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 sing le i.p. dose of 100 or 250 mg/kg body weight of a mixture of polychlor inated biphenyls (Aroclor 1254). This treatment caused significant inc reases in both material and neonatal hepatic cytochrome P-450, cytochr ome b(5), and cytochrome-c-(P-450) reductase. Transfer of PCBs via lac tation 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 dimethylnitro samine and aminopyrine was only marginally (up to 2-fold) increased in maternal animals four days post treatment. Further measurements showe d significant increases in maternal and neonatal epoxide hydrolase, gl utathione-S-transferase, and UDP-glucuronyl transferase activities, th us suggesting a coordinated response in maternal and neonatal oxidativ e and post-oxidative drug metabolism. Western blot analysis provided e vidence for an induction of CYP1A1, CYP1A2, CYP2A1, CYP2B1, CYP2E1, CY P3A1, and CYP4A1 in both maternal and neonatal liver, albeit at varyin g intensities. However, PCBs did not modulate the expres sion of mater nal and neonatal CYP2C6, and at the higher dose the expression of neon atal CYP2E1 was significantly reduced. Northern blot analysis provided further evidence for significant increases in maternal and neonatal h epatic CYP1A1, CYP1A2, CYP2B1, and CYP2E1 mRNA, but reduced amounts of CYP2C7 and CYP4A1 mRNA. Additional Northern blot hybridization experi ments may suggest an increased expression of the protooncogenes c-Ha-r as and c-raf in the mother and the neonate upon treatment of maternal rats with Aroclor 1254. Lactation itself may result in an increased ex pression of the latter protooncogenes, but the mRNA of the protooncoge nes c-erb A and c-erb B was not detected in any of the tissues examine d.