Epigenetic changes by per- and polyfluoroalkyl substances (PFAS)

Kim, Sujin; Thapar, Isha; Brooks, Bryan W.

doi:10.1016/j.envpol.2021.116929

Cited by 72 publications

(33 citation statements)

References 68 publications

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“…These findings, along with the increases in MetS-associated phenotypes seen in these groups later in life, suggest developmental exposure to GenX results in lifelong alterations in metabolic function, making metabolic disease a concern for both GenX and PFOA exposures [ 5 ]. Metabolic programming in response to chemical exposure has previously been documented with bisphenol A(BPA) and phthalates through various proposed mechanisms including epigenetic regulation [ 65 – 68 ].…”

Section: Discussionmentioning

confidence: 99%

Latent, sex-specific metabolic health effects in CD-1 mouse offspring exposed to PFOA or HFPO-DA (GenX) during gestation

Cope

Blake

Love

et al. 2021

Emerging Contaminants

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Background: Perfluorooctanoic acid (PFOA) is an environmental contaminant associated with adverse metabolic outcomes in developmentally exposed human populations and mouse models. Hexafluoropropylene oxide-dimer acid (HFPO-DA, commonly called GenX) has replaced PFOA in many industrial applications in the U.S. and Europe and has been measured in global water systems from <1 to 9350 ng/L HFPO-DA. Health effects data for GenX are lacking. Objective: Determine the effects of gestational exposure to GenX on offspring weight gain trajectory, adult metabolic health, liver pathology and key adipose gene pathways in male and female CD-1 mice. Methods: Daily oral doses of GenX (0.2, 1.0, 2.0 mg/kg), PFOA (0.1, 1.0 mg/kg), or vehicle control were administered to pregnant mice (gestation days 1.5–17.5). Offspring were fed a high- or low-fat diet (HFD or LFD) at weaning until necropsy at 6 or 18 weeks, and metabolic endpoints were measured over time. PFOA and GenX serum and urine concentrations, weight gain, serum lipid parameters, body mass composition, glucose tolerance, white adipose tissue gene expression, and liver histopathology were evaluated. Results: Prenatal exposure to GenX led to its accumulation in the serum and urine of 5-day old pups (P = 0.007, P < 0.001), which was undetectable by weaning. By 18 weeks of age, male mice fed LFD in the 2.0 mg/kg GenX group displayed increased weight gain (P < 0.05), fat mass (P = 0.016), hepatocellular microvesicular fatty change (P = 0.015), and insulin sensitivity (P = 0.014) in comparison to control males fed LFD. Female mice fed HFD had a significant increase in hepatocyte single cell necrosis in 1.0 mg/kg GenX group (P = 0.022) and 1.0 mg/kg PFOA group (P = 0.003) compared to control HFD females. Both sexes were affected by gestational GenX exposure; however, the observed phenotype varied between sex with males displaying more characteristics of metabolic disease and females exhibiting liver damage in response to the gestational exposure. Conclusions: Prenatal exposure to 1 mg/kg GenX and 1 mg/kg PFOA induces adverse metabolic outcomes in adult mice that are diet- and sex-dependent. GenX also accumulated in pup serum, suggesting that placental and potentially lactational transfer are important exposure routes for GenX.

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Section: Discussionmentioning

confidence: 99%

Latent, sex-specific metabolic health effects in CD-1 mouse offspring exposed to PFOA or HFPO-DA (GenX) during gestation

Cope

Blake

Love

et al. 2021

Emerging Contaminants

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“…Alternatively, elevated exposure to PFAS has been positively correlated with increased serum cholesterol in humans ( 1 ), which may lead to an increase in the production of steroid hormones. Of concern, the consequences of alterations resulting from prenatal PFAS exposure have the potential to be passed on to offspring through epigenetic transgenerational inheritance modalities ( 183 ) and may thus increase the susceptibility of future generations to disease, as demonstrated with other environmental factors ( 121 , 184 ).…”

Section: Known Effects Of Pfas Exposure On Male Fertilitymentioning

confidence: 99%

Assessment of the Emerging Threat Posed by Perfluoroalkyl and Polyfluoroalkyl Substances to Male Reproduction in Humans

et al. 2022

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Per-fluoroalkyl and polyfluoroalkyl substances (PFAS) are a diverse group of synthetic fluorinated chemicals used widely in industry and consumer products. Due to their extensive use and chemical stability, PFAS are ubiquitous environmental contaminants and as such, form an emerging risk factor for male reproductive health. The long half-lives of PFAS is of particular concern as the propensity to accumulate in biological systems prolong the time taken for excretion, taking years in many cases. Accordingly, there is mounting evidence supporting a negative association between PFAS exposure and an array of human health conditions. However, inconsistencies among epidemiological and experimental findings have hindered the ability to definitively link negative reproductive outcomes to specific PFAS exposure. This situation highlights the requirement for further investigation and the identification of reliable biological models that can inform health risks, allowing sensitive assessment of the spectrum of effects of PFAS exposure on humans. Here, we review the literature on the biological effects of PFAS exposure, with a specific focus on male reproduction, owing to its utility as a sentinel marker of general health. Indeed, male infertility has increasingly been shown to serve as an early indicator of a range of co-morbidities such as coronary, inflammatory, and metabolic diseases. It follows that adverse associations have been established between PFAS exposure and the incidence of testicular dysfunction, including pathologies such as testicular cancer and a reduction in semen quality. We also give consideration to the mechanisms that render the male reproductive tract vulnerable to PFAS mediated damage, and discuss novel remediation strategies to mitigate the negative impact of PFAS contamination and/or to ameliorate the PFAS load of exposed individuals.

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“…Even though cadmium has been banned in consumer products, it remains widely used in industry, particularly in the production of nickel-cadmium (Ni-Cd) rechargeable batteries, solar cells, plastic stabilizers and pigments. While the exposure of humans to PFOS and PFOA may not have a causal relationship between cancer [ 79 ] and any immune-related health condition [ 80 ], the potential risk of human exposure to PFOS/PFOA and neurotoxicity, developmental toxicity (e.g., inducing neonatal mortality) and genetic aberration [ 81 , 82 , 83 ] have led to the global PFOA ban with exemptions of industrial use. This is due to its thermal and chemical stability, stain resistance, and surfactant nature, making it a key ingredient in fire-fighting foam, hydraulic fluid for aviation and photolithography ( (accessed on 7 December 2021).…”

Section: Unique Features Of Cell Junctions In the Testismentioning

confidence: 99%

Cell-Cell Interaction-Mediated Signaling in the Testis Induces Reproductive Dysfunction—Lesson from the Toxicant/Pharmaceutical Models

Wang

et al. 2022

Cells

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Emerging evidence has shown that cell-cell interactions between testicular cells, in particular at the Sertoli cell-cell and Sertoli-germ cell interface, are crucial to support spermatogenesis. The unique ultrastructures that support cell-cell interactions in the testis are the basal ES (ectoplasmic specialization) and the apical ES. The basal ES is found between adjacent Sertoli cells near the basement membrane that also constitute the blood-testis barrier (BTB). The apical ES is restrictively expressed at the Sertoli-spermatid contact site in the apical (adluminal) compartment of the seminiferous epithelium. These ultrastructures are present in both rodent and human testes, but the majority of studies found in the literature were done in rodent testes. As such, our discussion herein, unless otherwise specified, is focused on studies in testes of adult rats. Studies have shown that the testicular cell-cell interactions crucial to support spermatogenesis are mediated through distinctive signaling proteins and pathways, most notably involving FAK, Akt1/2 and Cdc42 GTPase. Thus, manipulation of some of these signaling proteins, such as FAK, through the use of phosphomimetic mutants for overexpression in Sertoli cell epithelium in vitro or in the testis in vivo, making FAK either constitutively active or inactive, we can modify the outcome of spermatogenesis. For instance, using the toxicant-induced Sertoli cell or testis injury in rats as study models, we can either block or rescue toxicant-induced infertility through overexpression of p-FAK-Y397 or p-FAK-Y407 (and their mutants), including the use of specific activator(s) of the involved signaling proteins against pAkt1/2. These findings thus illustrate that a potential therapeutic approach can be developed to manage toxicant-induced male reproductive dysfunction. In this review, we critically evaluate these recent findings, highlighting the direction for future investigations by bringing the laboratory-based research through a translation path to clinical investigations.

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Epigenetic changes by per- and polyfluoroalkyl substances (PFAS)

Cited by 72 publications

References 68 publications

Latent, sex-specific metabolic health effects in CD-1 mouse offspring exposed to PFOA or HFPO-DA (GenX) during gestation

Latent, sex-specific metabolic health effects in CD-1 mouse offspring exposed to PFOA or HFPO-DA (GenX) during gestation

Assessment of the Emerging Threat Posed by Perfluoroalkyl and Polyfluoroalkyl Substances to Male Reproduction in Humans

Cell-Cell Interaction-Mediated Signaling in the Testis Induces Reproductive Dysfunction—Lesson from the Toxicant/Pharmaceutical Models

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