Intergenerational response to the endocrine disruptor vinclozolin is influenced by maternal genotype and crossing scheme

Reprod Toxicol. 2018 Jun;78:9-19. doi: 10.1016/j.reprotox.2018.03.005. Epub 2018 Mar 10.

Abstract

In utero exposure to vinclozolin (VIN), an antiandrogenic fungicide, is linked to multigenerational phenotypic and epigenetic effects. Mechanisms remain unclear. We assessed the role of antiandrogenic activity and DNA sequence context by comparing effects of VIN vs. M2 (metabolite with greater antiandrogenic activity) and wild-type C57BL/6 (B6) mice vs. mice carrying mutations at the previously reported VIN-responsive H19/Igf2 locus. First generation offspring from VIN-treated 8nrCG mutant dams exhibited increased body weight and decreased sperm ICR methylation. Second generation pups sired by affected males exhibited decreased neonatal body weight but only when dam was unexposed. Offspring from M2 treatments, B6 dams, 8nrCG sires or additional mutant lines were not similarly affected. Therefore, pup response to VIN over two generations detected here was an 8nrCG-specific maternal effect, independent of antiandrogenic activity. These findings demonstrate that maternal effects and crossing scheme play a major role in multigenerational response to in utero exposures.

Keywords: DNA methylation; Endocrine disruptor; Epigenetic inheritance; Gene-environment; Genomic imprinting; Maternal effect; Vinclozolin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Breeding
  • DNA Methylation
  • Endocrine Disruptors / toxicity*
  • Epigenesis, Genetic
  • Female
  • Fungicides, Industrial / toxicity*
  • Genotype
  • Male
  • Maternal-Fetal Exchange
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Oxazoles / toxicity*
  • Phenotype
  • Pregnancy
  • Prenatal Exposure Delayed Effects*
  • Sperm Count
  • Spermatozoa / drug effects

Substances

  • Endocrine Disruptors
  • Fungicides, Industrial
  • Oxazoles
  • vinclozolin