Article ; Online: Biologically relevant reductions in fetal testosterone and Insl3 induced by in utero exposure to high levels of di-isononyl phthalate (DINP) in male rats.
Toxicology and applied pharmacology
2023 Volume 465, Page(s) 116454
Abstract: 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 ... ...
| Abstract | 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. |
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| MeSH term(s) | Rats ; Male ; Animals ; Testosterone/metabolism ; Cytochrome P-450 CYP2B1/metabolism ; Cytochrome P-450 CYP2B1/pharmacology ; Rats, Sprague-Dawley ; Semen/metabolism ; Phthalic Acids/toxicity ; Phthalic Acids/metabolism ; Testis ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Cholesterol/metabolism ; Diethylhexyl Phthalate |
| Chemical Substances | Testosterone (3XMK78S47O) ; phthalic acid (6O7F7IX66E) ; Cytochrome P-450 CYP2B1 (EC 1.14.14.1) ; Phthalic Acids ; RNA, Messenger ; Cholesterol (97C5T2UQ7J) ; Diethylhexyl Phthalate (C42K0PH13C) |
| Language | English |
| Publishing date | 2023-03-13 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. |
| ZDB-ID | 204477-8 |
| ISSN | 1096-0333 ; 0041-008X |
| ISSN (online) | 1096-0333 |
| ISSN | 0041-008X |
| DOI | 10.1016/j.taap.2023.116454 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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