RNA‐sequencing analysis reveals the hepatotoxic mechanism of perfluoroalkyl alternatives, HFPO2 and HFPO4, following exposure in mice

Wang, Jianshe; Wang, Xiaoyang; Sheng, Nan; Zhou, Xiujuan; Cui, Ruina; Zhang, Hongxia; Dai, Jiayin

doi:10.1002/jat.3376

Cited by 61 publications

(69 citation statements)

References 59 publications

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“…Figure shows the peroxisomal β‐oxidase enzyme activity in the livers of mice and rats following exposure to GenX for 28 days. The most direct evidence for PPARα activation comes from a recent study where significant pathway enrichment for PPARα signaling pathways was observed in the livers of male ICR mice exposed to 1 mg/kg GenX by oral gavage once daily for 4 weeks (Wang et al, ). GenX also induced other effects consistent with PPARα activation such as increased liver weight, liver hypertrophy and increased cell proliferation (evidenced by increases of mitotic figures), as well as changes in two of the three target tissues associated with the PPARα tumor triad (see Section ).…”

Section: Resultsmentioning

confidence: 99%

“…That PPARα‐related signaling is significantly elevated in mice following exposure to 1 mg/kg GenX (Wang et al, ) suggests that PPARα is likely activated at lower doses. Because the Wang et al study included only a single dose of GenX, we modeled the dose‐response for acyl‐CoA oxidase enzyme activity in male and female mice following 28 days of exposure (same data as in Figure ) as a proxy for PPARα activation.…”

Section: Resultsmentioning

confidence: 99%

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Development of an oral reference dose for the perfluorinated compound GenX

Thompson

Fitch

Ring

et al. 2019

J of Applied Toxicology

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Ammonium 2,3,3,3‐tetrafluoro‐2‐(heptafluoropropoxy)‐propanoate, also known as GenX, is a processing aid used in the manufacture of fluoropolymers. GenX is one of several chemistries developed as an alternative to long‐chain poly‐fluoroalkyl substances, which tend to have long clearance half‐lives and are environmentally persistent. Unlike poly‐fluoroalkyl substances, GenX has more rapid clearance, but has been detected in US and international water sources. There are currently no federal drinking water standards for GenX in the USA; therefore, we developed a non‐cancer oral reference dose (RfD) for GenX based on available repeated dose studies. The review of the available data indicate that GenX is unlikely to be genotoxic. A combination of traditional frequentist benchmark dose models and Bayesian benchmark dose models were used derive relevant points of departure from mammalian toxicity studies. In addition, deterministic and probabilistic RfD values were developed using available tools and regulatory guidance. The two approaches resulted in a narrow range of RfD values for liver lesions observed in a 2‐year bioassay in rats (0.01–0.02 mg/kg/day). The probabilistic approach resulted in the lower, i.e., more conservative RfD. The probabilistic RfD of 0.01 mg/kg/day results in a maximum contaminant level goal of 70 ppb. It is anticipated that these values, along with the hazard identification and dose‐response modeling described herein, should be informative for risk assessors and regulators interested in setting health‐protective drinking water guideline values for GenX.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Development of an oral reference dose for the perfluorinated compound GenX

Thompson

Fitch

Ring

et al. 2019

J of Applied Toxicology

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“…A study by Rae et al () implied a LOAEL of 1 mg/kg/day for effects of GenX in livers and kidneys of male rats, indicating that effects may occur at lower administered doses than those reported in the Rushing et al () study. Another study in male mice given a single dose of 1 mg/kg/day of GenX for four weeks demonstrated injury and alteration of genes associated with lipid metabolism in livers (Wang et al ). However, this study focused only on a single administered dose, so the dose‐responsiveness of these effects cannot be determined or applied to health goals.…”

Section: Toxicity Of Genx and North Carolina Health Goalmentioning

confidence: 99%

Recently Detected Drinking Water Contaminants: GenX and Other Per‐ and Polyfluoroalkyl Ether Acids

et al. 2018

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For several decades, a common processing aid in the production of fluoropolymers was the ammonium salt of perfluorooctanoic acid (PFOA). Because PFOA is persistent, bioaccumulative, and toxic, its production and use are being phased out in the United States. In 2009, the US Environmental Protection Agency stipulated conditions for the manufacture and commercial use of GenX, a PFOA replacement. While GenX is produced for commercial purposes, the acid form of GenX is also generated as a byproduct during the production of fluoromonomers. The discovery of high concentrations of GenX and related perfluoroalkyl ether acids (PFEAs) in the Cape Fear River and in finished drinking water of more than 200,000 North Carolina residents required quick action by researchers, regulators, public health officials, commercial laboratories, drinking water providers, and consulting engineers. Information about sources and toxicity of GenX as well as an analytical method for the detection of GenX and eight related PFEAs is presented. GenX/PFEA occurrence in water and GenX/PFEA removal by different drinking water treatment processes are also discussed.

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“…2016; Rushing et al. 2017; Wang et al. 2017a), guideline registration studies from the manufacturer of HFPO-DA are publicly available (https://hero.epa.gov/hero/index.cfm/project/page/project_id/2627); however, even though in utero exposure to PFOS and other PFAS induced extensive neonatal mortality and reduced offspring body weights in rats, similar studies have not been conducted with HFPO-DA to our knowledge.…”

Section: Introductionmentioning

confidence: 99%

Adverse Maternal, Fetal, and Postnatal Effects of Hexafluoropropylene Oxide Dimer Acid (GenX) from Oral Gestational Exposure in Sprague-Dawley Rats

Conley

Lambright

Evans

et al. 2019

Environ Health Perspect

130

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Background:Hexafluoropropylene oxide dimer acid [(HFPO-DA), GenX] is a member of the per- and polyfluoroalkyl substances (PFAS) chemical class, and elevated levels of HFPO-DA have been detected in surface water, air, and treated drinking water in the United States and Europe.Objectives:We aimed to characterize the potential maternal and postnatal toxicities of oral HFPO-DA in rats during sexual differentiation. Given that some PFAS activate peroxisome proliferator-activated receptors (PPARs), we sought to assess whether HFPO-DA affects androgen-dependent development or interferes with estrogen, androgen, or glucocorticoid receptor activity.Methods:Steroid receptor activity was assessed with a suite of in vitro transactivation assays, and Sprague-Dawley rats were used to assess maternal, fetal, and postnatal effects of HFPO-DA exposure. Dams were dosed daily via oral gavage during male reproductive development (gestation days 14–18). We evaluated fetal testes, maternal and fetal livers, maternal serum clinical chemistry, and reproductive development of F1 animals.Results:HFPO-DA exposure resulted in negligible in vitro receptor activity and did not impact testosterone production or expression of genes key to male reproductive development in the fetal testis; however, in vivo exposure during gestation resulted in higher maternal liver weights (≥62.5mg/kg), lower maternal serum thyroid hormone and lipid profiles (≥30mg/kg), and up-regulated gene expression related to PPAR signaling pathways in maternal and fetal livers (≥1mg/kg). Further, the pilot postnatal study indicated lower female body weight and lower weights of male reproductive tissues in F1 animals.Conclusions:HFPO-DA exposure produced multiple effects that were similar to prior toxicity evaluations on PFAS, such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), but seen as the result of higher oral doses. The mean dam serum concentration from the lowest dose group was 4-fold greater than the maximum serum concentration detected in a worker in an HFPO-DA manufacturing facility. Research is needed to examine the mechanisms and downstream events linked to the adverse effects of PFAS as are mixture-based studies evaluating multiple PFAS. https://doi.org/10.1289/EHP4372

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RNA‐sequencing analysis reveals the hepatotoxic mechanism of perfluoroalkyl alternatives, HFPO2 and HFPO4, following exposure in mice

Cited by 61 publications

References 59 publications

Development of an oral reference dose for the perfluorinated compound GenX

Development of an oral reference dose for the perfluorinated compound GenX

Recently Detected Drinking Water Contaminants: GenX and Other Per‐ and Polyfluoroalkyl Ether Acids

Adverse Maternal, Fetal, and Postnatal Effects of Hexafluoropropylene Oxide Dimer Acid (GenX) from Oral Gestational Exposure in Sprague-Dawley Rats

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