TY - JOUR
T1 - Disruption of vitamin A homeostasis by the biocide tetrakis(hydroxymethyl) phosphonium sulphate in pregnant rabbits
AU - Estrada-Ortiz, Natalia
AU - Starokozhko, Viktoriia
AU - van Steenwijk, Hidde
AU - van der Heide, Cor
AU - Permentier, Hjalmar
AU - van Heemskerk, Lisanne
AU - Prins, Grietje Harmanna
AU - Heegsma, Janette
AU - Faber, Klaas Nico
AU - Bressers, Steffi
AU - Steiblen, Guy
AU - de Groot, Antoinette
AU - Groome, Steve
AU - van Miert, Erik
AU - Groothuis, Geny
AU - de Graaf, Inge Anne Maria
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - precision-cut liver slices
KW - retinoid binding proteins
KW - retinoids
KW - teratogenicity
KW - tetrakis(hydroxymethyl) phosphonium sulphate
KW - THPS
KW - VAD
KW - vitamin A homeostasis
KW - ACUTE-PHASE RESPONSE
KW - RETINOL-BINDING-PROTEIN
KW - PRECISION-CUT LIVER
KW - ACID
KW - METABOLISM
KW - EXPRESSION
KW - SECRETION
KW - ALCOHOL
KW - EMBRYO
KW - ESTERS
U2 - 10.1002/jat.4364
DO - 10.1002/jat.4364
M3 - Article
SN - 0260-437X
VL - 42
SP - 1921
EP - 1936
JO - Journal of Applied Toxicology
JF - Journal of Applied Toxicology
IS - 12
ER -