Maternal protein-and-energy restriction reduces the developmental toxicity of cyclophosphamide and hydroxyurea in
Ibrahim Chahoud1, Sérgio N Kuriyama, Francisco J R Paumgartten
1Institut für Klinische Pharmakologie und Toxikologie, Freie Universität Berlin, 14195 Berlin, Germany. chahoud@zedat.fu-berlin.de
Insights
Maternal protein-and-energy restriction (PER) caused low fetal weight but no malformations. PER attenuated the developmental toxicity of cyclophosphamide (CP) and hydroxyurea (HU) in pregnant rats.
Area of Science:
- Reproductive toxicology
- Developmental biology
- Nutritional science
Background:
- Maternal malnutrition can impact pregnancy outcomes and fetal development.
- Protein-and-energy restriction (PER) is a model for nutritional deficits during gestation.
- The combined effects of maternal malnutrition and teratogenic agents require further investigation.
Purpose of the Study:
- To investigate the relationship between maternal weight gain deficits from PER and pregnancy outcomes.
- To determine if PER modifies the developmental toxicity of cyclophosphamide (CP) and hydroxyurea (HU).
Main Methods:
- Two experiments were conducted using rats with induced protein-and-energy malnourishment.
- Experiment 1: Rats received CP on day 11 of gestation under normal or restricted feeding conditions.
- Experiment 2: Rats received HU on day 11 of gestation on either a normal or a protein-and-energy deficient diet.
Main Results:
- PER alone resulted in reduced maternal weight gain and low fetal body weight, without significant embryolethality or malformations (except rare sternum anomalies).
- PER attenuated the embryolethal and teratogenic effects of cyclophosphamide (CP).
- PER reduced the teratogenicity of hydroxyurea (HU) but did not alter its effects on embryolethality or fetal body weight.
Conclusions:
- Severe maternal weight gain deficits do not invariably lead to embryolethality or malformations.
- Protein-and-energy restriction (PER) can mitigate the developmental toxicity of certain teratogenic agents like CP and HU.
Abstract:
In this study, we examined the relationship between maternal weight gain deficits induced by protein-and-energy restriction (PER) and pregnancy outcome. We also evaluated whether PER would potentiate the developmental toxicity of cyclophosphamide (CP) and hydroxyurea (HU). Two independent experiments--employing two different methods of inducing protein-and-energy malnourishment-were performed. In the first experiment, well-nourished (fed ad libitum, normal diet, 22% of protein, 11.9 kJ/g) and food restricted (fed approximately half of ad libitum food intake, i.e. 12 g/day) rats received CP (0, 5 and 7.5 mg/kg sc) on pregnancy day 11. In the second experiment, well-nourished (normal diet, 24% of protein, 12.4 kJ/g) and malnourished (protein-and-energy deficient diet, 8% of protein, 6.2 kJ/g) rats received HU (0, 300 and 500 mg/kg ip) on pregnancy day 11. PER alone caused pronounced reductions of pregnancy weight gain and low fetal body weight, but induce no embryolethality and, except for a few sternum anomalies, no malformation. PER attenuated embryolethal and teratogenic effects of CP. PER reduced teratogenicity but did not alter effects of HU on embryolethality and fetal body weight. Therefore severe maternal weight gain deficits are not necessarily associated to embryolethality and terata and PER attenuates the teratogenic effects of CP and HU.
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