Polychlorobiphenyls inhibit skeletal muscle differentiation in culture

Polychlorinated biphenyls (PCBs) are ubiquitous and persistent pollutants w hose role in developmental toxicity is of great concern. The observation th at the offspring of PCB-exposed mothers (both in humans and rodents) displa y reduced body mass prompted us to investigate the effects of commercial mi xtures of PCB congeners (Aroclor 1232, 1254, and 1262) on differentiation o f both a myogenic cell line and primary myogenic cell cultures. The fusion of L6 myoblasts into multinucleated myotubes and the increase of creatine k inase (CK) activity were dose-dependently inhibited by Aroclor 1254 at conc entrations (0.1-4 mug/ml) that caused no effect on cell density. Ultrastruc tural analysis demonstrated that Aroclor 1254 also prevented the accumulati on of contractile filaments while inducing hypertrophy of the smooth endopl asmic reticulum and appearance of membrane-filled autophagosomes. Half-maxi mal inhibition (IC50) of CK activity accumulation occurred at 0.01 mug/ml f or Aroclor 1262, 2 mug/ml for Aroclor 1254, and 8 mug/ml for Aroclor 1232. Aroclor-dependent inhibition of myogenic differentiation was also shown by the reduced expression and nuclear accumulation of beta -galactosidase in p rimary cultures of fetal myoblasts from transgenic mice expressing this rep orter gene under the control of the myosin light chain promoter. These data show that skeletal muscle differentiation is specifically impaired by PCBs and may explain the reported depression of body mass growth in PCB-exposed offspring at birth. Furthermore, myogenic cell cultures are highly sensiti ve to PCBs and allow the detection of biological effects of environmental l evels of these pollutants. (C) 2001 Academic Press.