PMID- 32628958
OWN - NLM
STAT- MEDLINE
DCOM- 20210106
LR  - 20220815
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Print)
IS  - 0041-008X (Linking)
VI  - 402
DP  - 2020 Sep 1
TI  - Multi and transgenerational epigenetic effects of di-(2-ethylhexyl) phthalate 
      (DEHP) in liver.
PG  - 115123
LID - S0041-008X(20)30249-0 [pii]
LID - 10.1016/j.taap.2020.115123 [doi]
AB  - Di-(2-ethylhexyl) phthalate (DEHP), a ubiquitous industrial pollutant, is a known 
      endocrine disrupter implicated in metabolic diseases. Prenatal DEHP exposure 
      promotes epigenetic multi- and transgenerational inheritance of adult onset 
      disease in subsequent generations (F1-F3). However, the epigenetic toxicity is 
      less understood in the liver. In this study, CD-1 mice were prenatally exposed to 
      20 mug/kg/day, 200 mug/kg/day, 500 mg/kg/day, or 750 mg/kg/day DEHP from 
      gestational day (GD) 10.5 until birth of pups. Following prenatal exposure, the 
      multigenerational and transgenerational effects of mRNA expression of epigenetic 
      regulators were evaluated in F1, F2, and F3 generation mouse livers at postnatal 
      days (PNDs) 8 and 60. Results showed that DEHP exposed mice livers exhibited 
      significant changes in global DNA methylation levels in all three generations, 
      with the effect being different in F2 after high dosage exposure. Histopathology 
      indicated that DEHP exposure could induce mild damage in F1 livers. The 
      expression levels of DNA methyltransferase 1 (Dnmt1) were significantly changed 
      in both the F1 and F2 generations at PND 8, suggesting that maintenance Dnmt1 
      plays a major role in the multigenerational effect that occur in the early 
      developmental stages. Additionally, DEHP exposure caused significant changes in 
      ten-eleven translocation methylcytosine (Tet) dioxygenases encoding Tet1 
      expression in all three generations and Tet2 expression in F3 at PND 60, 
      implicating their contributions in inducing both multi- and transgenerational 
      effects after DEHP exposure in mouse liver. Overall, our results establish that 
      prenatal and ancestral DEHP exposure are critical for epigenetic regulation of 
      DNA methylation in female mouse livers.
CI  - Copyright (c) 2020 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Wen, Yi
AU  - Wen Y
AD  - Department of Bioengineering. University of Illinois at Urbana-Champaign, Urbana, 
      IL 61801, USA; Biomedical Research Center in Mills Breast Cancer Institute, Carle 
      Foundation Hospital, Urbana, IL 61801, USA.
FAU - Rattan, Saniya
AU  - Rattan S
AD  - Department of Comparative Biosciences, College of Veterinary Medicine, University 
      of Illinois at Urbana-Champaign, Urbana, IL 61802, USA.
FAU - Flaws, Jodi A
AU  - Flaws JA
AD  - Department of Comparative Biosciences, College of Veterinary Medicine, University 
      of Illinois at Urbana-Champaign, Urbana, IL 61802, USA.
FAU - Irudayaraj, Joseph
AU  - Irudayaraj J
AD  - Department of Bioengineering. University of Illinois at Urbana-Champaign, Urbana, 
      IL 61801, USA; Biomedical Research Center in Mills Breast Cancer Institute, Carle 
      Foundation Hospital, Urbana, IL 61801, USA; Department of Comparative 
      Biosciences, College of Veterinary Medicine, University of Illinois at 
      Urbana-Champaign, Urbana, IL 61802, USA; Micro and Nanotechnology Laboratory. 
      University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Electronic 
      address: jirudaya@illinois.edu.
LA  - eng
GR  - F31 ES030467/ES/NIEHS NIH HHS/United States
GR  - P01 ES022848/ES/NIEHS NIH HHS/United States
GR  - T32 ES007326/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200703
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Endocrine Disruptors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - C42K0PH13C (Diethylhexyl Phthalate)
RN  - EC 1.13.11.- (Dioxygenases)
RN  - EC 1.13.11.- (Tet2 protein, mouse)
RN  - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases)
SB  - IM
MH  - Animals
MH  - *Chemical and Drug Induced Liver Injury
MH  - DNA (Cytosine-5-)-Methyltransferases/genetics/metabolism
MH  - DNA Methylation
MH  - DNA-Binding Proteins/genetics/metabolism
MH  - Diethylhexyl Phthalate/*toxicity
MH  - Dioxygenases
MH  - Endocrine Disruptors/*toxicity
MH  - Epigenesis, Genetic/*drug effects
MH  - Female
MH  - Gene Expression Regulation/drug effects
MH  - Male
MH  - Maternal Exposure
MH  - Mice
MH  - Pregnancy
MH  - Prenatal Exposure Delayed Effects
MH  - Proto-Oncogene Proteins/genetics/metabolism
MH  - Real-Time Polymerase Chain Reaction
PMC - PMC9374193
MID - NIHMS1612513
OTO - NOTNLM
OT  - DEHP
OT  - DNA methylation
OT  - Dnmt
OT  - Liver
OT  - Tet
OT  - Toxicology
OT  - Transgenerational
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2020/07/07 06:00
MHDA- 2021/01/07 06:00
PMCR- 2022/08/12
CRDT- 2020/07/07 06:00
PHST- 2020/02/20 00:00 [received]
PHST- 2020/06/01 00:00 [revised]
PHST- 2020/06/12 00:00 [accepted]
PHST- 2020/07/07 06:00 [pubmed]
PHST- 2021/01/07 06:00 [medline]
PHST- 2020/07/07 06:00 [entrez]
PHST- 2022/08/12 00:00 [pmc-release]
AID - S0041-008X(20)30249-0 [pii]
AID - 10.1016/j.taap.2020.115123 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2020 Sep 1;402:115123. doi: 10.1016/j.taap.2020.115123. 
      Epub 2020 Jul 3.