Reproductive Toxicology 51 (2015) 133–144 Contents lists available at ScienceDirect Reproductive Toxicology j ourna l h o mepa ge: www.elsevier.com/locate/reprotox Developmental toxicity of perfluorononanoic acid in mice  Kaberi P. Das a , Brian E. Grey a , Mitchell B. Rosen b , Carmen R. Wood a , Katoria R. Tatum-Gibbs a , R. Daniel Zehr c , Mark J. Strynar d , Andrew B. Lindstrom d , Christopher Lau a,∗ a Toxicity Assessment Division b Integrated Systems Toxicology Division c Research Core Unit, National Health and Environmental Effects Research Laboratory d Human Exposure and Atmospheric Sciences Division, National Exposure Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, United States a r t i c l e i n f o Article history: Received 27 September 2014 Received in revised form 22 November 2014 Accepted 16 December 2014 Available online 25 December 2014 Keywords: Perfluorononanoic acid CD-1 mice Developmental toxicity Gene expression a b s t r a c t Perfluorononanoic acid (PFNA) is a ubiquitous and persistent environmental contaminant. Although its levels in the environment and in humans are lower than those of perfluorooctane sulfonate (PFOS) or perfluorooctanoic acid (PFOA), a steady trend of increases in the general population in recent years has drawn considerable interest and concern. Previous studies with PFOS and PFOA have indicated develop- mental toxicity in laboratory rodent models. The current study extends the evaluation of these adverse outcomes to PFNA in mice. PFNA was given to timed-pregnant CD-1 mice by oral gavage daily on ges- tational day 1–17 at 1, 3, 5 or 10 mg/kg; controls received water vehicle. Dams given 10 mg/kg PFNA could not carry their pregnancy successfully and effects of this dose group were not followed. Similar to PFOS and PFOA, PFNA at 5 mg/kg or lower doses produced hepatomegaly in the pregnant dams, but did not affect the number of implantations, fetal viability, or fetal weight. Mouse pups were born alive and postnatal survival in the 1 and 3 mg/kg PFNA groups was not different from that in controls. In contrast, although most of the pups were also born alive in the 5 mg/kg PFNA group, 80% of these neonates died in the first 10 days of life. The pattern of PFNA-induced neonatal death differed somewhat from those elicited by PFOS or PFOA. A majority of the PFNA-exposed pups survived a few days longer after birth than those exposed to PFOS or PFOA, which typically died within the first 2 days of postnatal life. Surviv- ing neonates exposed to PFNA exhibited dose-dependent delays in eye opening and onset of puberty. In addition, increased liver weight seen in PFNA-exposed offspring persisted into adulthood and was likely related to the persistence of the chemical in the tissue. Evaluation of gene expression in fetal and neona- tal livers revealed robust activation of peroxisome proliferator-activated receptor-alpha (PPAR) target genes by PFNA that resembled the responses of PFOA. Our results indicate that developmental toxicity of PFNA in mice is comparable to that of PFOS and PFOA, and that these adverse effects are likely common to perfluoroalkyl acids that persist in the body. Published by Elsevier Inc. Abbreviations: PFAA, perfluoroalkyl acid; PFOS, perfluorooctane sulfonate; PFOA, perfluorooctanoic acid; PFNA, perfluorononanoic acid; PFBA, perfluo- robutanoic acid; PPAR, peroxisome proliferator activated receptor-alpha; CAR, constitutive androstane receptor; PXR, pregnane X receptor; PND, postnatal day.  The information in this document has been funded by the U.S. Environmental Protection Agency. It has been subjected to review by the National Health and Envi- ronmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. ∗ Corresponding author at: Mail Drop B105-04, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, United States. Tel.: +1 919 541 5097; fax: +1 919 541 4849. E-mail address: lau.christopher@epa.gov (C. Lau). 1. Introduction Perfluoroalkyl acids (PFAAs) and their derivatives are syn- thetic materials that have unique physico-chemical characteristics of low surface free energy and surface active properties, which make them highly suitable for a wide range of industrial processes and consumer applications [1]. These may include metal electroplating, emulsifiers for polymer production, fire- fighting foams, water- and stain-resistant coatings for textiles and carpets, and grease-proof paper products for food packag- ing. These chemicals are non-biodegradable in the environment, many of which are ubiquitously distributed in all environmen- tal media, and detected worldwide in humans and wildlife [2–7]. http://dx.doi.org/10.1016/j.reprotox.2014.12.012 0890-6238/Published by Elsevier Inc.