Maternal protein-and-energy restriction reduces the developmental toxicity of cyclophosphamide and hydroxyurea in rats.
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.
Institut für Klinische Pharmakologie und Toxikologie, Freie Universität Berlin, 14195 Berlin, Germany. chahoud@zedat.fu-berlin.de
Ibrahim
I
Chahoud
Sérgio N
SN
Kuriyama
Francisco J R
FJ
Paumgartten
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D003520:Cyclophosphamide / Q000633:toxicity*; D004032:Diet; D004040:Dietary Carbohydrates / Q000494:pharmacology*; D004622:Embryo, Mammalian / Q000187:drug effects / Q000473:pathology; D005260:Female; D005333:Fetus / Q000002:abnormalities*; D006918:Hydroxyurea / Q000633:toxicity*; D008297:Male; D010920:Placenta / Q000187:drug effects / Q000473:pathology; D010927:Placental Insufficiency / Q000473:pathology*; D011247:Pregnancy; D011502:Protein-Energy Malnutrition / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D015430:Weight Gain / Q000187:drug effects
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D004040:Dietary Carbohydrates; D003520:Cyclophosphamide; D006918:Hydroxyurea