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

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

doi:10.1016/j.scitotenv.2023.164609

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

Sci Total Environ. 2023 Sep 20:892:164609. doi: 10.1016/j.scitotenv.2023.164609. Epub 2023 Jun 2.

Authors

Affiliations

¹ U.S. Environmental Protection Agency, Office of Research & Development, Center for Public Health and Environmental Assessment, Research Triangle Park, NC, USA. Electronic address: conley.justin@epa.gov.
² U.S. Environmental Protection Agency, Office of Research & Development, Center for Public Health and Environmental Assessment, Research Triangle Park, NC, USA. Electronic address: lambright.christy@epa.gov.
³ U.S. Environmental Protection Agency, Office of Research & Development, Center for Public Health and Environmental Assessment, Research Triangle Park, NC, USA. Electronic address: evans.nicola@epa.gov.
⁴ U.S. Environmental Protection Agency, Office of Research & Development, Center for Public Health and Environmental Assessment, Research Triangle Park, NC, USA. Electronic address: Farraj.aimen@epa.gov.
⁵ ORISE Participant, U.S. Environmental Protection Agency, Office of Research & Development, Center for Public Health and Environmental Assessment, Research Triangle Park, NC, USA. Electronic address: smoot.jacob@epa.gov.
⁶ U.S. Environmental Protection Agency, Office of Research & Development, Center for Public Health and Environmental Assessment, Research Triangle Park, NC, USA.
⁷ U.S. Environmental Protection Agency, Office of Research & Development, Center for Public Health and Environmental Assessment, Research Triangle Park, NC, USA. Electronic address: hill.donna@epa.gov.
⁸ U.S. Environmental Protection Agency, Office of Research & Development, Center for Environmental Measurement and Modeling, Research Triangle Park, NC, USA. Electronic address: mccord.james@epa.gov.
⁹ U.S. Environmental Protection Agency, Office of Research & Development, Center for Public Health and Environmental Assessment, Research Triangle Park, NC, USA. Electronic address: medlockkakaley.elizabeth@epa.gov.
¹⁰ U.S. Environmental Protection Agency, Office of Research & Development, Center for Public Health and Environmental Assessment, Research Triangle Park, NC, USA. Electronic address: dixon.aaron@epa.gov.
¹¹ U.S. Environmental Protection Agency, Office of Research & Development, Center for Public Health and Environmental Assessment, Research Triangle Park, NC, USA. Electronic address: hines.erin@epa.gov.
¹² U.S. Environmental Protection Agency, Office of Research & Development, Center for Public Health and Environmental Assessment, Research Triangle Park, NC, USA. Electronic address: gray.earl@epa.gov.

PMID: 37271399
PMCID: PMC10681034 (available on 2024-09-20)
DOI: 10.1016/j.scitotenv.2023.164609

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 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: Birthweight; Cumulative effects; Dose addition; Liver; Relative potency factor; Thyroid.

Published by Elsevier B.V.

MeSH terms

Adult
Alkanesulfonic Acids* / toxicity
Animals
Female
Fluorocarbons* / toxicity
Humans
Male
Maternal Exposure / adverse effects
Pregnancy
Prenatal Exposure Delayed Effects* / chemically induced
Rats
Rats, Sprague-Dawley

Substances

ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate
perfluorosulfonic acid
perfluorooctane sulfonic acid
Fluorocarbons
Alkanesulfonic Acids

Grants and funding

EPA999999/ImEPA/Intramural EPA/United States