PMID- 36921846
OWN - NLM
STAT- MEDLINE
DCOM- 20230328
LR  - 20240416
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Print)
IS  - 0041-008X (Linking)
VI  - 465
DP  - 2023 Apr 15
TI  - Biologically relevant reductions in fetal testosterone and Insl3 induced by in 
      utero exposure to high levels of di-isononyl phthalate (DINP) in male rats.
PG  - 116454
LID - S0041-008X(23)00092-3 [pii]
LID - 10.1016/j.taap.2023.116454 [doi]
AB  - Some phthalate esters alter male rat reproductive development during sexual 
      differentiation by interfering with fetal testis maturation resulting in reduced 
      Leydig Cell synthesis of testosterone and insulin-like 3 (Insl3) hormones. Gene 
      transcripts associated with steroid hormone and cholesterol transport, and 
      cholesterol synthesis and lipid metabolism also are reduced. These alterations 
      cause permanent malformations of hormone-dependent tissues, sperm production and 
      fertility in male offspring; effects known as the "Phthalate Syndrome." We have 
      shown that administration of a high dose of 750 mg diisononyl phthalate 
      (750 mg/kg/d DINP) during sex differentiation reduced fetal testis testosterone 
      production (T Prod), testis gene expression and induced a low incidence of 
      reproductive malformations in male rat offspring. In the current study we 
      administered DINP at even higher dose levels (1.0 and 1.5 g/kg/d) from 
      gestational day (GD) 14 to postnatal (PND) 3 to determine if these effects were 
      dose related and if the magnitude of the effects could be predicted from a 
      statistical model of fetal testosterone production (T Prod) and Insl3 mRNA 
      levels. These models were previously developed using dipentyl phthalate (DPeP) 
      data from fetal T Prod and postnatal studies. We found that the severity of the 
      demasculinizing effects on the androgen-dependent organs and gubernaculum by DINP 
      were accurately predicted from the statistical models of fetal T prod and Insl3 
      mRNA, respectively. Taken together, our results indicate that reductions fetal T 
      prod and Insl3 predict the severity of demasculinizing effects in utero exposure 
      to the phthalates DINP and DPeP regardless of potency.
CI  - Published by Elsevier Inc.
FAU - Earl Gray, L Jr
AU  - Earl Gray L Jr
AD  - Reproductive And Developmental Toxicology Branch, PHITD, CPHEA, Office of 
      Research and Development, US Environmental Protection Agency, Research Triangle 
      Park, Mail Drop-72, NC 27711, United States of America. Electronic address: 
      gray.earl@epa.gov.
LA  - eng
GR  - EPA999999/ImEPA/Intramural EPA/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20230313
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 3XMK78S47O (Testosterone)
RN  - 6O7F7IX66E (phthalic acid)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2B1)
RN  - 0 (Phthalic Acids)
RN  - 0 (RNA, Messenger)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - C42K0PH13C (Diethylhexyl Phthalate)
SB  - IM
MH  - Rats
MH  - Male
MH  - Animals
MH  - Testosterone/metabolism
MH  - Cytochrome P-450 CYP2B1/metabolism/pharmacology
MH  - Rats, Sprague-Dawley
MH  - Semen/metabolism
MH  - *Phthalic Acids/toxicity/metabolism
MH  - Testis
MH  - RNA, Messenger/genetics/metabolism
MH  - Cholesterol/metabolism
MH  - *Diethylhexyl Phthalate
PMC - PMC10405973
MID - NIHMS1904710
OTO - NOTNLM
OT  - Altered sexual differentiation
OT  - Biologically relevant reductions in fetal testosterone
OT  - DINP
OT  - New approach methodologies
OT  - Phthalates
OT  - Reproductive tract malformations
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- 2023/03/16 06:00
MHDA- 2023/03/28 17:16
PMCR- 2024/04/15
CRDT- 2023/03/15 20:29
PHST- 2022/10/30 00:00 [received]
PHST- 2023/03/02 00:00 [revised]
PHST- 2023/03/04 00:00 [accepted]
PHST- 2023/03/28 17:16 [medline]
PHST- 2023/03/16 06:00 [pubmed]
PHST- 2023/03/15 20:29 [entrez]
PHST- 2024/04/15 00:00 [pmc-release]
AID - S0041-008X(23)00092-3 [pii]
AID - 10.1016/j.taap.2023.116454 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2023 Apr 15;465:116454. doi: 10.1016/j.taap.2023.116454. 
      Epub 2023 Mar 13.