Benzo(a)pyrene inhibits epidermal growth factor binding and receptor autophosphorylation in human placental cell cultures.
Studies investigated the effects of benzo(a)pyrene (BP) treatment on epidermal growth factor (EGF) receptor binding and kinase activity in human placental cell cultures. Specific binding of 125I-EGF to cells from early gestation placentae was significantly decreased by 37 and 60% following exposure to 1 and 10 microM BP, respectively, for 24 hr. In contrast, cells cultured from term placentae showed no inhibitory effect of either concentration of BP. Specific binding of 125I-labeled insulin and insulin-like growth factors-I and -II to early gestation cells was decreased only 15-18% at 10 microM BP, which indicates that loss of membrane receptors appears to be selective for EGF. Scatchard analysis of early gestation cells revealed that BP was associated with a dose-dependent loss in the number of high affinity EGF binding sites. Evidence from cross-linking and autophosphorylation experiments confirmed that the Mr 170,000 binding protein was decreased in a dose-dependent manner following BP treatment. In comparison, term placental cells exhibit a 26% loss of EGF receptor autophosphorylation without alteration in binding following exposure to 10 microM BP. Thus, early gestation cells exhibit a BP-related down-regulation of EGF receptors, whereas term placental cells show receptor desensitization. No adverse effect of BP treatment was observed on the incorporation of [35S] methionine into proteins secreted by early gestation cells. Further experiments compared the effects of BP with the related poly-cyclic compounds beta-naphthoflavone, alpha-naphthoflavone, and 3-methylcholanthrene. In early gestation cells, EGF binding and receptor autophosphorylation were measurably decreased at 10 microM concentrations of these polycyclic compounds, but to a lesser extent than observed with BP. In term placental cells, however, EGF binding was unchanged or increased, whereas receptor autophosphorylation was decreased 10-26%. Thus, exposure of term placental cells to these polycyclic compounds leads to a dissociation between EGF binding and receptor protein kinase activity. Finally, aryl hydrocarbon hydroxylase activity was induced 20- to 200-fold in early placental cells exposed to BP, beta-naphthoflavone, and 3-methylcholanthrene. In summary, the direct effects of BP and related compounds observed on placental EGF receptors may indicate altered function of EGF in the regulation of cell growth and differentiation in the human placenta.
Guyda
H J
HJ
Department of Pediatrics, Montreal Children's Hospital-McGill University Research Institute, Quebec, Canada.
Mathieu
L
L
Lai
W
W
Manchester
D
D
Wang
S L
SL
Ogilvie
S
S
Shiverick
K T
KT
D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D001564:Benzo(a)pyrene / Q000494:pharmacology*; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D066246:ErbB Receptors / Q000187:drug effects* / Q000378:metabolism; D005865:Gestational Age; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D010766:Phosphorylation; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011083:Polycyclic Compounds / Q000494:pharmacology; D011257:Pregnancy Proteins / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011972:Receptor, Insulin / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000187:drug effects; D017451:Receptors, Somatomedin
D011083:Polycyclic Compounds; D011257:Pregnancy Proteins; D011956:Receptors, Cell Surface; D017451:Receptors, Somatomedin; D001564:Benzo(a)pyrene; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D001189:Aryl Hydrocarbon Hydroxylases; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin