Transfer of PCBs via lactation simultaneously induces the expression of P450 isoenzymes and the protooncogenes c-Ha-ras and c-raf in neonates.
At the first day of lactation, maternal rats were injected with a single i.p. dose of 100 or 250 mg/kg body weight of a mixture of polychlorinated biphenyls (Aroclor 1254). This treatment caused significant increases in both material and neonatal hepatic cytochrome P-450, cytochrome b5, and cytochrome-c-(P-450) reductase. Transfer of PCBs via lactation resulted in significant increases in hepatic enzyme activities catalysed by neonatal CYP1A1, CYP1A2, CYP2B1, CYP3A1, and CYP2E1 using a variety of substrates. In contrast, the metabolism of dimethylnitrosamine and aminopyrine was only marginally (up to 2-fold) increased in maternal animals four days post treatment. Further measurements showed significant increases in maternal and neonatal epoxide hydrolase, glutathione-S-transferase, and UDP-glucuronyl transferase activities, thus suggesting a coordinated response for an induction of CYP1A1, CYP1A2, CYP2A1, CYP2B1, CYP2E1, CYP3A1, and CYP4A1 in both maternal and neonatal CYP2C6, and at the higher dose the expression of neonatal CYP2E1 was significantly reduced. Northern blot analysis provided further evidence for significant increases in maternal and neonatal hepatic CYP1A1, CYP1A2, CYP2B1, and CYP2E1 mRNA, but reduced amounts of CYP2C7 and CYP4A1 mRNA. Additional Northern blot hybridization experiments may suggest an increased expression of the protooncogenes c-Ha-ras and c-raf in the mother and the neonate upon treatment of maternal rats with Aroclor 1254. Lactation itself may result in an increased expression of the latter protooncogenes, but the mRNA of the protooncogenes c-erb A and c-erb B was not detected in any of the tissues examined.
Borlak
J T
JT
University of Reading, Department of Biochemistry and Physiology, UK.
Scott
A
A
Henderson
C J
CJ
Jenke
H J
HJ
Wolf
C R
CR
D000818:Animals; D000831:Animals, Newborn; D001140:Aroclors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002273:Carcinogens / Q000493:pharmacokinetics / Q000494:pharmacology; D020111:Chlorodiphenyl (54% Chlorine); D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003600:Cytosol / Q000201:enzymology; D004790:Enzyme Induction; D004851:Epoxide Hydrolases / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D011905:Genes, ras; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D005982:Glutathione Transferase / Q000096:biosynthesis; D007527:Isoenzymes / Q000096:biosynthesis*; D007774:Lactation; D008099:Liver / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology*; D049590:Postpartum Period; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D019908:Proto-Oncogene Proteins c-raf; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis; D011519:Proto-Oncogenes; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values
D001140:Aroclors; D002273:Carcinogens; D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; D020111:Chlorodiphenyl (54% Chlorine); D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D004851:Epoxide Hydrolases; D016283:Proto-Oncogene Proteins p21(ras)