Synchronization of hepatic DNA synthesis by scheduled feeding and lighting in mice treated with the chemical inducer of liver growth alpha-hexachlorocyclohexane.

Abstract

A single dose of alpha-hexachlorocyclohexane (alpha-HCH) induces liver enlargement in adolescent mice. Concomitantly, the DNA content of the organ increases, and DNA synthesis is enhanced in parenchymal cells after a lag phase ('pre-replicative period') of 12-20 hr. DNA replication appears not to be followed by mitosis. Adaptation of the mice to a controlled feeding and lighting schedule provides synchronization of the hepatic DNA synthesis response to alpha-HCH. This appeared due to the provision, by the feeding and lighting schedule, of permissive signals which are required for stimulation of hepatic DNA synthesis in addition to alpha-HCH. One such signal is provided by food consumption before alpha-HCH administration, i.e. in the G0 phase. A second signal is provided after alpha-HCH administration in the late prereplicative period by feeding a protein-containing diet, and by other events, possibly related to the light-dark shift. Without this signal, the majority of hepatocytes stimulated to replicate DNA is arrested and accumulates at a stage a few hours before the start of DNA synthesis. The signal provides release from the block fairly synchronously. Both permissive signals seem also operative in the control of 'physiological' DNA synthesis in the liver of untreated mice. In conclusion, use of alpha-HCH and proper timing of feeding and lighting periods should provide an experimental model helpful for studying the interaction of growth stimuli with endogenous regulators of hepatic DNA replication.