EFFICIENT TISSUE-REPAIR UNDERLIES THE RESILIENCY OF POSTNATALLY DEVELOPING RATS TO CHLORDECONE PLUS CCL4 HEPATOTOXICITY

It is often assumed that at a younger age populations are at higher ri sk of toxic effects from exposure to toxic chemicals. Recent studies h ave demonstrated that neonate and postnatally developing rats are resi lient to a wide variety of structurally and mechanistically dissimilar hepatotoxicants such as galactosamine, acetaminophen, allyl alcohol, and CCl4. Most interestingly, young rats survive exposure to the letha l combination of chlordecone (CD) + CCl4 known to cause 100% mortality in adult male and female rats. In a study where postnatally developin g (20- and 45-day), and adult (60-day) male Sprague Dawley rats were u sed, administration of CCl4 (100 mu l/kg, i.p.) alone resulted in tran sient liver injury regardless of age as indicated by plasma alanine tr ansaminase (ALT), sorbitol dehydrogenase (SDH) levels and histopatholo gical lesions. In CD-pretreated rats, CCl4-induced toxicity progressed with time culminating in 25 and 100% mortality by 72 h after CCl4 in 45- and 60-day rats, respectively, in contrast to regression of CCl4-i nduced toxicity and 0% mortality in 20-day rats. [H-3]thymidine (H-3-T ) incorporation and proliferating cell nuclear antigen (PCNA) studies revealed an association between delayed and diminished DNA synthesis, unrestrained progression of liver injury, and animal death. Time-cours e studies revealed that the loss of resiliency in the two higher age g roups might be due to inability to repair the injured liver rather tha n due to infliction of higher injury. Intervention of cell division in 45-day CD rats by colchicine (CLC, 1 mg/kg, i.p.) 30 h after CCl4 cha llenge increased mortality from 25 to 85%, confirming the importance o f stimulated tissue repair in animal survival. In contrast, efficient and substantial DNA synthesis observed in 20-day rats allows them to l imit further progression of liver injury, thereby leading to full reco very of this age group with 0% mortality. Examination of growth factor s and proto-oncogene expression revealed a 3- and 3.5-fold increase in transforming growth factor-alpha (TGF-alpha) and H-ras mRNA expressio ns, respectively, coinciding with maximal hepatocyte DNA synthesis in 20-day normal diet (ND) rats, as opposed to only 2- and 2.5-fold incre ases observed in 60-day ND rats, respectively. Increased expression of c-fos (10-fold) in 20-day rats occurred 1 h after CCl4 compared to le ss than a 2-fold increase in 60-day rats. These findings suggest that prompt stimulation of tissue repair permits efficient recovery from in jury during early postnatal development of rats.