The Long-Lasting Rodenticide Brodifacoum Induces Neuropathology in Adult Male Rats

Toxicol Sci. 2017 Sep 1;159(1):224-237. doi: 10.1093/toxsci/kfx134.

Abstract

Superwarfarins are very long-lasting rodenticides effective in warfarin-resistant rodents at extremely low doses. The consequences of chronic superwarfarin levels in tissues, due to biological half-lives on the order of 20 days, have not been examined. We now characterized the neurological effects of brodifacoum (BDF), one of the most widely used superwarfarins, in adult male Sprague Dawley rats. Dosing curves established the acute oral lethal dose for BDF as 221 ± 14 μg/kg. Measurement of tissue BDF levels showed accumulation throughout the body, including the central nervous system, with levels diminishing over several days. Immunocytochemical staining showed that both astrocyte and microglial activation was increased 4 days after BDF administration, as were levels of carbonylated proteins, and neuronal damage assessed by fluorojade B staining. Direct toxic effects of BDF on neurons and glia were observed using enriched cultures of cerebellar neurons and cortical astrocytes. Proteomic analysis of cerebellar lysates revealed that BDF altered expression of 667 proteins in adult rats. Gene ontology and pathway analysis identified changes in several functional pathways including cell metabolism, mitochondria function, and RNA handling with ribosomal proteins comprising the largest group. In vitro studies using primary astrocytes showed that BDF suppressed de novo protein synthesis. These findings demonstrate that superwarfarin accumulation increases indices of neuroinflammation and neuropathology in adult rodents, suggesting that methods which minimize BDF toxicity may not address delayed neurological sequelae.

Keywords: astrocyte; brodifacoum; microglia; neuroinflammation; superwarfarins.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • 4-Hydroxycoumarins / administration & dosage
  • 4-Hydroxycoumarins / pharmacokinetics
  • 4-Hydroxycoumarins / toxicity*
  • Administration, Oral
  • Animals
  • Chromatography, High Pressure Liquid
  • Lethal Dose 50
  • Male
  • Nervous System / drug effects*
  • Nervous System / metabolism
  • Nervous System / pathology
  • Proteomics
  • Rats
  • Rats, Sprague-Dawley
  • Rodenticides / administration & dosage
  • Rodenticides / pharmacokinetics
  • Rodenticides / toxicity*
  • Tandem Mass Spectrometry
  • Tissue Distribution

Substances

  • 4-Hydroxycoumarins
  • Rodenticides
  • bromfenacoum