Decreased human birth weights after in utero exposure to PCBs and PCDFs are associated with decreased placental EGF-stimulated receptor autophosphorylation capacity

Abstract

Yucheng (oil disease) is a clinical and metabolic syndrome reported in Taiwanese who consumed rice oil contaminated with large amounts of various polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs), including the 2,3,4,7,8- and 1,2,3,4,7,8-PCDF congeners which are similar in structure and toxicity to 2,3,7,8-tetrachlorodibenzo-p-dioxin. A well known characteristic of Yucheng is the marked decrease in birth weights, although the underlying mechanism of this effect is unclear. Placental epidermal growth factor (EGF) receptor binding and autophosphorylation studies were done using tissue samples taken from Yucheng and unexposed control patients. EGF-stimulated receptor autophosphorylation of the human placental EGF receptor in the Yucheng subjects was decreased more than 60% of control levels, 4-5 years after the exposure had occurred. The decrease in EGF receptor phosphorylation was significantly correlated with decrease in birth weights. Nonlinear regression analysis of the 125I-EGF receptor binding data revealed that there were two distinct EGF receptor binding isotherms representing the high affinity-low capacity (HALC) and the low affinity-high capacity (LAHC) binding sites. In contrast to the placental EGF-stimulated phosphorylation data described above, the binding kinetics of the EGF receptor were not significantly altered in the control [HALC site Kd = 0.10 +/- 0.02 (SE) nM, Bmax = 788 +/- 255 fmol/mg of protein; LAHC site Kd = 17.4 +/- 8.2 nM, Bmax = 62 +/- 32 pmol/mg) compared to the Yucheng subjects (HALC site Kd = 0.11 +/- 0.02 nM, Bmax = 784 +/- 305 fmol/mg; LAHC site Kd = 49.5 +/- 24.7 nM, Bmax = 147 +/- 80 pmol/mg). GC-MS analysis of placental specimens showed elevated levels of selected PCB and PCDF congeners in the Yucheng compared to control individuals. Total PCB levels were 0.5 +/- 0.2 ppb and 20.0 +/- 4.8 ppb for the control and Yucheng subjects, respectively. A significant dose-response relationship was observed between the placental EGF receptor phosphorylation levels and the PCB concentrations (total or concentrations of 2,2',4,4',5,5'-hexa- and 2,2'3,3'4,4',5-heptachlorobiphenyls). In contrast, no significant relationship was found between the EGF receptor phosphorylation activity and the 2,3,4,7,8- or 1,2,3,4,7,8-PCDF congeners, which were at nondetectable levels in the control and between 104 and 374 parts per trillion in the Yucheng subjects. In summary, our data reveal that decreased placental EGF receptor phosphorylation capacity is associated with decreased birth weight. Furthermore, PCB tissue concentrations might be a better predictor of effects than are PCDF concentrations.