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  1. Article ; Online: Maternal and Neonatal Effects of Maternal Oral Exposure to Perfluoro-2-methoxyacetic Acid (PFMOAA) during Pregnancy and Early Lactation in the Sprague-Dawley Rat.

    Conley, Justin M / Lambright, Christy S / Evans, Nicola / Bangma, Jacqueline / Ford, Jermaine / Hill, Donna / Medlock-Kakaley, Elizabeth / Gray, L Earl

    Environmental science & technology

    2024  Volume 58, Issue 2, Page(s) 1064–1075

    Abstract: Perfluoro-2-methoxyacetic acid (PFMOAA) is a short-chain perfluoroalkyl ether carboxylic acid that has been detected at high concentrations (∼10 μg/L) in drinking water in eastern North Carolina, USA, and in human serum and breastmilk in China. Despite ... ...

    Abstract Perfluoro-2-methoxyacetic acid (PFMOAA) is a short-chain perfluoroalkyl ether carboxylic acid that has been detected at high concentrations (∼10 μg/L) in drinking water in eastern North Carolina, USA, and in human serum and breastmilk in China. Despite documented human exposure there are almost no toxicity data available to inform risk assessment of PFMOAA. Here we exposed pregnant Sprague-Dawley rats to a range of PFMOAA doses (10-450 mg/kg/d) via oral gavage from gestation day (GD) 8 to postnatal day (PND) 2 and compared results to those we previously reported for perfluorooctanoic acid (PFOA) and hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX). Newborn pups displayed reduced birthweight (≥30 mg/kg), depleted liver glycogen concentrations (all doses), hypoglycemia (≥125 mg/kg), and numerous significantly altered genes in the liver associated with fatty acid and glucose metabolism similar to gene changes produced by HFPO-DA. Pup survival was significantly reduced at ≥125 mg/kg, and at necropsy on PND2 both maternal and neonatal animals displayed increased liver weights, increased serum aspartate aminotransferase (AST), and reduced serum thyroid hormones at all doses (≥10 mg/kg). Pups also displayed highly elevated serum cholesterol at all doses. PFMOAA concentrations in serum and liver increased with maternal oral dose in both maternal and F1 animals and were similar to those we reported for PFOA but considerably higher than HFPO-DA. We calculated 10% effect levels (ED10 or EC10) and relative potency factors (RPF; PFOA = index chemical) among the three compounds based on maternal oral dose and maternal serum concentration (μM). Reduced pup liver glycogen, increased liver weights and reduced thyroid hormone levels (maternal and pup) were the most sensitive end points modeled. PFMOAA was ∼3-7-fold less potent than PFOA for most end points based on maternal serum RPFs, but slightly more potent for increased maternal and pup liver weights. PFMOAA is a maternal and developmental toxicant in the rat producing a constellation of adverse effects similar to PFOA and HFPO-DA.
    MeSH term(s) Pregnancy ; Humans ; Female ; Rats ; Animals ; Rats, Sprague-Dawley ; Liver Glycogen ; Fluorocarbons/toxicity ; Lactation ; Thyroid Hormones ; Maternal Exposure ; Caprylates ; Propionates
    Chemical Substances perfluoro-2-methoxyacetic acid ; ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate ; Liver Glycogen ; perfluorooctanoic acid (947VD76D3L) ; Fluorocarbons ; Thyroid Hormones ; Caprylates ; Propionates
    Language English
    Publishing date 2024-01-01
    Publishing country United States
    Document type Journal Article
    ISSN 1520-5851
    ISSN (online) 1520-5851
    DOI 10.1021/acs.est.3c08559
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: In vitro activity of a panel of per- and polyfluoroalkyl substances (PFAS), fatty acids, and pharmaceuticals in peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, and estrogen receptor assays.

    Evans, Nicola / Conley, Justin M / Cardon, Mary / Hartig, Phillip / Medlock-Kakaley, Elizabeth / Gray, L Earl

    Toxicology and applied pharmacology

    2022  Volume 449, Page(s) 116136

    Abstract: Data demonstrate numerous per- and polyfluoroalkyl substances (PFAS) activate peroxisome proliferator-activated receptor alpha (PPARα), however, additional work is needed to characterize PFAS activity on PPAR gamma (PPARγ) and other nuclear receptors. We ...

    Abstract Data demonstrate numerous per- and polyfluoroalkyl substances (PFAS) activate peroxisome proliferator-activated receptor alpha (PPARα), however, additional work is needed to characterize PFAS activity on PPAR gamma (PPARγ) and other nuclear receptors. We utilized in vitro assays with either human or rat PPARα or PPARγ ligand binding domains to evaluate 16 PFAS (HFPO-DA, HFPO-DA-AS, NBP2, PFMOAA, PFHxA, PFOA, PFNA, PFDA, PFOS, PFBS, PFHxS, PFOSA, EtPFOSA, and 4:2, 6:2 and 8:2 FTOH), 3 endogenous fatty acids (oleic, linoleic, and octanoic), and 3 pharmaceuticals (WY14643, clofibrate, and the metabolite clofibric acid). We also tested chemicals for human estrogen receptor (hER) transcriptional activation. Nearly all compounds activated both PPARα and PPARγ in both human and rat ligand binding domain assays, except for the FTOH compounds and PFOSA. Receptor activation and relative potencies were evaluated based on effect concentration 20% (EC
    MeSH term(s) Animals ; Fatty Acids ; Female ; Fluorocarbons/toxicity ; Ligands ; Male ; PPAR alpha/genetics ; PPAR gamma ; Rats ; Receptors, Estrogen
    Chemical Substances Fatty Acids ; Fluorocarbons ; Ligands ; PPAR alpha ; PPAR gamma ; Receptors, Estrogen
    Language English
    Publishing date 2022-06-22
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 204477-8
    ISSN 1096-0333 ; 0041-008X
    ISSN (online) 1096-0333
    ISSN 0041-008X
    DOI 10.1016/j.taap.2022.116136
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: 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

    Conley, Justin M. / Lambright, Christy S. / Evans, Nicola / Farraj, Aimen K. / Smoot, Jacob / Grindstaff, Rachel D. / Hill, Donna / McCord, James / Medlock-Kakaley, Elizabeth / Dixon, Aaron / Hines, Erin / Gray, L. Earl

    Science of the Total Environment. 2023 Sept., v. 892 p.164609-

    2023  

    Abstract: Simultaneous exposure to multiple per- and polyfluoroalkyl substances (PFAS) is common in humans across the globe. Individual PFAS are associated with adverse health effects, yet the nature of mixture effects after exposure to two or more PFAS remains ... ...

    Abstract Simultaneous exposure to multiple per- and polyfluoroalkyl substances (PFAS) is common in humans across the globe. Individual PFAS are associated with adverse health effects, yet the nature of mixture effects after exposure to two or more PFAS remains unclear. Previously we reported that oral administration of hexafluoropropylene oxide-dimer acid (HFPO-DA, or GenX), Nafion byproduct 2 (NBP2), or perfluorooctane sulfonate (PFOS) individually during pregnancy produced maternal and F1 effects. Here, we hypothesized that responses to the combined exposure to these three PFAS would be dose additive. Pregnant Sprague-Dawley rats were exposed to a fixed-ratio equipotent mixture where the top dose contained each PFAS at their ED50 for neonatal mortality (100 % dose = PFOS 3 mg/kg; NBP2 10 mg/kg; HFPO-DA 110 mg/kg), followed by a dilution series (33.3, 10, 3.3, and 1 %) and vehicle controls (0 % dose). Consistent with the single chemical studies, dams were exposed from gestation day (GD)14–18 or from GD8-postnatal day (PND2). Fetal and maternal livers on GD18 displayed multiple significantly upregulated genes associated with lipid and carbohydrate metabolism at all dose levels, while dams displayed significantly increased liver weight (≥3.3 % dose) and reduced serum thyroid hormones (≥33.3 % dose). Maternal exposure from GD8-PND2 significantly reduced pup bodyweights at birth (≥33.3 % dose) and PND2 (all doses), increased neonatal liver weights (≥3.3 % dose), increased pup mortality (≥3.3 % dose), and reduced maternal bodyweights and weight gain at the top dose. Echocardiography of adult F1 males and females identified significantly increased left ventricular anterior wall thickness (~10 % increase), whereas other cardiac morphological, functional, and transcriptomic measures were unaffected. Mixture effects in maternal and neonatal animals conformed to dose addition using a relative potency factor (RPF) analysis. Results support dose addition-based cumulative assessment approaches for estimating combined effects of PFAS co-exposure.
    Keywords adults ; blood serum ; byproducts ; carbohydrate metabolism ; echocardiography ; environment ; lipids ; liver ; maternal exposure ; neonatal mortality ; oral administration ; perfluorooctane sulfonic acid ; pregnancy ; progeny ; rats ; transcriptomics ; weight gain ; Cumulative effects ; Dose addition ; Relative potency factor ; Thyroid ; Birthweight
    Language English
    Dates of publication 2023-09
    Publishing place Elsevier B.V.
    Document type Article ; Online
    ZDB-ID 121506-1
    ISSN 1879-1026 ; 0048-9697
    ISSN (online) 1879-1026
    ISSN 0048-9697
    DOI 10.1016/j.scitotenv.2023.164609
    Database NAL-Catalogue (AGRICOLA)

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  4. Article ; Online: Water, Water Everywhere, but Every Drop Unique: Challenges in the Science to Understand the Role of Contaminants of Emerging Concern in the Management of Drinking Water Supplies.

    Glassmeyer, Susan T / Burns, Emily E / Focazio, Michael J / Furlong, Edward T / Gribble, Matthew O / Jahne, Michael A / Keely, Scott P / Kennicutt, Alison R / Kolpin, Dana W / Medlock Kakaley, Elizabeth K / Pfaller, Stacy L

    GeoHealth

    2023  Volume 7, Issue 12, Page(s) e2022GH000716

    Abstract: The protection and management of water resources continues to be challenged by multiple and ongoing factors such as shifts in demographic, social, economic, and public health requirements. Physical limitations placed on access to potable supplies include ...

    Abstract The protection and management of water resources continues to be challenged by multiple and ongoing factors such as shifts in demographic, social, economic, and public health requirements. Physical limitations placed on access to potable supplies include natural and human-caused factors such as aquifer depletion, aging infrastructure, saltwater intrusion, floods, and drought. These factors, although varying in magnitude, spatial extent, and timing, can exacerbate the potential for contaminants of concern (CECs) to be present in sources of drinking water, infrastructure, premise plumbing and associated tap water. This monograph examines how current and emerging scientific efforts and technologies increase our understanding of the range of CECs and drinking water issues facing current and future populations. It is not intended to be read in one sitting, but is instead a starting point for scientists wanting to learn more about the issues surrounding CECs. This text discusses the topical evolution CECs over time (Section 1), improvements in measuring chemical and microbial CECs, through both analysis of concentration and toxicity (Section 2) and modeling CEC exposure and fate (Section 3), forms of treatment effective at removing chemical and microbial CECs (Section 4), and potential for human health impacts from exposure to CECs (Section 5). The paper concludes with how changes to water quantity, both scarcity and surpluses, could affect water quality (Section 6). Taken together, these sections document the past 25 years of CEC research and the regulatory response to these contaminants, the current work to identify and monitor CECs and mitigate exposure, and the challenges facing the future.
    Language English
    Publishing date 2023-12-28
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2471-1403
    ISSN (online) 2471-1403
    DOI 10.1029/2022GH000716
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: 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.

    Conley, Justin M / Lambright, Christy S / Evans, Nicola / Farraj, Aimen K / Smoot, Jacob / Grindstaff, Rachel D / Hill, Donna / McCord, James / Medlock-Kakaley, Elizabeth / Dixon, Aaron / Hines, Erin / Gray, L Earl

    The Science of the total environment

    2023  Volume 892, Page(s) 164609

    Abstract: Simultaneous exposure to multiple per- and polyfluoroalkyl substances (PFAS) is common in humans across the globe. Individual PFAS are associated with adverse health effects, yet the nature of mixture effects after exposure to two or more PFAS remains ... ...

    Abstract Simultaneous exposure to multiple per- and polyfluoroalkyl substances (PFAS) is common in humans across the globe. Individual PFAS are associated with adverse health effects, yet the nature of mixture effects after exposure to two or more PFAS remains unclear. Previously we reported that oral administration of hexafluoropropylene oxide-dimer acid (HFPO-DA, or GenX), Nafion byproduct 2 (NBP2), or perfluorooctane sulfonate (PFOS) individually during pregnancy produced maternal and F1 effects. Here, we hypothesized that responses to the combined exposure to these three PFAS would be dose additive. Pregnant Sprague-Dawley rats were exposed to a fixed-ratio equipotent mixture where the top dose contained each PFAS at their ED50 for neonatal mortality (100 % dose = PFOS 3 mg/kg; NBP2 10 mg/kg; HFPO-DA 110 mg/kg), followed by a dilution series (33.3, 10, 3.3, and 1 %) and vehicle controls (0 % dose). Consistent with the single chemical studies, dams were exposed from gestation day (GD)14-18 or from GD8-postnatal day (PND2). Fetal and maternal livers on GD18 displayed multiple significantly upregulated genes associated with lipid and carbohydrate metabolism at all dose levels, while dams displayed significantly increased liver weight (≥3.3 % dose) and reduced serum thyroid hormones (≥33.3 % dose). Maternal exposure from GD8-PND2 significantly reduced pup bodyweights at birth (≥33.3 % dose) and PND2 (all doses), increased neonatal liver weights (≥3.3 % dose), increased pup mortality (≥3.3 % dose), and reduced maternal bodyweights and weight gain at the top dose. Echocardiography of adult F1 males and females identified significantly increased left ventricular anterior wall thickness (~10 % increase), whereas other cardiac morphological, functional, and transcriptomic measures were unaffected. Mixture effects in maternal and neonatal animals conformed to dose addition using a relative potency factor (RPF) analysis. Results support dose addition-based cumulative assessment approaches for estimating combined effects of PFAS co-exposure.
    MeSH term(s) Pregnancy ; Rats ; Animals ; Humans ; Male ; Female ; Adult ; Maternal Exposure/adverse effects ; Rats, Sprague-Dawley ; Prenatal Exposure Delayed Effects/chemically induced ; Fluorocarbons/toxicity ; Alkanesulfonic Acids/toxicity
    Chemical Substances ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate ; perfluorosulfonic acid (39464-59-0) ; perfluorooctane sulfonic acid (9H2MAI21CL) ; Fluorocarbons ; Alkanesulfonic Acids
    Language English
    Publishing date 2023-06-02
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 121506-1
    ISSN 1879-1026 ; 0048-9697
    ISSN (online) 1879-1026
    ISSN 0048-9697
    DOI 10.1016/j.scitotenv.2023.164609
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: A mixture of 15 phthalates and pesticides below individual chemical no observed adverse effect levels (NOAELs) produces reproductive tract malformations in the male rat.

    Conley, Justin M / Lambright, Christy S / Evans, Nicola / Cardon, Mary / Medlock-Kakaley, Elizabeth / Wilson, Vickie S / Gray, L Earl

    Environment international

    2021  Volume 156, Page(s) 106615

    Abstract: Humans carry residues of multiple synthetic chemicals at any given point in time. Research has demonstrated that compounds with varying molecular initiating events (MIE) that disrupt common key events can act in concert to produce cumulative adverse ... ...

    Abstract Humans carry residues of multiple synthetic chemicals at any given point in time. Research has demonstrated that compounds with varying molecular initiating events (MIE) that disrupt common key events can act in concert to produce cumulative adverse effects. Congenital defects of the male reproductive tract are some of the most frequently diagnosed malformations in humans and chemical exposures in utero can produce these effects in laboratory animals and humans. Here, we hypothesized that in utero exposure to a mixture of pesticides and phthalates, each of which produce male reproductive tract defects individually, would produce cumulative effects even when each chemical is present at a no observed adverse effect level (NOAEL) specific for male reproductive effects. Pregnant Sprague-Dawley rats were exposed via oral gavage to a fixed-ratio dilution mixture of 5 pesticides (vinclozolin, linuron, procymidone, prochloraz, pyrifluquinazon), 1 pesticide metabolite (dichlorodiphenyldichloroethylene (DDE)), and 9 phthalates (dipentyl, dicyclohexyl, di-2-ethylhexyl, dibutyl, benzyl butyl, diisobutyl, diisoheptyl, dihexyl, and diheptyl) during the critical window of rat fetal masculinization (gestation day 14-18). The top dose (100% dose) contained each compound at a concentration 2-fold greater than the individual chemical NOAEL followed by a dilution series that represented each chemical at NOAEL, NOAEL/2, NOAEL/4, NOAEL/8, NOAEL/15, NOAEL/100, NOAEL/1000. Reduced fetal testis gene expression occurred at NOAEL/15, reduced fetal testis testosterone production occurred at NOAEL/8, reduced anogenital distance, increased nipple retention, and delayed puberty occurred at NOAEL/4, and severe effects including genital malformations and weight reductions in numerous reproductive tissues occurred at NOAEL/2. This study demonstrates that these phthalates and pesticides acted cumulatively to produce adverse effects at doses below which any individual chemical had been shown to produce an effect alone and even though they have different MIEs.
    MeSH term(s) Animals ; Female ; Genitalia, Male ; Male ; No-Observed-Adverse-Effect Level ; Pesticides/toxicity ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Reproduction ; Testis
    Chemical Substances Pesticides
    Language English
    Publishing date 2021-05-14
    Publishing country Netherlands
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 554791-x
    ISSN 1873-6750 ; 0160-4120
    ISSN (online) 1873-6750
    ISSN 0160-4120
    DOI 10.1016/j.envint.2021.106615
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX) alters maternal and fetal glucose and lipid metabolism and produces neonatal mortality, low birthweight, and hepatomegaly in the Sprague-Dawley rat

    Conley, Justin M / Lambright, Christy S / Evans, Nicola / McCord, James / Strynar, Mark J / Hill, Donna / Medlock-Kakaley, Elizabeth / Wilson, Vickie S / Gray, L. Earl

    Environment international. 2021 Jan., v. 146

    2021  

    Abstract: Hexafluoropropylene oxide dimer acid (HFPO-DA or GenX) is an industrial replacement for the straight-chain perfluoroalkyl substance (PFAS), perfluorooctanoic acid (PFOA). Previously we reported maternal, fetal, and postnatal effects from gestation day ( ... ...

    Abstract Hexafluoropropylene oxide dimer acid (HFPO-DA or GenX) is an industrial replacement for the straight-chain perfluoroalkyl substance (PFAS), perfluorooctanoic acid (PFOA). Previously we reported maternal, fetal, and postnatal effects from gestation day (GD) 14-18 oral dosing in Sprague-Dawley rats. Here, we further evaluated the perinatal toxicity of HFPO-DA by orally dosing rat dams with 1–125 mg/kg/d (n = 4 litters per dose) from GD17-21 and with 10–250 mg/kg/d (n = 5) from GD8 – postnatal day (PND) 2. Effects of GD17-21 dosing were similar to those previously reported for GD14-18 dosing and included increased maternal liver weight, altered maternal serum lipid and thyroid hormone concentrations, and altered expression of peroxisome proliferator-activated receptor (PPAR) pathway genes in maternal and fetal livers. Dosing from GD8-PND2 produced similar effects as well as dose-responsive decreased pup birth weight (≥30 mg/kg), increased neonatal mortality (≥62.5 mg/kg), and increased pup liver weight (≥10 mg/kg). Histopathological evaluation of newborn pup livers indicated a marked reduction in glycogen stores and pups were hypoglycemic at birth. Quantitative gene expression analyses of F1 livers revealed significant alterations in genes related to glucose metabolism at birth and on GD21. Maternal serum and liver HFPO-DA concentrations were similar between dosing intervals, indicating rapid clearance, however dams dosed GD8 – PND2 had greater liver weight and gestational weight gain effects at lower doses than GD17-21 dosing, indicating the importance of exposure duration. Comparison of neonatal mortality dose–response curves between HFPO-DA and previously published perfluorooctane sulfonate (PFOS) data indicated that, based on serum concentration, the potency of these two PFAS are similar in the rat. Overall, HFPO-DA is a developmental toxicant in the rat and the spectrum of adverse effects is consistent with prior PFAS toxicity evaluations, such as PFOS and PFOA.
    Keywords blood lipids ; blood serum ; dose response ; environment ; exposure duration ; gene expression ; glucose ; glycogen ; histopathology ; lipid metabolism ; liver ; low birth weight ; neonatal mortality ; neonates ; perfluorocarbons ; perfluorooctane sulfonic acid ; perfluorooctanoic acid ; peroxisome proliferator-activated receptors ; pregnancy ; rats ; thyroid hormones ; toxicity ; weight gain
    Language English
    Dates of publication 2021-01
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 554791-x
    ISSN 1873-6750 ; 0160-4120
    ISSN (online) 1873-6750
    ISSN 0160-4120
    DOI 10.1016/j.envint.2020.106204
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  8. Article: A mixture of 15 phthalates and pesticides below individual chemical no observed adverse effect levels (NOAELs) produces reproductive tract malformations in the male rat

    Conley, Justin M / Lambright, Christy S / Evans, Nicola / Cardon, Mary / Medlock-Kakaley, Elizabeth / Wilson, Vickie S / Gray, L. Earl

    Environment international. 2021 Nov., v. 156

    2021  

    Abstract: Humans carry residues of multiple synthetic chemicals at any given point in time. Research has demonstrated that compounds with varying molecular initiating events (MIE) that disrupt common key events can act in concert to produce cumulative adverse ... ...

    Abstract Humans carry residues of multiple synthetic chemicals at any given point in time. Research has demonstrated that compounds with varying molecular initiating events (MIE) that disrupt common key events can act in concert to produce cumulative adverse effects. Congenital defects of the male reproductive tract are some of the most frequently diagnosed malformations in humans and chemical exposures in utero can produce these effects in laboratory animals and humans. Here, we hypothesized that in utero exposure to a mixture of pesticides and phthalates, each of which produce male reproductive tract defects individually, would produce cumulative effects even when each chemical is present at a no observed adverse effect level (NOAEL) specific for male reproductive effects. Pregnant Sprague-Dawley rats were exposed via oral gavage to a fixed-ratio dilution mixture of 5 pesticides (vinclozolin, linuron, procymidone, prochloraz, pyrifluquinazon), 1 pesticide metabolite (dichlorodiphenyldichloroethylene (DDE)), and 9 phthalates (dipentyl, dicyclohexyl, di-2-ethylhexyl, dibutyl, benzyl butyl, diisobutyl, diisoheptyl, dihexyl, and diheptyl) during the critical window of rat fetal masculinization (gestation day 14–18). The top dose (100% dose) contained each compound at a concentration 2-fold greater than the individual chemical NOAEL followed by a dilution series that represented each chemical at NOAEL, NOAEL/2, NOAEL/4, NOAEL/8, NOAEL/15, NOAEL/100, NOAEL/1000. Reduced fetal testis gene expression occurred at NOAEL/15, reduced fetal testis testosterone production occurred at NOAEL/8, reduced anogenital distance, increased nipple retention, and delayed puberty occurred at NOAEL/4, and severe effects including genital malformations and weight reductions in numerous reproductive tissues occurred at NOAEL/2. This study demonstrates that these phthalates and pesticides acted cumulatively to produce adverse effects at doses below which any individual chemical had been shown to produce an effect alone and even though they have different MIEs.
    Keywords DDE (pesticide) ; environment ; gene expression ; linuron ; males ; masculinization ; maternal exposure ; no observed adverse effect level ; pesticide metabolites ; phthalates ; pregnancy ; prochloraz ; procymidone ; puberty ; rats ; testes ; testosterone ; vinclozolin
    Language English
    Dates of publication 2021-11
    Publishing place Elsevier Ltd
    Document type Article
    Note NAL-AP-2-clean
    ZDB-ID 554791-x
    ISSN 1873-6750 ; 0160-4120
    ISSN (online) 1873-6750
    ISSN 0160-4120
    DOI 10.1016/j.envint.2021.106615
    Database NAL-Catalogue (AGRICOLA)

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  9. Article: Developmental toxicity of Nafion byproduct 2 (NBP2) in the Sprague-Dawley rat with comparisons to hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX) and perfluorooctane sulfonate (PFOS)

    Conley, Justin M. / Lambright, Christy S. / Evans, Nicola / Medlock-Kakaley, Elizabeth / Hill, Donna / McCord, James / Strynar, Mark J. / Wehmas, Leah C. / Hester, Susan / MacMillan, Denise K. / Gray, L. Earl

    Environment international. 2022 Feb., v. 160

    2022  

    Abstract: Nafion byproduct 2 (NBP2) is a polyfluoroalkyl ether sulfonic acid that was recently detected in surface water, drinking water, and human serum samples from monitoring studies in North Carolina, USA. We orally exposed pregnant Sprague-Dawley rats to NBP2 ...

    Abstract Nafion byproduct 2 (NBP2) is a polyfluoroalkyl ether sulfonic acid that was recently detected in surface water, drinking water, and human serum samples from monitoring studies in North Carolina, USA. We orally exposed pregnant Sprague-Dawley rats to NBP2 from gestation day (GD) 14–18 (0.1–30 mg/kg/d), GD17-21, and GD8 to postnatal day (PND) 2 (0.3–30 mg/kg/d) to characterize maternal, fetal, and postnatal effects. GD14-18 exposures were also conducted with perfluorooctane sulfonate (PFOS) for comparison to NBP2, as well as data previously published for hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX). NBP2 produced stillbirth (30 mg/kg), reduced pup survival shortly after birth (10 mg/kg), and reduced pup body weight (10 mg/kg). Histopathological evaluation identified reduced glycogen stores in newborn pup livers and hepatocyte hypertrophy in maternal livers at ≥ 10 mg/kg. Exposure to NBP2 from GD14-18 reduced maternal serum total T₃ and cholesterol concentrations (30 mg/kg). Maternal, fetal, and neonatal liver gene expression was investigated using RT-qPCR pathway arrays, while maternal and fetal livers were also analyzed using TempO-Seq transcriptomic profiling. Overall, there was limited alteration of genes in maternal or F1 livers from NBP2 exposure with significant changes mostly occurring in the top dose group (30 mg/kg) associated with lipid and carbohydrate metabolism. Metabolomic profiling indicated elevated maternal bile acids for NBP2, but not HFPO-DA or PFOS, while all three reduced 3-indolepropionic acid. Maternal and fetal serum and liver NBP2 concentrations were similar to PFOS, but ∼10–30-fold greater than HFPO-DA concentrations at a given maternal oral dose. NBP2 is a developmental toxicant in the rat, producing neonatal mortality, reduced pup body weight, reduced pup liver glycogen, reduced maternal thyroid hormones, and altered maternal and offspring lipid and carbohydrate metabolism similar to other studied PFAS, with oral toxicity for pup loss that is slightly less potent than PFOS but more potent than HFPO-DA.
    Keywords bile ; blood serum ; body weight ; byproducts ; carbohydrate metabolism ; cholesterol ; developmental toxicity ; environment ; fetal death ; gene expression ; glycogen ; histopathology ; humans ; hypertrophy ; liver ; metabolomics ; neonatal mortality ; neonates ; oral administration ; perfluorooctane sulfonic acid ; pregnancy ; progeny ; rats ; sulfonic acids ; surface water ; transcriptomics ; North Carolina
    Language English
    Dates of publication 2022-02
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 554791-x
    ISSN 1873-6750 ; 0160-4120
    ISSN (online) 1873-6750
    ISSN 0160-4120
    DOI 10.1016/j.envint.2021.107056
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  10. Article ; Online: Ligand-Mediated Receptor Assembly as an End Point for High-Throughput Chemical Toxicity Screening.

    Medlock Kakaley, Elizabeth K / Eytcheson, Stephanie A / LeBlanc, Gerald A

    Environmental science & technology

    2017  Volume 51, Issue 16, Page(s) 9327–9333

    Abstract: The high throughput screening of chemicals for interaction with intracellular targets is gaining prominence in the toxicity evaluation of environmental chemicals. We describe ligand-mediated receptor assembly as an early event in receptor signaling and ... ...

    Abstract The high throughput screening of chemicals for interaction with intracellular targets is gaining prominence in the toxicity evaluation of environmental chemicals. We describe ligand-mediated receptor assembly as an early event in receptor signaling and its application to the screening of chemicals for interaction with targeted receptors. We utilized bioluminescence resonance energy transfer (BRET) to detect and quantify assembly of the methyl farnesoate receptor (MfR) in response to various high-production volume and other chemicals. The hormone methyl farnesoate binds to the MfR to regulate various aspects of reproduction and development in crustaceans. The MfR protein subunits Met and SRC, cloned from Daphnia pulex, were fused to the fluorophore, mAmetrine and the photon generator, Rluc2, respectively. Ligand-mediated receptor assembly was measured by photon transfer from the photon donor to the fluorophore resulting in fluorescence emission. Overall, the BRET assay had comparable or greater sensitivity as compared to a traditional reporter gene assay. Further, chemicals that screened positive in the BRET assay also stimulated phenotypic outcomes in daphnids that result from MfR signaling. We concluded the BRET assay is an accurate, sensitive, and cost/time efficient alternative to traditional screening assays.
    MeSH term(s) Animals ; Daphnia ; Energy Transfer ; Genes, Reporter ; Ligands ; Reproduction ; Toxicity Tests ; Water Pollutants, Chemical/toxicity
    Chemical Substances Ligands ; Water Pollutants, Chemical
    Language English
    Publishing date 2017-07-28
    Publishing country United States
    Document type Journal Article
    ISSN 1520-5851
    ISSN (online) 1520-5851
    DOI 10.1021/acs.est.7b02882
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