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The acute effects of mono(2-ethylhexyl)phthalate (MEHP) on testes of prepubertal Wistar rats
M Dalgaard1, C Nellemann, H R Lam
1Danish Veterinary and Food Administration, Institute of Food Safety and Toxicology, Mørkhøj Bygade 19, 2860 Søborg, Denmark. mac@fdir.dk
Abstract:
A single oral dose of 400 mg/kg body weight of mono(2-ethylhexyl)phthalate (MEHP), the testis toxic metabolite of di(2-ethylhexyl)phthalate, was given to 28-day-old male Wistar rats and the testis toxic effects were investigated 3,6, and 12 h after exposure. Detachment and sloughing of germ cells were observed, and in the Sertoli cells the cytoplasmatic intermediate filament vimentin collapsed. In the immunohistochemical investigation the androgen receptor distribution was unchanged between the control group and treated groups. The expression of the testosterone-repressed-prostatic-message-2 gene in rat testis increased after 3 h, but returned to control levels after 6 and 12 h. Caspase-3 activity increased 3 and 12 h after MEHP exposure. This increase could not be correlated to an increase in DNA fragmentation or increase in apoptotic numbers of germ cells. In conclusion, the effect of MEHP in testis is apparently not involving the androgen receptor. Vimentin localisation in the Sertoli cells, and increased levels of caspase-3 activity appear to be sensitive and early markers of MEHP testis toxicity.
Insights
Mono(2-ethylhexyl)phthalate (MEHP), a toxic metabolite, causes testicular damage in rats. Vimentin disruption in Sertoli cells and increased caspase-3 activity are early indicators of MEHP toxicity.
Area of Science:
- Reproductive Toxicology
- Environmental Health
- Cell Biology
Background:
- Di(2-ethylhexyl)phthalate (DEHP) is a common plasticizer with known testicular toxicity.
- Mono(2-ethylhexyl)phthalate (MEHP) is the active metabolite responsible for DEHP's adverse effects on the testes.
- Understanding the early cellular mechanisms of MEHP toxicity is crucial for risk assessment.
Purpose of the Study:
- To investigate the acute testicular toxicity of mono(2-ethylhexyl)phthalate (MEHP) in young male rats.
- To identify early cellular and molecular markers of MEHP-induced testicular damage.
- To determine the role of the androgen receptor pathway in MEHP toxicity.
Main Methods:
- Administration of a single oral dose of MEHP (400 mg/kg) to 28-day-old male Wistar rats.
- Evaluation of testicular effects at 3, 6, and 12 hours post-exposure.
- Histological examination for germ cell detachment and vimentin changes in Sertoli cells.
- Immunohistochemical analysis of androgen receptor distribution.
- Gene expression analysis of testosterone-repressed-prostatic-message-2.
- Assay of caspase-3 activity and assessment of DNA fragmentation and apoptosis.
Main Results:
- MEHP exposure led to germ cell detachment and sloughing, along with vimentin collapse in Sertoli cells.
- Androgen receptor distribution remained unchanged in MEHP-exposed testes compared to controls.
- Testosterone-repressed-prostatic-message-2 gene expression transiently increased at 3 hours post-exposure.
- Caspase-3 activity was elevated at 3 and 12 hours, but not correlated with increased DNA fragmentation or germ cell apoptosis.
- Vimentin localization changes and elevated caspase-3 activity were identified as sensitive early markers.
Conclusions:
- The testicular toxicity of MEHP in young rats does not appear to involve the androgen receptor pathway.
- Disruption of vimentin in Sertoli cells and increased caspase-3 activity are sensitive and early indicators of MEHP-induced testicular damage.
- These findings provide insights into the mechanisms of phthalate ester toxicity and potential biomarkers for exposure.
