PFAS Modulate Osmotic Signaling Independent of Gravimetric Changes in the Rat Uterus DOI Creative Commons
Aaron Dixon,

Evelyn G. Rowan,

Allison N. Yackley

et al.

Toxics, Journal Year: 2024, Volume and Issue: 12(3), P. 170 - 170

Published: Feb. 23, 2024

Various PFAS have been identified as potential endocrine-disrupting chemicals due to estrogen receptor activation, impacts on puberty timing, or hormonally sensitive endpoints in fish. This study screened multiple the rat uterotrophic assay determine estrogenic effects uterus with exposure. also explored PFAS-dependent uterine signaling an osmotic stress mRNA gene expression array. Briefly, Sprague–Dawley rats (26–39 days old) were ovariectomized, and tissue was allowed regress for a 3-week period of recovery. Animals then exposed daily via oral gavage 4 days, weight determined. In contrast positive control estrogens, tested (4:2, 6:2, 8:2FTOH; perfluorooctanesulfonamide (PFOSA), perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), perfluorooctane (PFOS), nafion byproduct 2 (NBP2), 1H,1H,8H,8H-perfluorooctane-1,8-diol (FC8-diol) 1H,1H,10H,10H-perfluorodecane-1,10-diol (FC10-diol)) caused no significant changes weight. Hormonally active compounds can act carcinogens, because earlier rodent work has demonstrated that chronic PFOA exposure is associated increased risk cancer, RT-qPCR significantly upregulated genes across array, PFOSA being compound most similar reference estrogens (estradiol benzoate ethinyl estradiol) its pattern. Also, all PFAS, pathway analysis revealed paxillin pathway, important tumor suppressor SHP-2 signaling, These results demonstrate vitro screens fish may show different responses from direct mammalian assessed assay. builds out new mechanisms contribute understanding carcinogenic seen after

Language: Английский

Exploring maternal and developmental toxicity of perfluoroalkyl ether acids PFO4DA and PFO5DoA using hepatic transcriptomics and serum metabolomics DOI
Thomas W. Jackson,

Christy Lambright,

Nicola Evans

et al.

The Science of The Total Environment, Journal Year: 2024, Volume and Issue: 953, P. 175978 - 175978

Published: Sept. 1, 2024

Language: Английский

Citations

6
Dose additive maternal and offspring effects of oral maternal exposure to a mixture of three PFAS (HFPO-DA, NBP2, PFOS) during pregnancy in the Sprague-Dawley rat DOI
Justin M. Conley,

Christy Lambright,

Nicola Evans

et al.

The Science of The Total Environment, Journal Year: 2023, Volume and Issue: 892, P. 164609 - 164609

Published: June 3, 2023

Language: Английский

Citations

13
Unveiling the intricate connection between per- and polyfluoroalkyl substances and prostate hyperplasia DOI
Tian Wang, Jijingru Yang,

Yapeng Han

et al.

The Science of The Total Environment, Journal Year: 2024, Volume and Issue: 932, P. 173085 - 173085

Published: May 8, 2024

Language: Английский

Citations

4
Long-chain perfluoroalkylether carboxylic acids PFO5DoA and PFO4DA alter glucose, bile acid, and thyroid hormone homeostasis in fetal rats from 5-day maternal oral exposure DOI
Justin M. Conley,

Christy Lambright,

Nicola Evans

et al.

Environmental Research, Journal Year: 2024, Volume and Issue: unknown, P. 120210 - 120210

Published: Oct. 1, 2024

Language: Английский

Citations

4
Cumulative Risk Evaluation of Phthalates Under TSCA DOI Open Access
Devon Payne-Sturges,

Sulakkhana De Saram,

Deborah A. Cory‐Slechta

et al.

Environmental Science & Technology, Journal Year: 2023, Volume and Issue: 57(16), P. 6403 - 6414

Published: April 12, 2023

The U.S. Environmental Protection Agency (EPA) is currently conducting separate Toxic Substances Control Act (TSCA) risk evaluations for seven phthalates: dibutyl phthalate (DBP), butyl benzyl (BBP), di(2-ethylhexyl) (DEHP), diisobutyl (DIBP), dicyclohexyl (DCHP), di-isodecyl (DIDP), and diisononyl (DINP). Phthalates are highly abundant plastic additives used primarily to soften materials make them flexible, biomonitoring shows widespread human exposure a mixture of phthalates. Evidence supports biological additivity exposures, including the enhancement toxicity affecting common targets. Risk estimates based on individual may not be protective public health. Thus, cumulative approach warranted. While EPA initially did signal that it would incorporate assessment (CRA) as part its current evaluation phthalates, agency recently announced reconsidering if CRA phthalates appropriate. Based our review existing chemical mixtures guidance, TSCA scoping documents pertinent peer-reviewed literature, we delineate can easily implement strategy using inform chemicals upon integrative physiology adverse health outcome algorithm identifying grouping relevant nonchemical stressors. We recommend adjustments how hazard indices (HIs) or margins (MOEs) interpreted determining "unreasonable risk" under TSCA.

Language: Английский

Citations

10
A putative adverse outcome network for neonatal mortality and lower birth weight in rodents: Applicability to per‐ and polyfluoroalkyl substances and relevance to human health DOI Creative Commons
John M. Rogers, Melissa M. Heintz, Chad M. Thompson

et al.

Birth Defects Research, Journal Year: 2023, Volume and Issue: 115(11), P. 1011 - 1062

Published: May 23, 2023

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, developmental targets. used reviews established biology described results studies with prenatal PFAS exposure that survival. Molecular initiating events (MIEs) key (KEs) were proposed KE relationships (KERs), assessed. Results Neonatal has been observed rodents following gestational most longer chain studied, often coincident weight. In 1, PPARα activation PPARγ or downregulation are MIEs; placental insufficiency, fetal nutrient restriction, hepatic glycogen deficit, hypoglycemia KEs leading 2, constitutive androstane (CAR) pregnane X (PXR) upregulates Phase II metabolism, lowering maternal circulating thyroid hormones. 3, disrupted pulmonary surfactant function airway collapse from respiratory failure. Conclusions It is likely different components will apply largely determined by which receptors they activate. The MIEs can occur humans, but differences PPAR structure function, timeline liver lung development, suggest humans may be less susceptible network. This elucidates knowledge gaps research needed better understand toxicity

Language: Английский

Citations

10
Comparative study on gene expression profiles in the liver of male neonatal mice prenatally exposed to PFOA and its alternative HFPO-DA. DOI

Wataru Murase,

Atsuhito Kubota,

Ryo Hakota

et al.

Toxicology, Journal Year: 2025, Volume and Issue: unknown, P. 154048 - 154048

Published: Jan. 1, 2025

Language: Английский

Citations

0
Extracellular Vesicle (EV) Mechanisms of Toxicity for Per and Polyfluoroalkyl Substances: Comparing Transcriptomic Points of Departure Across Global Versus EV Regulatory Gene Sets DOI Open Access
Celeste K. Carberry, Hadley J. Hartwell, Cynthia V. Rider

et al.

Environmental and Molecular Mutagenesis, Journal Year: 2025, Volume and Issue: unknown

Published: March 19, 2025

ABSTRACT Extracellular vesicles (EVs) are emitted from cells throughout the body and serve as signaling molecules that mediate disease development. Emerging evidence suggests per‐ polyfluoroalkyl substances (PFAS) impact EV release content, influencing liver toxicity. Still, upstream regulators of changes affected by PFAS exposure remain unclear. This study evaluated hypothesis exposures, individually in a mixture, alter expression genes involved regulation at concentrations comparable to global biological response mechanisms. HepG2 were treated multiple with individual PFOS, PFOA, or PFHxA, addition an equimolar mixture. Gene data analyzed using three pipelines for concentration‐response modeling, results compared against empirically derived datasets. Final benchmark concentration (BMC) modeling was conducted via Laplace model averaging BMDExpress (v3). BMCs gene level across different sets, including Ontology (GO) annotations well custom set. To determine relative contributions potency factors calculated resulting PFOS standard reference chemical. Results demonstrated exposures altered regulation, particularly overlapping endoplasmic reticulum stress. regulatory occurred similar set alterations, supporting concurrent role EVs toxicology. application transcriptomics‐based BMC further validates its utility capturing both established novel pathways

Language: Английский

Citations

0
The use of canonical dose–response models for benchmark dose analysis of continuous toxicological data DOI Creative Commons

Wout Slob,

Martine Bakker,

Bas Bokkers

et al.

Critical Reviews in Toxicology, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 25

Published: April 9, 2025

The benchmark dose (BMD) approach employs dose-response modeling to determine the associated with a small change in response relative background response. Here, we introduce conceptual framework for continuous data that is based on key risk assessment principles and requirements. Based this framework, define class of models sharing same four biologically interpretable model parameters, while exhibiting five common properties are essential from perspective: such denoted as "canonical" models. first two canonical straightforward: property 1. should predict positive values only (as measurements endpoints typically positive) 2. outcomes not depend measurement unit. Canonical 3 reflects observation toxicological related different subgroups (e.g. species, sexes, exposure durations) (at least approximately) parallel log-dose scale, which at time an implicit assumption defining fundamental concepts, extrapolation factors, potency factors (RPFs), sensitivity (RSFs). Property 4 needed enable comparisons differing maximum A fifth our view choices regarding expression, assumed distribution within-group variation, (BMR) being used be internally consistent. discuss suitable fit curves combined datasets durations). Doing so provides tool check particular analyzed. We provide review empirical evidence indicating has general validity, highly fortunate, legitimizes use RPFs assessment. then evaluate what extent approaches current BMD guidance by European Food Safety Authority (EFSA) or U.S. Environmental Protection Agency (US-EPA) comply modeling, concluding partly case. latter can have unfavorable sometimes far-reaching consequences. For instance, some recommended non-canonical result BMDs when changing unit µg mg). As another example, recently developed EFSA implements covariate analysis way cannot possibly represented any disadvantage, preclude effective development prior distributions Bayesian approach. Finally, argue concomitant but important advantage using methodology will more transparent, assessors better able understand it, high societal impact easily defended. present paper may helpful toxicologists critically follow developments level.

Language: Английский

Citations

0
Cumulative Risk Assessment as the Pathway to Public Health Protection for Behavioral Neurotoxicity DOI
Deborah A. Cory‐Slechta, Cynthia J. Downs, Marissa Sobolewski

et al.

NeuroToxicology, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Language: Английский

Citations

0