title: Diethylstilbestrol (DES)-stimulated hormonal toxicity is mediated by ERα alteration of target gene methylation patterns and epigenetic modifiers (DNMT3A, MBD2, and HDAC2) in the mouse seminal vesicle.
abstract: BACKGROUND
  Diethylstilbestrol (DES) is a synthetic estrogen associated with adverse effects on reproductive organs. DES-induced toxicity of the mouse seminal vesicle (SV) is mediated by estrogen receptor α (ERα), which alters expression of seminal vesicle secretory protein IV (Svs4) and lactoferrin (Ltf) genes.
  
  
  OBJECTIVE
  We examined a role for nuclear receptor activity in association with DNA methylation and altered gene expression.
  
  
  METHODS
  We used the neonatal DES exposure mouse model to examine DNA methylation patterns via bisulfite conversion sequencing in SVs of wild-type (WT) and ERα-knockout (αERKO) mice.
  
  
  RESULTS
  The DNA methylation status at four specific CpGs (-160, -237, -306, and -367) in the Svs4 gene promoter changed during mouse development from methylated to unmethylated, and DES prevented this change at 10 weeks of age in WT SV. At two specific CpGs (-449 and -459) of the Ltf gene promoter, DES altered the methylation status from methylated to unmethylated. Alterations in DNA methylation of Svs4 and Ltf were not observed in αERKO SVs, suggesting that changes of methylation status at these CpGs are ERα dependent. The methylation status was associated with the level of gene expression. In addition, gene expression of three epigenetic modifiers-DNMT3A, MBD2, and HDAC2-increased in the SV of DES-exposed WT mice.
  
  
  CONCLUSIONS
  DES-induced hormonal toxicity resulted from altered gene expression of Svs4 and Ltf associated with changes in DNA methylation that were mediated by ERα. Alterations in gene expression of DNMT3A, MBD2, and HDAC2 in DES-exposed male mice may be involved in mediating the changes in methylation status in the SV.
  
  
  BACKGROUND
  Li Y, Hamilton KJ, Lai AY, Burns KA, Li L, Wade PA, Korach KS. 2014. Diethylstilbestrol (DES)-stimulated hormonal toxicity is mediated by ERα alteration of target gene methylation patterns and epigenetic modifiers (DNMT3A, MBD2, and HDAC2) in the mouse seminal vesicle. Environ Health Perspect 122:262-268; http://dx.doi.org/10.1289/ehp.1307351.
authors: Laboratory of Reproductive and Developmental Toxicology.
authors: Yin
authors: Y
authors: Li
authors: Katherine J
authors: KJ
authors: Hamilton
authors: Anne Y
authors: AY
authors: Lai
authors: Katherine A
authors: KA
authors: Burns
authors: Leping
authors: L
authors: Li
authors: Paul A
authors: PA
authors: Wade
authors: Kenneth S
authors: KS
authors: Korach
mesh_terms: D000818:Animals; D019175:DNA Methylation / Q000187:drug effects; D004054:Diethylstilbestrol / Q000633:toxicity*; D004781:Environmental Exposure; D044127:Epigenesis, Genetic; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D007781:Lactoferrin / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D029607:Seminal Vesicle Secretory Proteins / Q000235:genetics / Q000378:metabolism; D012669:Seminal Vesicles / Q000187:drug effects* / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; C552902:Ltf protein, mouse; C573954:SVS4 protein, mouse; D029607:Seminal Vesicle Secretory Proteins; D004054:Diethylstilbestrol; D007781:Lactoferrin