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PURPOSE: Over 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function. METHODS: We created an Adam19 knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Mouse body composition was assessed using dual-energy X-ray absorptiometry. Mouse lung function was measured using flexiVent. RESULTS: Contrary to prior publications, the KO was not neonatal lethal. KO mice had lower body weight and shorter tibial length than wild-type (WT) mice. Their body composition revealed lower soft weight, fat weight, and bone mineral content. Adam19 KO had decreased baseline respiratory system elastance, minute work of breathing, tissue damping, tissue elastance, and forced expiratory flow at 50% forced vital capacity but higher FEV0.1 and FVC. Adam19 KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. Adam19 KO also exhibited attenuated neutrophil extravasation into the airway after LPS administration compared to WT. RNA-Seq analysis of KO and WT lungs identified several differentially expressed genes (Cd300lg, Kpna2, and Pttg1) implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways. CONCLUSION: Our murine findings support a causal role of ADAM19, implicated in human GWAS, in regulating pulmonary function.
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Respiratory diseases are one of the leading causes of death and disability around the world. Mice are commonly used as models of human respiratory disease. Phenotypic analysis of mice with spontaneous, congenital, inherited, or treatment-related respiratory tract abnormalities requires investigators to discriminate normal anatomic features of the respiratory system from those that have been altered by disease. Many publications describe individual aspects of normal respiratory tract development, primarily focusing on morphogenesis of the trachea and lung. However, a single reference providing detailed low- and high-magnification, high-resolution images of routine hematoxylin and eosin (H&E)-stained sections depicting all major structures of the entire developing murine respiratory system does not exist. The purpose of this atlas is to correct this deficiency by establishing one concise reference of high-resolution color photomicrographs from whole-slide scans of H&E-stained tissue sections. The atlas has detailed descriptions and well-annotated images of the developing mouse upper and lower respiratory tracts emphasizing embryonic days (E) 9.0 to 18.5 and major early postnatal events. The selected images illustrate the main structures and events at key developmental stages and thus should help investigators both confirm the chronological age of mouse embryos and distinguish normal morphology as well as structural (cellular and organ) abnormalities.
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Sistema Respiratório , Animais , Camundongos , Sistema Respiratório/embriologia , Sistema Respiratório/anatomia & histologia , Sistema Respiratório/crescimento & desenvolvimento , Feminino , Atlas como Assunto , Gravidez , Pulmão/embriologia , Pulmão/patologiaRESUMO
New Approach Methodologies (NAMs) are being widely used to reduce, refine, and replace, animal use in studying toxicology. For respiratory toxicology, this includes in silico and in vitro alternatives using air:liquid interface (ALI) exposures to replace traditional in vivo inhalation studies. In previous studies using 1,3-dichloropropene (1,3-DCP), a 5-day 4 h repeat exposures of MucilAir™ nasal cell culture models caused, dose-dependent cytotoxicity, depletion of GSH, changes in differential gene expression and histopathological transitions in cellular morphology from pseudostratified columnar epithelium to squamous epithelium. In this report we attempted to extend these studies using 15-day 1,3-DCP 4 h exposures to using MucilAir™ nasal cultures as outlined by an US EPA recent task order (US EPA 2023). For the 15-day repeat exposure, there were severe histopathologic changes in the MucilAir™ nasal mock-treatment (air-only) VITROCELL® chamber controls compared to incubator controls preventing any further analysis. The histopathological transitions in cellular morphology from pseudostratified columnar epithelium to squamous epithelium observed in the air only control in this study and previously with 1,3-DCP in MucilAir™ nasal cultures is also a hallmark of chemically induced cytotoxic responses in vivo in the respiratory tract. Histopathology assessments of 3D respiratory tract models used in ALI exposures can provide the linkage between in vitro to in vivo outcomes as part of the validation efforts of ALI use in regulatory toxicology. This report indicates that importance of histopathological assessments of incubator and mock-treatment (air-only) controls from each ALI exposure experiment along with exposed cell based model.
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Sucralose, a sugar substitute first approved for use in 1991, is a non-caloric sweetener regulated globally as a food additive. Based on numerous experimental animal studies (dating to the 1980s) and human epidemiology studies, international health agencies have determined that sucralose is safe when consumed as intended. A single lifetime rodent carcinogenicity bioassay conducted by the Ramazzini Institute (RI) reported that mice fed diets containing sucralose develop hematopoietic neoplasia, but controversy continues regarding the validity and relevance of these data for predicting health effects in humans. The present paper addresses the controversy by providing the perspective of experienced pathologists on sucralose-related animal toxicity and carcinogenicity data generally, and the RI carcinogenicity bioassay findings specifically, using results from publicly available papers and international regulatory authority decisions. In the authors' view, flaws in the design, methodology, data evaluation, and reporting of the RI carcinogenicity bioassay for sucralose diminish the value of the data as evidence that this agent represents a carcinogenic hazard to humans. This limitation will remain until the RI bioassay is repeated under Good Laboratory Practices and the design, data, and accuracy of the pathology diagnoses and interpretations are reviewed by qualified pathologists with experience in evaluating potential chemically-induced carcinogenic hazards.
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Testes de Carcinogenicidade , Sacarose , Animais , Sacarose/análogos & derivados , Sacarose/toxicidade , Camundongos , Humanos , Projetos de Pesquisa , Bioensaio/métodos , Edulcorantes/toxicidade , Ratos , Carcinógenos/toxicidade , PatologistasRESUMO
The evaluation of changes in the immune system serves to determine the efficacy and potential immunotoxicologic effects of new products under development. Toxicologic pathologists play critical roles in identifying immune system changes that drive the immunosafety determination. Standard pathology evaluations of therapies and chemicals remain similar; however, biopharmaceutical therapies have moved from simply affecting the immune system to being specifically developed to modify the immune system, which can impact interpretation. Recent explosive growth in immunomodulatory therapies presents a challenge to the toxicologic pathologist, toxicologist, and regulatory reviewer in terms of evaluating the clinical relevance and potential adversity of immune system changes. Beyond the recognition of such changes, there is an increasing expectation to evaluate, describe, and interpret how therapies affect complex immune system pathways for both immunomodulatory therapies and non-immunomodulatory drugs with off-target immunotoxic effects. In this opinion piece, considerations regarding immune system evaluation, the current landscape of immunomodulatory therapies, a brief description of immunotoxicologic (and immunopathologic) endpoints, the importance of integrating such immunosafety data, and relevance to adversity determination are discussed. Importantly, we describe how the current paradigm of determining adversity for immune system changes may be challenging or insufficient and propose a harmonized and flexible approach for assessing adversity.
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N-butylbenzenesulfonamide (NBBS) is a high-production volume plasticizer that is an emerging contaminant of concern for environmental and human health. To understand the risks and health effects of exposure to NBBS, studies were conducted in adult-exposed mice and developmentally exposed rats to evaluate the potential for NBBS to modulate the immune system. Beginning between 8 and 9 weeks of age, dosed feed containing NBBS at concentrations of 0, 313, 625, 1250, 2500, and 5000 ppm was continuously provided to B6C3F1/N female mice for 28 days. Dosed feed was also continuously provided to time-mated Harlan Sprague Dawley (Sprague Dawley SD) rats at concentrations of 0-, 250-, 500-, and 1000-ppm NBBS from gestation day 6 to postnatal day 28 and in F1 rats until 11-14 weeks of age. Functional assessments of innate, humoral, and cell-mediated immunity were conducted in adult female mice and F1 rats following exposure to NBBS. In female mice, NBBS treatment suppressed the antibody-forming cell (AFC) response to SRBC with small increases in T-cell responses and natural killer (NK)-cell activity. In developmentally exposed rats, NBBS treatment-related immune effects were sex dependent. A positive trend in NK-cell activity occurred in male F1 rats while a negative trend occurred in female F1 rats. The AFC response to SRBC was decreased in female F1 rats but not in male F1 rats. These data provide evidence that oral exposure to NBBS has the potential to produce immunomodulatory effects on both innate and adaptive immune responses, and these effects appear to have some dependence on species, sex, and period of exposure (developmental vs adult).
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Imunidade , Sulfonamidas , Humanos , Ratos , Camundongos , Animais , Masculino , Feminino , Ratos Sprague-Dawley , Sulfonamidas/toxicidade , Camundongos EndogâmicosRESUMO
Aspartame, an artificial sweetener commonly used as a sugar substitute, is currently authorized for use in more than 100 countries. Hundreds of studies, conducted in various countries dating back to the 1970s, have shown that aspartame is safe at real-world exposure levels. Furthermore, multiple human epidemiology studies have provided no indication that consumption of aspartame induces cancer. Given the continued controversy surrounding the Ramazzini Institute's (RI) studies suggesting that aspartame is a carcinogenic hazard in rodents and evaluation by the International Agency for Research on Cancer, this report aims to provide the perspective of experienced pathologists on publicly available pathology data regarding purported proliferative lesions in liver, lung, lymphoid organs, and mammary gland as well as their implications for human risk assessment as reported for three lifetime rodent carcinogenicity bioassays of aspartame conducted at the RI. In the authors' view, flaws in the design, methodology and reporting of the RI aspartame studies limit the utility of the data sets as evidence that this agent represents a carcinogenic hazard. Therefore, all three RI studies, and particularly the accuracy of their pathology diagnoses and interpretations, should be rigorously reviewed by qualified and experienced veterinary toxicologic pathologists in assessing aspartame's carcinogenic risk.
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Aspartame , Neoplasias , Animais , Feminino , Gravidez , Humanos , Roedores , Patologistas , Edulcorantes , Carcinógenos , Carcinogênese , Bioensaio/métodosRESUMO
The use of the mouse as a model organism is common in translational research. This mouse-human similarity holds true for placental development as well. Proper formation of the placenta is vital for development and survival of the maturing embryo. Placentation involves sequential steps with both embryonic and maternal cell lineages playing important roles. The first step in placental development is formation of the blastocyst wall (approximate embryonic days [E] 3.0-3.5). After implantation (â¼E4.5), extraembryonic endoderm progressively lines the inner surface of the blastocyst wall (â¼E4.5-5.0), forming the yolk sac that provides histiotrophic support to the embryo; subsequently, formation of the umbilical vessels (â¼E8.5) supports transition to the chorioallantoic placenta and hemotrophic nutrition. The fully mature ("definitive") placenta is established by â¼E12.5. Abnormal placental development often leads to embryonic mortality, with the timing of death depending on when placental insufficiency takes place and which cells are involved. This comprehensive macroscopic and microscopic atlas highlights the key features of normal and abnormal mouse placental development from E4.5 to E18.5. This in-depth overview of a transient (and thus seldom-analyzed) developmental tissue should serve as a useful reference to aid researchers in identifying and describing mouse placental changes in engineered, induced, and spontaneous disease models.
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Placenta , Placentação , Animais , Linhagem da Célula , Implantação do Embrião , Embrião de Mamíferos , Feminino , Camundongos , GravidezRESUMO
Animal models are commonly used to investigate the developmental basis of human birth defects. Such models may be used for safety assessment studies designed to reveal xenobiotic-related alterations in juvenile animals, or to investigate gene function or generate models of human disease, as with transgenics. Therefore, the evaluation of rodent embryos and placentas can be used to provide insight into various postnatal abnormalities such as structural or cellular abnormalities and early death. Depending on the defect, pups may be born dead, survive for only a short period of time, survive but with poor growth, or survive and be clinically normal. Mice are generally used to generate genetic alterations that can help in identifying genes involved in embryogenesis. Rats are more commonly used for toxicology studies. This article aims to share information on the importance of, and strategies for, mouse embryo, placenta, and metrial gland evaluations. Information on early postnatal development is also provided as well as select examples of developmental information on organ systems needed for postnatal evaluations. A list of additional studies that can aid in the evaluation of prenatal and postnatal phenotypes is also provided.
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Glândula Metrial , Animais , Embrião de Mamíferos , Desenvolvimento Embrionário , Feminino , Camundongos , Placenta , Gravidez , RatosRESUMO
The 2021 annual National Toxicology Program (NTP) Satellite Symposium, entitled "Pathology Potpourri," was the 20th anniversary of the symposia and held virtually on June 25th, in advance of the Society of Toxicologic Pathology's 40th annual meeting. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks along with select images that were presented to the audience for voting and discussion. Various lesions and topics covered during the symposium included differentiation of canine oligodendroglioma, astrocytoma, and undefined glioma with presentation of the National Cancer Institute's updated diagnostic terminology for canine glioma; differentiation of polycystic kidney, dilated tubules and cystic tubules with a discussion of human polycystic kidney disease; a review of various rodent nervous system background lesions in control animals from NTP studies with a focus on incidence rates and potential rat strain differences; vehicle/excipient-related renal lesions in cynomolgus monkeys with a discussion on the various cyclodextrins and their bioavailability, toxicity, and tumorigenicity; examples of rodent endometrial tumors including intestinal differentiation in an endometrial adenocarcinoma that has not previously been reported in rats; a review of various rodent adrenal cortex lesions including those that represented diagnostic challenges with multiple processes such as vacuolation, degeneration, necrosis, hyperplasia, and hypertrophy; and finally, a discussion of diagnostic criteria for uterine adenomyosis, atypical hyperplasia, and adenocarcinoma in the rat.
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Adenocarcinoma , Neoplasias do Endométrio , Toxicologia , Animais , Cães , Feminino , Hiperplasia , Necrose , RatosRESUMO
Toxicologic Pathology is the official journal of the Society of Toxicologic Pathology (STP), the British Society of Toxicological Pathology, and the European STP (ESTP). Toxicologic Pathology publishes articles related to topics in various aspects of toxicologic pathology such as anatomic pathology, clinical pathology, experimental pathology, and biomarker research. Publications include society-endorsed Best Practice/Position and Points to Consider publications and ESTP Expert Workshop articles that are relevant to toxicologic pathology and scientific regulatory processes, Opinion articles under the banner of the STP Toxicologic Pathology Forum, Original Articles, Review Articles (unsolicited/contributed, mini, and invited), Brief Communications, Letters to the Editor, Meeting Reports, and Book Reviews. This article provides details on the various publication categories in Toxicologic Pathology and will serve as a reference for authors and readers.
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Patologia Clínica , Patologia , Publicações/classificação , HumanosRESUMO
A host of novel renal biomarkers have been developed over the past few decades which have enhanced monitoring of renal disease and drug-induced kidney injury in both preclinical studies and in humans. Since chronic kidney disease (CKD) and acute kidney injury (AKI) share similar underlying mechanisms and the tubulointerstitial compartment has a functional role in the progression of CKD, urinary biomarkers of AKI may provide predictive information in chronic renal disease. Numerous studies have explored whether the recent AKI biomarkers could improve upon the standard clinical biomarkers, estimated glomerular filtration rate (eGFR), and urinary albumin to creatinine ratio, for predicting outcomes in CKD patients. This review is an introduction to alternative assays that can be utilized in chronic (>3 months duration) nonclinical safety studies to provide information on renal dysfunction and to demonstrate specific situations where these assays could be utilized in nonclinical drug development. Novel biomarkers such as symmetrical dimethyl arginine, dickkopf homolog 3, and cystatin C predict chronic renal injury in animals, act as surrogates for GFR, and may predict changes in GFR in patients over time, ultimately providing a bridge from preclinical to clinical renal monitoring.
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Injúria Renal Aguda , Insuficiência Renal Crônica , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Biomarcadores , Creatinina , Taxa de Filtração Glomerular , Humanos , Rim , Insuficiência Renal Crônica/induzido quimicamenteRESUMO
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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Resveratrol is a naturally occurring polyphenol that is being investigated to treat and prevent various diseases, both experimentally and in the clinic. Despite increased use and interest in resveratrol due to its immunomodulatory properties, there is a lack of studies evaluating potential toxicities, particularly immunotoxicity, associated with resveratrol use. A previous 2-week study found decreasing thymus weight in male B6C3F1/N mice with increasing exposure to trans-resveratrol. This study is a follow-up on those findings by evaluating immune function. Male adult B6C3F1/N mice were given trans-resveratrol (0, 156, 312, 625, 1250, 2500 mg/kg/day) via oral gavage for 28 days and functional immune tests and histopathology were evaluated. There were no treatment-related effects on body weight during the study. Humoral, cell-mediated, and innate immune function were not altered after 28 days of trans-resveratrol treatment. There were also no changes in organ weight or microscopic alterations in immune organs. Overall, under the conditions of this study, there was no evidence of immunotoxicity or improvements in immune function associated with oral exposure to trans-resveratrol in male mice. Importantly, the immunomodulatory benefits of resveratrol may require a prerequisite level of inflammatory activity and may not be observable in healthy individuals.
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Suplementos Nutricionais/efeitos adversos , Sistema Imunitário/efeitos dos fármacos , Fatores Imunológicos/efeitos adversos , Resveratrol/efeitos adversos , Timo/patologia , Administração Oral , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Imunidade Celular , Imunidade Humoral , Imunidade Inata , Fatores Imunológicos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Resveratrol/administração & dosagem , Timo/efeitos dos fármacosRESUMO
Exposure to ambient ozone has been associated with increased human mortality. Ozone exposure can introduce oxygen-containing functional groups in particulate matter (PM) effecting a greater capacity of the particle for metal complexation and inflammatory effect. We tested the postulate that (1) a fulvic acid-like substance can be produced through a reaction of a carbonaceous particle with high concentrations of ozone and (2) such a fulvic acid-like substance included in the PM can initiate inflammatory effects following exposure of respiratory epithelial (BEAS-2B) cells and an animal model (male Wistar Kyoto rats). Carbon black (CB) was exposed for 72 hours to either filtered air (CB-Air) or approximately 100 ppm ozone (CB-O3). Carbon black exposure to high levels of ozone produced water-soluble, fluorescent organic material. Iron import by BEAS-2B cells at 4 and 24 hours was not induced by incubations with CB-Air but was increased following coexposures of CB-O3 with ferric ammonium citrate. In contrast to CB-Air, exposure of BEAS-2B cells and rats to CB-O3 for 24 hours increased expression of pro-inflammatory cytokines and lung injury, respectively. It is concluded that inflammatory effects of carbonaceous particles on cells can potentially result from (1) an inclusion of a fulvic acid-like substance after reaction with ozone and (2) changes in iron homeostasis following such exposure.
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Poluentes Atmosféricos , Ozônio , Poluentes Atmosféricos/toxicidade , Animais , Benzopiranos , Humanos , Masculino , Ozônio/toxicidade , Material Particulado/toxicidade , Ratos , Fuligem/toxicidadeRESUMO
The National Toxicology Program (NTP) now uses an extended longitudinal sectioning protocol for the uterus to better evaluate female rodent reproductive tract toxicity for all developmental and reproductive toxicology and 2-year toxicity and carcinogenicity bioassays. The previous protocol for toxicity/carcinogenicity studies involved 1 cross section midway through each uterine horn and collection of uterine cervix and vagina only if gross lesions were present. Here we compare the histological findings of the original cross sections with the additional longitudinal sections of residual uterine tissues of 7 chronic NTP rat bioassays. The goal of this study was to determine whether there might be any advantages to examining additional uterine tissue. The longitudinal protocol allowed for 10 to 20 times more uterine tissue for evaluation. Results indicate that the potential advantages of a more complete evaluation of female reproductive tract tissue include increased detection of reproductive targets, increased detection of neoplastic and nonneoplastic lesions, improved detection of tissue origin of neoplasms, less reliance on gross identification of lesions, improved accuracy in the application of severity grades, and increased detection of preneoplastic or subtle lesions.
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Neoplasias , Reprodução , Animais , Bioensaio , Testes de Carcinogenicidade , Feminino , Técnicas Histológicas , Ratos , ÚteroRESUMO
Predatory journals-also called fraudulent, deceptive, or pseudo-journals-are publications that claim to be legitimate scholarly journals but misrepresent their publishing practices. Some common forms of predatory publishing practices include falsely claiming to provide peer review, hiding information about article processing charges, misrepresenting members of the journal's editorial board, and other violations of copyright or scholarly ethics. Because of their increasing prevalence, this article aims to provide helpful information for authors on how to identify and avoid predatory journals.
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Publicações Periódicas como Assunto , Humanos , Revisão da Pesquisa por Pares , EditoraçãoRESUMO
BACKGROUND: Perfluorooctanoic acid (PFOA) is a poly- and perfluoroalkyl substance (PFAS) associated with adverse pregnancy outcomes in mice and humans, but little is known regarding one of its replacements, hexafluoropropylene oxide dimer acid (HFPO-DA, referred to here as GenX), both of which have been reported as contaminants in drinking water. OBJECTIVES: We compared the toxicity of PFOA and GenX in pregnant mice and their developing embryo-placenta units, with a specific focus on the placenta as a hypothesized target. METHODS: Pregnant CD-1 mice were exposed daily to PFOA (0, 1, or 5mg/kg) or GenX (0, 2, or 10mg/kg) via oral gavage from embryonic day (E) 1.5 to 11.5 or 17.5 to evaluate exposure effects on the dam and embryo-placenta unit. Gestational weight gain (GWG), maternal clinical chemistry, maternal liver histopathology, placental histopathology, embryo weight, placental weight, internal chemical dosimetry, and placental thyroid hormone levels were determined. RESULTS: Exposure to GenX or PFOA resulted in increased GWG, with increase in weight most prominent and of shortest latency with 10mg/kg/d GenX exposure. Embryo weight was significantly lower after exposure to 5mg/kg/d PFOA (9.4% decrease relative to controls). Effect sizes were similar for higher doses (5mg/kg/d PFOA and 10mg/kg/d GenX) and lower doses (1mg/kg/d PFOA and 2mg/kg/d GenX), including higher maternal liver weights, changes in liver histopathology, higher placental weights and embryo-placenta weight ratios, and greater incidence of placental abnormalities relative to controls. Histopathological features in placentas suggested that PFOA and GenX may exhibit divergent mechanisms of toxicity in the embryo-placenta unit, whereas PFOA- and GenX-exposed livers shared a similar constellation of adverse pathological features. CONCLUSIONS: Gestational exposure to GenX recapitulated many documented effects of PFOA in CD-1 mice, regardless of its much shorter reported half-life; however, adverse effects toward the placenta appear to have compound-specific signatures. https://doi.org/10.1289/EHP6233.