Named Series: Diet, Inflammation and the Brain Prenatal air pollution exposure induces sexually dimorphic fetal programming of metabolic and neuroinflammatory outcomes in adult offspring Jessica L. Bolton a,⇑ , Richard L. Auten b , Staci D. Bilbo a a Department of Psychology & Neuroscience, Duke University, Durham, NC 27708, USA b Department of Pediatrics, Division of Neonatal Medicine, Duke University Medical Center, Durham, NC 27708, USA article info Article history: Received 31 July 2013 Received in revised form 7 October 2013 Accepted 26 October 2013 Available online xxxx Keywords: Fetal programming Diesel exhaust particles High-fat diet Insulin resistance Anxiety Microglia Macrophages Hypothalamus Hippocampus Adipose tissue abstract Environmental chemical exposures during critical windows of development may contribute to the escalating prevalence of obesity. We tested the hypothesis that prenatal exposure to diesel exhaust particles (DEP), a primary component of air pollution, would prime microglia long-term, resulting in exacerbated metabolic and affective outcomes following exposure to a high-fat diet in adulthood. Time-mated mouse dams were intermittently exposed to respiratory instillations of either vehicle (VEH) or DEP throughout gestation. Adult male and female offspring were then fed either a low-fat diet (LFD) or high-fat diet (HFD) for 9 weeks. The male offspring of DEP-exposed dams exhibited exaggerated weight gain, insulin resistance, and anxiety-like behavior on HFD compared to the male offspring of VEH- exposed dams, whereas female offspring did not differ according to prenatal treatment. Furthermore, HFD induced evidence of macrophage infiltration of both adipose tissue and the brain in both sexes, but these cells were more activated specifically in DEP/HFD males. DEP/HFD males also expressed mark- edly higher levels of microglial/macrophage, but not astrocyte, activation markers in the hippocampus, whereas females exhibited only a suppression of astrocyte activation markers due to HFD. In a second experiment, DEP male offspring mounted an exaggerated peripheral IL-1b response to an LPS challenge at postnatal day (P)30, whereas their central IL-1b response did not differ from VEH male offspring, which is suggestive of macrophage priming due to prenatal DEP exposure. In sum, prenatal air pollution exposure ‘‘programs’’ offspring for increased susceptibility to diet-induced metabolic, behavioral, and neuroinflammatory changes in adulthood in a sexually dimorphic manner. Ó 2013 Elsevier Inc. All rights reserved. 1. Introduction A growing number of environmental chemicals have been implicated as potential contributors to the global obesity epidemic, as changes in diet and exercise alone may not fully account for the escalating prevalence of obesity over the past 2 decades (Grün and Blumberg, 2009; Keith et al., 2006). Prenatal exposures to these environmental chemicals, or so-called ‘‘obesogens’’, during critical windows of development may be especially important for shifting the set point of multiple homeostatic systems, which can have sig- nificant consequences for adult physiology and behavior through- out the lifespan, a concept known generally as ‘‘fetal programming’’ (Heindel and vom Saal, 2009; Lawlor and Chaturv- edi, 2006). Air pollution, one of the most relevant and pervasive environmental toxins in the modern world, is gaining recognition as a candidate obesogen. For example, maternal exposure to air pollution during pregnancy is associated with childhood obesity in humans (Rundle et al., 2012). Furthermore, maternal exposure to diesel exhaust in mice exacerbates weight gain in offspring fol- lowing exposure to a high-fat diet in adulthood (Bolton et al., 2012). The mechanisms by which this long-term programming of metabolic set points occurs remains unclear, but a large body of evidence suggests it critically involves both central and peripheral inflammation, which can lead to endocrine disruption, changes in adipose tissue development, and long-term neuroendocrine and neuroimmune dysregulation (Heindel and vom Saal, 2009; Das, 2007; Dahlgren et al., 2006). Chemicals such as environmental estrogens, polycyclic aromatic hydrocarbons, and particulate mat- ter found in air pollution have all been linked to inflammation (Jin et al., 2010; Burchiel and Luster, 2001; van Eeden et al., 2001). Obesity is well-characterized as a disease of low-grade systemic inflammation that involves proinflammatory cytokine production and macrophage infiltration in adipose tissue (Cancello and 0889-1591/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bbi.2013.10.029 ⇑ Corresponding author. Address: Duke University, Department of Psychology and Neuroscience, 210 Research Dr., 3019 GSRB II, Durham, NC 27710, USA. Tel.: +1 919 660 5700; fax: +1 919 660 5798. E-mail addresses: jessica.bolton@duke.edu, jib74@duke.edu (J.L. Bolton). Brain, Behavior, and Immunity xxx (2013) xxx–xxx Contents lists available at ScienceDirect Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi Please cite this article in press as: Bolton, J.L., et al. Prenatal air pollution exposure induces sexually dimorphic fetal programming of metabolic and neur- oinflammatory outcomes in adult offspring. Brain Behav. Immun. (2013), http://dx.doi.org/10.1016/j.bbi.2013.10.029