Efficient tissue repair underlies the resiliency of postnatally developing rats to chlordecone + CCl4 hepatotoxicity

It is often assumed that at a younger age populations are at higher risk of toxic effects from exposure to toxic chemicals. Recent studies have demonstrated that neonate and postnatally developing rats are resilient 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 lethal combination of chlordecone (CD) + CCl4 known to cause 100% mortality in adult male and female rats. In a study where postnatally developing (20- and 45-day), and adult (60-day) male Sprague Dawley rats were used, administration of CCl4 (100 microliters/kg, i.p.) alone resulted in transient liver injury regardless of age as indicated by plasma alanine transaminase (ALT), sorbitol dehydrogenase (SDH) levels and histopathological 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-induced toxicity and 0% mortality in 20-day rats. [3H]Thymidine (3H-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-course studies revealed that the loss of resiliency in the two higher age groups might be due to inability to repair the injured liver rather than 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 challenge increased mortality from 25 to 85%, confirming the importance of stimulated tissue repair in animal survival. In contrast, efficient and substantial DNA synthesis observed in 20-day rats allows them to limit further progression of liver injury, thereby leading to full recovery of this age group with 0% mortality. Examination of growth factors and proto-oncogene expression revealed a 3- and 3.5-fold increase in transforming growth factor-alpha (TGF-alpha) and H-ras mRNA expressions, respectively, coinciding with maximal hepatocyte DNA synthesis in 20-day normal diet (ND) rats, as opposed to only 2- and 2.5-fold increases 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 less than a 2-fold increase in 60-day rats. These findings suggest that prompt stimulation of tissue repair permits efficient recovery from injury during early postnatal development of rats.