 ).…”

Section: Discussionmentioning

confidence: 97%

Stochastic Pharmacokinetic-Pharmacodynamic Modeling for Assessing the Systemic Health Risk of Perfluorooctanoate (PFOA)

Convertino

Olsen

Liu

et al. 2018

Toxicological Sciences

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A phase 1 dose-escalation trial assessed the chemotherapeutic potential of ammonium perfluorooctanoate (APFO). Forty-nine primarily solid-tumor cancer patients who failed standard therapy received weekly APFO doses (50–1200 mg) for 6 weeks. Clinical chemistries and plasma PFOA (anionic APFO) were measured predose and weekly thereafter. Several clinical measures including total cholesterol, high-density lipoproteins (HDLs), thyroid stimulating hormone (TSH), and free thyroxine (fT4), relative to PFOA concentrations were examined by: Standard statistical analyses using generalized estimating equations (GEE) and a probabilistic analysis using probability distribution functions (pdf) at various PFOA concentrations; and a 2-compartment pharmacokinetic/pharmacodynamic (PK/PD) model to directly estimate mean changes. Based on the GEE, the average rates of change in total cholesterol and fT4 associated with increasing PFOA were approximately −1.2×10−3 mmol/l/μM and 2.8×10−3 pmol/l/μM, respectively. The PK/PD model predicted more closely the trends observed in the data as well as the pdfs of biomarkers. A decline in total cholesterol was observed, with a clear transition in shape and range of the pdfs, manifested by the maximum value of the Kullback-Leibler (KL) divergence, that occurred at plasma PFOA between 420 and 565 μM (175 000–230 000 ng/ml). High-density lipoprotein was unchanged. An increase in fT4 was observed at a higher PFOA transition point, albeit TSH was unchanged. Our findings are consistent with some animal models and may motivate re-examination of the epidemiologic studies to PFOA at levels several orders of magnitude lower than this study. These observational studies have reported contrary associations, but currently understood biology does not support the existence of such conflicting effects.

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Hypercholesterolemia with consumption of PFOA-laced Western diets is dependent on strain and sex of mice

Cited by 57 publications

References 74 publications

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

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

Key scientific issues in developing drinking water guidelines for perfluoroalkyl acids: Contaminants of emerging concern

Stochastic Pharmacokinetic-Pharmacodynamic Modeling for Assessing the Systemic Health Risk of Perfluorooctanoate (PFOA)

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