Perinatal exposure to low-level PBDE-47 programs gut microbiota, host metabolism and neurobehavior in adult rats: An integrated analysis

Abstract

Polybrominated diphenyl ethers (PBDEs), a major class of flame retardants, have been extensively applied in plastics, electrical equipment, textile fabrics, and so on. Early-life exposure to PBDEs is correlated to neurobehavioral deficits in adulthood, yet the underlying mechanism has not been fully understood. Increasing evidence has demonstrated that gut microbiota dysbiosis and serum metabolites alterations play a role in behavioral abnormalities. However, whether their perturbation is implicated in PBDEs-induced neurotoxicity remains unclear. Here, we sought to explore the effects of developmental exposure to environmentally relevant levels of 2, 2', 4, 4'-tetrabromodiphenyl ether (PBDE-47), a major congener in human samples, on gut microbiota and serum metabolic profile as well as their link to neurobehavioral parameters in adult rats. The open field test showed that gestational and lactational exposure to PBDE-47 caused hyperactivity and anxiety-like behavior. Moreover, 16S rRNA sequencing of fecal samples identified a distinct community composition in gut microbiota following PBDE-47 exposure, manifested as decreased genera Ruminococcaceae and Moraxella, increased families Streptococcaceae and Deferribacteraceae as well as genera Escherichia-Shigella, Pseudomonas and Peptococcus. Additionally, the metabolomics of the blood samples based on liquid chromatography-mass spectrometry revealed a significant shift after PBDE-47 treatment. Notably, these differential serum metabolites were mainly involved in amino acid, carbohydrate, nucleotide, xenobiotics, and lipid metabolisms, which were further validated by pathway analysis. Importantly, the disturbed gut microbiota and the altered serum metabolites were associated with each other and with neurobehavioral disorders, respectively. Collectively, these results suggest that gut microbiota dysbiosis and serum metabolites alterations potentially mediated early-life low-dose PBDE-47 exposure-induced neurobehavioral impairments, which provides a novel perspective on understanding the mechanisms of PBDE-47 neurotoxicity.

Keywords: 2, 2′, 4, 4′-Tetrabromodiphenyl ether; Anxiety-like behavior; Developmental neurotoxicity; Intestinal flora; Serum metabolomics.