Experimental hyperphenylalaninemia in the pregnant guinea pig: possible phenylalanine teratogenesis and p-chlorophenylalanine embryotoxicity.
Maternal hyperphenylalaninemia (HPH) due to deficient phenylalanine (Phe) hydroxylation is a recognized human teratogen associated with an increased incidence of intrauterine growth retardation, microcephaly, congenital heart disease, and mental retardation. There are no previous reports of experimental HPH during organogenesis. Sustained HPH was produced in pregnant guinea pigs by adding 3.5% Phe and 1.0% parachlorophenylalanine (pCPA), an inhibitor of Phe hydroxylase, to standard guinea pig chow. Animals consumed the supplemented test diets from gestation day 1 until killed on gestation day 17. Examination of day 17 embryos revealed that embryonic mortality was associated only with maternal pCPA administration and was independent of the degree of maternal HPH. Embryonic malformation was associated with maternal HPH as well as maternal pCPA administration. Both maternal HPH and pCPA administration were associated with embryonic growth retardation. There was no association between maternal food intake or plasma tyrosine levels and embryonic abnormality or mortality. Both Phe and tyrosine were found to be concentrated in gestation day 17 yolk sac fluid when compared to maternal plasma Phe and tyrosine. The association of embryonic malformation and maternal HPH is consistent with human data. The embryotoxicity of pCPA requires further study and highlights the necessity of appropriate controls in models of experimental HPH.
D000818:Animals; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D010134:Fenclonine / Q000633:toxicity*; D005313:Fetal Death / Q000139:chemically induced; D006168:Guinea Pigs; D008099:Liver / Q000201:enzymology; D008431:Maternal-Fetal Exchange; D010649:Phenylalanine / Q000097:blood / Q000633:toxicity*; D010651:Phenylalanine Hydroxylase / Q000172:deficiency / Q000378:metabolism; D011247:Pregnancy
D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase; D010134:Fenclonine