Low molecular weight ortho-phthalate compounds have been implicated in disruption of androgen pathways when exposure occurs during the masculinization programming window. Di-isononyl phthalate (DINP) is a high and production volume chemical. To understand potential for DINP its metabolites to disrupt endocrine pathways, evidence assessment was conducted according European Chemicals Agency (ECHA)/ Food Safety Authority (EFSA) Endocrine Disruptor Guidance (2018). Toxicological data related...

Exposure of pregnant rats to some phthalates during the masculinization programming window (MPW) can lower fetal testis testosterone production and adversely affect development male reproductive tract. Some effects in are androgen-dependent, while others also occur mice without production. An adverse outcome pathway (AOP) network has been proposed for these developmental that includes both androgen-dependent androgen-independent pathways, latter which a short list putative molecular...

Use of cannabidiol (CBD) in humans has increased considerably recent years. While currently available studies suggest that CBD is relatively safe for human consumption, data from publicly on conducted according to modern testing guidelines are lacking. In the current study, potential toxicity following repeated oral exposure hemp-derived isolate was evaluated male and female Sprague Dawley rats. No adverse treatment-related effects were observed administration via gavage 14 90 days at...

HFPO-DA (ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate; CASRN 62037-80-3) is a component of the GenX technology platform used as polymerization aid in manufacture some types fluoropolymers. The liver primary target toxicity for rodents and previous examination hepatic transcriptomic responses mice following oral exposure to 90 days showed induction peroxisome proliferator-activated receptor signaling pathways, predominantly by PPARα, well increased gene expression both...

Traditional approaches for quantitatively characterizing uncertainty in risk assessment require adaptation to accommodate increased reliance on observational (vs. experimental) studies developing toxicity values. Herein, a case study with PFOA and PFOS vaccine response explores qualitative and-where possible-quantitative assessments of at each step the value development process when using data, including review appraisal individual studies, candidate selection, dose-response modeling,...

Abstract Recent in vitro transcriptomic analyses for short-chain per- and polyfluoroalkyl substances (PFAS) HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate) added to the weight of evidence supporting peroxisome proliferator-activated receptor alpha (PPARα) activator-induced hepatocarcinogenesis mode action (MOA) HFPO-DA-mediated liver effects rodents. Importantly, PPARα-mediated key events (KEs) including hepatocellular hypertrophy proliferation that have been shown...

Abstract Background Some per‐ and poly‐fluoroalkyl substances (PFAS) cause neonatal mortality lower birth weight in rodents. We constructed an Adverse Outcome Pathway (AOP) network for rodents, comprising three putative AOPs. then assessed strengths of the evidence AOPs applicability to PFAS. Finally, we considered relevance this AOP human health. Methods Literature searches targeted PFAS, peroxisome proliferator‐activated receptor (PPAR) agonists, other nuclear receptors, relevant tissues,...

Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate (HFPO-DA) is a short chain member of per- and polyfluoroalkyl substances (PFAS). To better understand the relevance histopathological effects seen in livers mice exposed to HFPO-DA for human health risk assessment, were summarized from hematoxylin eosin (H&E)-stained sections several repeat-dose toxicity studies mice. Findings across revealed changes consistent with peroxisomal proliferation, whereas two reports steatosis...

Abstract Like many per- or polyfluorinated alkyl substances (PFAS), toxicity studies with HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate), a short-chain PFAS used in the manufacture of some types fluorinated polymers, indicate that liver is primary target rodents following oral exposure. Although current weight evidence supports PPARα mode action (MOA) for effects HFPO-DA-exposed mice, alternate MOAs have also been hypothesized including PPARγ cytotoxicity. To...

Endocrine disrupting compounds (EDCs) enter aquatic habitats from a variety of anthropogenic sources and can mimic, block, or modulate the synthesis natural hormones. EDCs affect both reproductive non-reproductive behaviors because hormones mediate responses associated with aggression fear. We examined effects two on risk-taking in guppies (Poecilia reticulata). quantified terms propensity to forage risky location tendency join groups presence predator. found that male female responded...

Abstract HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoate) is a short-chain polyfluorinated alkyl substance (PFAS) used in the manufacture of some types fluorinated polymers. Like many PFAS, toxicity studies with indicate liver primary target rodents following oral exposure. Due to structural diversity mode action (MOA) can differ between PFAS for same tissue. There significant evidence involvement peroxisome proliferator-activated receptor alpha (PPARα) activation...

Nonalcoholic fatty liver disease (NAFLD) is the most common disease; however, progression to nonalcoholic steatohepatitis (NASH) associated with adverse outcomes. CYP2B metabolizes multiple xeno- and endobiotics, male Cyp2b-null mice are diet-induced obese (DIO) increased NAFLD. However, DIO study was not performed long enough assess NASH. Therefore, role of Cyp2b in from NAFLD NASH, we treated wildtype (WT) a normal diet (ND) or choline-deficient, L-amino acid-defined high fat (CDAHFD) for...

Multiple factors in addition to over consumption lead obesity and non-alcoholic fatty liver disease (NAFLD) the United States worldwide. CYP2B6 is only human detoxification CYP whose loss associated with obesity, Cyp2b-null mice show greater diet-induced increased steatosis than wildtype mice. However, a putative mechanism has not been determined. LC-MS/MS revealed that metabolizes PUFAs, preference for metabolism of ALA 9-HOTrE lesser extent 13-HOTrE PUFAs at 9- 13-positions. To further...

Increases in traditional serum lipid profiles are associated with obesity, cancer, and cardiovascular disease. Recent lipidomic analysis has indicated changes lipidome profiles, especially regard to specific phosphatidylcholines, obesity. However, little work evaluated murine hepatic liver nor compared these across age, high-fat diet, or genotypes, this case the lack of Cyp2b enzymes. In study, effects age (9 months old), diet (4.5 loss three primarily xeno- endobiotic metabolizing...

Abstract Recent in vitro transcriptomic analyses for the short-chain polyfluoroalkyl substance, HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate), support conclusions from vivo data that HFPO-DA-mediated liver effects mice are part of early key events peroxisome proliferator-activated receptor alpha (PPARα) activator-induced rodent hepatocarcinogenesis mode action (MOA). Transcriptomic responses HFPO-DA-treated hepatocytes have high concordance with those treated a...

Cytochrome P450 2B6 (CYP2B6) is a human enzyme important in chemical detoxification, steroid and fatty acid metabolism that primarily hepatic. Therefore, induction or inhibition of CYP2B6 may perturb endo- xenobiotic cause adverse reactions. Recent research indicates mice lacking Cyp2b enzymes are obese with liver steatosis [1] (Heintz et al., J Nutr Biochem, 70:125–137, 2019). Current work underway to determine the role obesity metabolism, fluorescent assays were used IC50s multiple...

1,4-Dioxane is a volatile organic compound with industrial and commercial applications as solvent in the manufacture of other chemicals. has been demonstrated to induce liver tumors chronic rodent bioassays conducted at very high doses. The available evidence for 1,4-dioxane-induced rodents aligns threshold-dependent mode action (MOA), underlying mechanism being less clear mouse than rats. To gain better understanding molecular mechanisms related tumor development mice orally exposed...