Disruption of vitamin A homeostasis by the biocide tetrakis(hydroxymethyl) phosphonium sulphate in pregnant rabbits

Natalia Estrada-Ortiz, Viktoriia Starokozhko, Hidde van Steenwijk, Cor van der Heide, Hjalmar Permentier, Lisanne van Heemskerk, Grietje Harmanna Prins, Janette Heegsma, Klaas Nico Faber, Steffi Bressers, Guy Steiblen, Antoinette de Groot, Steve Groome, Erik van Miert, Geny Groothuis, Inge Anne Maria de Graaf*

*Corresponding author for this work

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The biocide tetrakis(hydroxymethyl)phosphonium sulphate (THPS) and other members of the tetrakis(hydroxymethyl) phosphonium salts (THPX) family are associated with liver toxicity in several mammalian species and teratogenicity in rabbits. Malformations include skeletal changes and abnormalities in eye development and are very similar to those seen with vitamin A deficiency or excess. For this reason, it was hypothesized that teratogenicity of THPS(X) might be attributed to disturbances in retinol availability and/or metabolism as a result of maternal toxicity, for example, either due to insufficient dietary intake by the mothers or due to liver toxicity. Therefore, in the present study, liver toxicity and vitamin A homeostasis were studied in pregnant rabbits that were exposed to 13.8 or 46.0 mg/kg THPS during organogenesis and in precision-cut liver slices of rats and rabbits exposed to 0-70 mu M THPS. Results show that in vivo exposure to THPS leads to a marked reduction of food intake, increased plasma concentrations of gamma-glutamytransferase, degenerative changes in the liver and to changes in retinoid content in liver and plasma in the rabbits during organogenesis. In addition, THPS, both in vivo and ex vivo, caused a change in expression of proteins related to vitamin A metabolism and transport. Together, these observations could explain the birth defects observed in earlier teratogenicity studies.

Original languageEnglish
Pages (from-to)1921-1936
Number of pages16
JournalJournal of Applied Toxicology
Issue number12
Early online date20-Jul-2022
Publication statusPublished - Dec-2022


  • precision-cut liver slices
  • retinoid binding proteins
  • retinoids
  • teratogenicity
  • tetrakis(hydroxymethyl) phosphonium sulphate
  • THPS
  • VAD
  • vitamin A homeostasis
  • ACID

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