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Inhibiting matrix metalloproteinases with prinomastat produces abnormalities in fetal growth and development in rats
Husam S Younis1, Bart A Jessen, Ellen Y Wu
1Worldwide Safety Sciences, Pfizer Global Research and Development, La Jolla Laboratories, San Diego, California 92121, USA. husam.younis@pfizer.com
Background:
Matrix metalloproteinases (MMPs) play key roles in remodeling of the extracellular matrix during embryogenesis and fetal development. The objective of this study was to determine the effects of prinomastat, a potent selective MMP inhibitor, on fetal growth and development.
Methods:
Prinomastat (25, 100, 250 mg/kg/day, p.o.) was administered to pregnant female Sprague-Dawley rats on gestational days (GD) 6-17. A Cesarian section was carried out on GD 20 and the fetuses were evaluated for viability and skeletal and soft tissue abnormalities.
Results:
Prinomastat treatment at the 250 mg/kg/day dose produced a decrease in body weight and food consumption in the dams. A dose-dependent increase in post-implantation loss was observed in the 100 and 250 mg/kg/day-dose groups, resulting in only 22% of the dams having viable litters for evaluation at the 250 mg/kg/day dose. Fetal skeletal tissue variations and malformations were present in all prinomastat treated groups and their frequency increased with dose. Variations and malformation in fetal soft tissue were also increased at the 100 and 250 mg/kg/day doses. Prinomastat also interfered with fetal growth of rat embryo cultures in vitro.
Conclusions:
These data confirm that MMP inhibition has a profound effect on fetal growth and development in vivo and in vitro.
Insights
Prinomastat, an MMP inhibitor, significantly harmed fetal development in rats, causing birth defects and reduced litter viability. This highlights the critical role of matrix metalloproteinases in embryogenesis.
Area of Science:
- Developmental biology
- Pharmacology
Background:
- Matrix metalloproteinases (MMPs) are crucial for extracellular matrix remodeling during embryonic and fetal development.
- Understanding MMP roles is key to identifying potential developmental risks of MMP inhibitors.
Purpose of the Study:
- To investigate the effects of prinomastat, a selective MMP inhibitor, on fetal growth and development in a rat model.
Main Methods:
- Pregnant Sprague-Dawley rats received prinomastat (25, 100, 250 mg/kg/day) orally from gestational days 6-17.
- Cesarean sections on day 20 assessed fetal viability, skeletal, and soft tissue abnormalities.
- In vitro rat embryo cultures were used to evaluate direct effects on embryonic growth.
Main Results:
- Prinomastat caused dose-dependent increases in post-implantation loss and reduced dam body weight and food consumption.
- All treated groups showed increased fetal skeletal and soft tissue variations and malformations, with higher doses leading to more frequent defects.
- Prinomastat impaired embryonic growth in vitro.
Conclusions:
- Matrix metalloproteinase inhibition profoundly impacts fetal development both in vivo and in vitro.
- Prinomastat poses significant risks to embryonic and fetal development.
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