Delayed response in the rat frontal lobe transcriptome to perinatal exposure to the flame retardant BDE‐47 Alexander Suvorov a† and Larissa Takser b * ABSTRACT: BDE‐47 is the most prevalent congener of polybrominated diphenyl ethers, which are widely used flame retardants, and is known for endocrine and behavioral disrupting properties in animals. Transient effect on spontaneous motor activity in rats following perinatal exposure to BDE‐47 at low doses, relevant to human exposure, was reported in our previous study. The objective of this study was to screen for the long‐term effects on gene expression in the brain of rats perinatally exposed to BDE‐47. Wistar dams were exposed to BDE‐47 (0.002 and 0.2 mg kg -1 body weight) from gestation day 15 to postnatal day (PND) 20. Total RNA was extracted from the whole brain at PND10 and the brain frontal lobes at PND41 and hybridized to whole‐genome RNA expression microarrays. The genes, differentially expressed 1.5‐fold, were analyzed with the DAVID bioinformatics resources for cluster and gene‐term enrichment. At PND41, clusters of genes involved in nerve impulse transmission, nervous system development and functioning, and core biosynthetic process were altered, including several downregulated genes of cation channels. Representation of LINE1 RNA was decreased significantly. Altered expression of genes involved in neurodevelopment occured at least 3 weeks after the last exposure and the behavioral manifestation of low dose BDE‐47 toxicity. Copyright © 2011 John Wiley & Sons, Ltd. Supporting information may be found in the online version of this article. Keywords: genomics; neurodevelopment; microarray; gene expression; rat; PBDE INTRODUCTION Polybrominated diphenyl ethers (PBDEs) are a group of flame‐ retardant chemicals added to synthetic polymers. A substantial body of evidence has accumulated on neurodevelopmental toxicity of PBDE in recent years (Costa and Giordano 2007; Kuriyama et al., 2005; Suvorov et al., 2008; Viberg et al., 2006). PBDEs cause change in spontaneous motor activity and disrupt performance in learning and memory in rodents. To our knowledge, only one study has evaluated the associations between concentrations of individual PBDE congeners in cord blood and neurodevelopmental indices in children (Herbstman et al., 2009). Children with higher concentrations of BDE 47, 99 or 100 scored lower on tests of mental development. The mechanisms of neurodevelopmental toxicity remain unknown. The experimental protocol used in this study was designed to study the effects of early exposures to BDE‐47 on developing rats. Fetuses were exposed via cord blood and newborns via the mother’ s milk. It is thought that exposure even to small daily doses throughout life, could affect offspring development on a long‐term basis due to PBDE accumulation. Indeed, the high lipophilic character of PBDEs and their long half‐life in human tissues (Geyer et al., 2004) can lead to substantial accumulation in tissues with high lipid content (Johnson‐Restrepo et al., 2005). Results of human studies and animal experiments indicate that PBDE probably mobilizes during pregnancy, increasing the developing organism’ s exposure via cord blood and then via milk (Antignac et al., 2008; Schecter et al., 2006). The choice of doses in our study was verified by internal doses estimated previously (Suvorov et al., 2009a). BDE‐47 concentrations in subcutaneous fat of the dams and pups 1 week after the last injection corresponded to the levels known for the North American human population (Suvorov et al., 2009a). Hyperac- tivity in rat offspring was observed after perinatal exposure to the lowest tested dose of BDE‐47 (0.002 mg kg -1 BW) – the most prevalent PBDE congener found in maternal milk (Schecter et al., 2003) and cord blood (Mazdai et al., 2003). Interestingly, the observed effects were transient. Both male and female pups had equally significantly higher spontaneous motor activity assessed by open field test on PND20 but their activity was similar to the activity of control pups on PND25. Insight from clinical observations of attention‐deficit hyper- activity disorder symptoms shows that they tend to decline with age (Biederman et al., 2000; Hart et al., 1995). However, several authors stress that early‐age hyperactivity could transform into long‐term alteration of other functions of brain, not yet well determined either in humans or in rodents (Faraone et al., 2006; McGough and Barkley 2004; Spencer et al., 2007). *Correspondence to: L. Takser, Département de Pédiatrie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, Québec, Canada J1H 5N4. E‐mail: larissa.takser@usherbrooke.ca † Present address: Department of Biology, Boston University, 5 Cummington St, Boston, MA 02215, USA a Département Obstétrique Gynécologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, Québec, Canada J1H 5N4 b Département de Pédiatrie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, Québec, Canada J1H 5N4 J. Appl. Toxicol. 2011; 31: 477 –483 Copyright © 2011 John Wiley & Sons, Ltd. Research Article Received: 13 September 2010, Revised: 20 December 2010, Accepted: 10 January 2011 Published online in Wiley Online Library: 11 March 2011 (wileyonlinelibrary.com) DOI 10.1002/jat.1667 477