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Perfluorooctanoic acid (PFOA)
Published in Mark S. Johnson, Michael J. Quinn, Marc A. Williams, Allison M. Narizzano, Understanding Risk to Wildlife from Exposures to Per- and Polyfluorinated Alkyl Substances (PFAS), 2021
When pregnant mice were exposed to PFOA from GD 1–17, maternal weight was unaffected in mice that received 3 mg/kg-d (Albrecht et al. 2013, Onishchenko et al. 2011) or 5 mg/kg-d (Abbott et al. 2007,2012, Fenton et al. 2009). Similarly, exposure of pregnant female mice to 5 mg/kg-d PFOA for GD 1–17, GD 8–17, or GD 12–17 did not affect gains in maternal body weight (White et al. 2007). However, PFOA treatment at a dose of 25 mg/kg-d for GD 11–16 reduced gains in maternal body weight (Suh et al. 2011) and PFOA treatment for GD 1–17 caused decreased weight gains at doses of 25 or 40 mg/kg-d (Lau et al. 2006). Furthermore, PFOA treatment throughout pregnancy at a dose of 30 mg/kg-d caused a 10 percent decrease in maternal body weight (Hinderliter et al. 2005). Exposure of female mice to PFOA doses up to 1 mg/kg-d from PND 18–20 did not affect body weight (Dixon et al. 2012). Some of the PFOA-mediated developmental effects appeared to be associated with expression of the peroxisome proliferator-activated receptor-alpha (PPARα) transcription factor (Abbott et al. 2007).
Understanding Brain Delivery
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Joana Bicker, Ana Fortuna, Gilberto Alves, Amílcar Falcäo
Drug-induced activation or induction of ABC transporters at the BBB has been less studied compared to efflux inhibition. Nonetheless, there is interest in this field concerning possible induction-mediated DDIs at the BBB and also induction for therapeutic purposes, namely the removal of amyloid-beta peptides from the CNS by P-gp at the BBB [90]. Chan et al. [91] assessed P-gp induction by dexamethasone (ligand of the pregnane X receptor) at the BBB of mice, using quinidine as P-gp substrate. Unbound quinidine concentrations in the brain ISF were 2.5-fold lower, while P-gp expression was 1.5-fold higher in dexamethasone-treated animals compared with vehicle-treated animals [91]. P-gp and BCRP induction has also been studied in human brain microvessel endothelial cells (hCMEC/d3). P-gp expression and function were induced following a 72 h exposure to antiretroviral drugs [92, 93], while selective ligands ofthe peroxisome proliferator-activated receptor alpha (PPAR-α) induced BCRP expression. The intracellular accumulation of mitoxantrone, a BCRP substrate, was significantly reduced after 72 h of exposure to PPAR-a ligands [94]. The upregulation of P-gp/BCRP expression at the BBB has also been reported following chronic exposure to opioids, which may lead to tolerance and pharmacoresistance [95]. Nevertheless, after 11–29 days of treatment of healthy human volunteers with rifampicin, a known P-gp inducer, there was no induction of P-gp at the BBB, using clinical doses which normally induce P-gp in the intestine. It was explained that rifampicin may not achieve sufficient concentrations in BECs to induce P-gp, in contrast to the high concentrations attained in the intestine. Additionally, P-gp at the human BBB may already be maximally induced by environmental or endogenous factors, meaning that further induction may not be feasible [96]. For these reasons, the ITC considers that the induction of efflux transporters at the human BBB appears improbable [89].
Perfluoroalkyl Substance Toxicity from Early-Life Exposure
Published in David M. Kempisty, Yun Xing, LeeAnn Racz, Perfluoroalkyl Substances in the Environment, 2018
The mechanism for PFAS toxicity has not yet been determined, but PFOA is known to be an agonist for peroxisome proliferator–activated receptor alpha (PPARα) and is suspected to partially explain toxicity (Vanden Heuvel et al. 2006; Abbott et al. 2009; Mattsson et al. 2015). PPARα is a ligand-activated nuclear receptor that regulates genes important for lipid catabolism, inhibition of arachidonic acid metabolism, and lipid homeostasis (Abbott et al. 2009). Activation of PPARα is linked to three cancers in rodents: hepatocellular adenoma, pancreatic acinar cell adenoma, and Leydig cell adenoma, all of which are associated with PFOA exposure in animals (Andersen et al. 2007). However, the clinical relevance of these cancers to humans is questionable (Klaunig et al. 2012). In vitro assays investigating PPARα sensitivity to PFOA between different species have had mixed results, but generally indicate that human and rodent PPARα have similar affinities to PFOA (Maloney and Waxman 1999; Vanden Heuvel et al. 2006; Wolf et al. 2006, 2012). PPARα is highly expressed in the liver (more so in rodents than humans) and is detected at various levels during gestational development in both rodents (gestational day [GD] 5 in mice) and humans (Holden and Tugwood 1999; Keller et al. 2000; Abbott 2009; Abbott et al. 2010). While the endogenous function of PPARα in the liver is maintaining lipid homeostasis, its role in gestational development is less clear. Mice that are genetic knockouts for PPARα do not suffer from obvious birth defects and are fertile, which indicates that it is not essential for reproductive development (Lee et al. 1995). Additionally, PPARα knockout mice are insensitive to the gestational effects of PFOA but are still sensitive to PFOS developmental toxicity, indicating different mechanisms of action that vary in dependence of PPARα activation (Abbott 2009; Abbott et al. 2010). Overall, there is a relationship with PFAS and PPARα that may partially explain the toxicity, especially with adiposity, but how much it impacts the human liver, which has lower PPARα levels, and developmental toxicity is unclear.
Hydroxychloroquine improves high-fat-diet-induced obesity and organ dysfunction via modulation of lipid level, oxidative stress, and inflammation
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Mohamed A Hasan, Omar A. Ammar, Maher A Amer, Azza I Othman, Fawzia Zigheber, Mohamed A El-Missiry
The improvement in adiponectin levels in HCQ-treated obese rats has a fundamental and beneficial effect. The ability of adiponectin to control obesity consequences is attributed to several mechanisms [8]. It can suppress the induction of TNF-α and enhance the level of anti-inflammatory IL-10. Moreover, adiponectin decreases the amount of adipose tissue TG and improves insulin signaling and sensitivity. It also activates β-oxidation through enhancing peroxisome proliferator-activated receptor alpha (PPAR-α) receptor phosphorylation and stimulating AMP-activated protein kinase (AMPK) cascade [8]. Thus, these findings indicate that the effect of HCQ on obesity is mediated by adiponectin. In patients with systemic lupus erythematosus, treatment with HCQ controls adipokines [39]. In general, obesity is characterized by hyperleptinemia and resistance to weight loss [40]. Thus, we suggest that HCQ might normalize leptin levels, suppress leptin resistance, and/or restore the balance between leptin and adiponectin in rats treated with HFD+HCQ. These data indicate that HCQ intervention in obese rats improved oxidative stress status, declined production of inflammatory adipokines and reduced fat storage.
Plant responses to per- and polyfluoroalkyl substances (PFAS): a molecular perspective
Published in International Journal of Phytoremediation, 2023
Ayesha Karamat, Rouzbeh Tehrani, Gregory D. Foster, Benoit Van Aken
At the molecular level, the effects of PFAS on the lipid metabolism and membrane integrity have been supported primarily through proteomic and metabolomic evidence. In their proteomic study of maize plants exposed to a mixture of 11 PFAS, Ebinezer et al. (2022) observed a significant increase of the NSLTP1 protein involved in lipid transport and metabolism. The analysis of fatty acids in exposed tissues confirmed alteration of the abundance of 8 fatty acids, which the authors related to PFAS surfactant properties, as it was observed in non-plant species (Dickman and Aga 2022). Studies on model organisms indicate that PFAS are capable to activate the peroxisome proliferator-activated receptor alpha (PPARα) involved in the regulation of the lipid metabolism – a similar mechanism could take place in plants, although currently not demonstrated (Ebinezer et al. 2022).
Relevance of mouse lung tumors to human risk assessment
Published in Journal of Toxicology and Environmental Health, Part B, 2020
Samuel M. Cohen, Yan Zhongyu, James S. Bus
This mode of action involves an increase in cell proliferation due to either intrinsic activity of the parent agent and/or its (generally non-DNA reactive) metabolite(s) (Cohen 2004; Cohen et al. 2019; Cohen and Ellwein 1990; 1991). Such agents include those that are either directly mitogenic, as is seen with constitutive androstane receptor (CAR) (Elcombe et al. 2014) or peroxisome proliferator-activated receptor alpha (PPARα) (Corton et al. 2014) receptor activation in liver carcinogenesis in rodents, or it might be attributed to cytotoxicity and associated reparative regeneration, as found with chloroform carcinogenesis in rodent liver and kidney or with ethanol carcinogenesis in humans. As will be discussed in greater detail below, there are examples of direct mitogenic modes of action and cytotoxicity with regenerative proliferation for chemicals that are carcinogenic in mouse lung. One mechanism that was suggested whereby a chemical may produce cytotoxicity is oxidative damage. However, evidence for this is lacking. Further, for lung tumors this is not likely to be operative, as chemicals, such as paraquat, produce marked oxidative damage and yet are not carcinogenic to the lung, or, for that matter, are not carcinogenic to any tissue (IPCS 1984; EPA 1997).