Neonatal exposure to organophosphorus flame retardant TDCPP elicits neurotoxicity in mouse hippocampus via microglia-mediated inflammation in vivo and in vitro

Arch Toxicol. 2020 Feb;94(2):541-552. doi: 10.1007/s00204-019-02635-y. Epub 2020 Jan 1.

Abstract

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is a phosphorus-based flame retardant common in consumer goods and baby products. Concerns have been raised about TDCPP exposure and neurodevelopmental toxicity. However, the mechanism and early response for TDCPP-induced neurotoxicity are poorly understood. This study investigates the role of microglia-mediated neuroinflammation in TDCPP-induced neurotoxicity in mice and primary cells. TDCPP was administered to C57BL/6 pups (0, 5, or 50 mg/kg/day) via an oral gavage from postnatal days 10-38 (28 days). The results showed that TDCPP exposure for 28 days altered the gene expression of neuronal markers Tubb3, Nefh, and Nes, and led to apoptosis in the hippocampus. The mRNA levels of pro-inflammatory factors Il-1β, Tnfα and Ccl2 dose dependently increased in the hippocampus at both 24 h and 28 days following exposure, accompanied by microglia activation characterized by an amoeboid-like phenotype. In in vitro studies using the primary microglia isolated from neonatal mice, exposure to TDCPP (0-100 μM) for 24 h resulted in cellular activation. It also increased the expression of genes responsible for inflammatory responses including surface markers and pro-inflammatory cytokines. These changes occurred in a dose-dependent fashion. Neurite outgrowth of primary mouse hippocampal neurons was inhibited by treatment with the conditioned medium harvested from microglia exposed to TDCPP. These results reveal that neonatal exposure to TDCPP induces neuronal damage through microglia-mediated inflammation. This provides insight into the mechanism of TDCPP's neurodevelopmental toxicity, and suggests that microglial cell is a sensitive responder for OPFRs exposure.

Keywords: Developmental toxicity; Inflammation; Microglia; Neurotoxicity; Tris(1,3-dichloro-2-propyl) phosphate (TDCPP).

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Biomarkers / metabolism
  • Body Weight / drug effects
  • Culture Media, Conditioned / pharmacology
  • Female
  • Flame Retardants / toxicity*
  • Gene Expression Regulation / drug effects
  • Hippocampus / drug effects*
  • Hippocampus / pathology
  • Hippocampus / physiology
  • Inflammation / chemically induced
  • Male
  • Mice, Inbred C57BL
  • Microglia / drug effects*
  • Microglia / pathology
  • Neurotoxicity Syndromes / etiology
  • Neurotoxicity Syndromes / pathology*
  • Organophosphorus Compounds / toxicity*
  • Toxicity Tests / methods

Substances

  • Biomarkers
  • Culture Media, Conditioned
  • Flame Retardants
  • Organophosphorus Compounds
  • tris(1,3-dichloro-2-propyl)phosphate