Fluorine probes for investigating the mechanism of activation of indeno[1,2,3-cd]pyrene to a tumorigenic agent.

Indeno[1,2,3-cd]pyrene (IP) is a non-alternant polycyclic aromatic hydrocarbon that has tumor-initiating activity on mouse skin and is carcinogenic in newborn mice and in rat lungs. Previous studies have shown that 8- and 9-hydroxyIP and IP-1,2-diol are major metabolites formed in vivo in mouse skin. 8-HydroxyIP-1,2-diol and 9-hydroxyIP-1,2-diol are also observed as in vivo metabolites of IP. Although 8-hydroxyIP had marginal tumor-initiating activity on mouse skin, IP-1,2-diol and its epoxide precursor, IP-1,2-oxide, had similar tumorigenic activity as IP. In the present study fluorine probes have been employed to investigate the contribution of metabolic activation at the 1,2 and 7-10 positions of IP. At a total initiating dose of 4.0 mumol, 2-fluoroIP induced skin tumors in 76% of the treated animals with an average of 3.9 tumors/mouse. At the same dose, IP induced a 72% incidence of tumor-bearing mice with 2.1 tumors/mouse. In contrast, 8,9-difluoroIP elicited a tumorigenic response in 40% of the treated animals with 0.6 tumors/animal. Five mice from each experimental group were killed at the conclusion of the initiation phase of the bioassay and DNA was isolated from the treated areas of skin. 32P-Postlabeling analysis of the hydrolyzed DNA indicated that IP forms one major detectable DNA adduct that migrates close to the origin. This adduct is absent in mice treated with 8,9-difluoroIP. In contrast, 2-fluoroIP forms one major adduct spot with different retention behavior as compared with the adduct formed from IP. DNA from mice treated topically with IP-1,2-diol and IP-1,2-oxide was subjected to 32P-postlabeling analysis. IP-1,2-diol forms one major DNA adduct spot with mobility similar to that observed for the IP-DNA adduct. IP-1,2-oxide displayed an intense pattern of DNA adducts centered around the location of the IP-DNA adduct. No adducts were detected which had mobility similar to that formed from 2-fluoroIP. These results are consistent with IP undergoing metabolic activation at positions 7-10 either alone or in conjunction with dihydrodiol formation at the 1,2 position.

On the maternal transfer of 4-aminobiphenyl in rats.

The potential for 4-aminobiphenyl (4-ABP) to be transferred from circulating blood into the milk of lactating Sprague-Dawley rats was determined. The distribution of 14C-labeled 4-ABP into milk was examined at time intervals of less than 1, 20, 60, 120, 240 and 480 min after i.v. dose administration. Elimination of radioactivity from blood and milk was determined to be biphasic. The levels of 4-ABP and/or metabolites were lower in milk than in blood at all time points examined. The levels of radioactivity detected in blood declined less rapidly than in milk. That is, the percent of the dose per ml of blood declined from 0.81-0.45, while the percent of the dose per ml of milk declined from 0.38-0.06 during the 8 h time period. The radioactivity present in milk was partially extractable with ethyl acetate with 43% of the radioactivity being extractable at the earliest time point while only 16% was extractable after 8 h. The level of radioactivity associated with the protein precipitate of the milk samples increased from 4-21% within 4 h after treatment. The potential of 4-ABP or its metabolites to exert a genotoxic effect on newborn pups via maternal transfer was also examined. Dams were treated on day 1 post partum and then daily with 4-ABP (10 mg/kg) in corn oil or corn oil alone for 2 weeks. Each experimental group had four liters of pups each containing 5 pups. Pups were sacrificed at 15 days of age, separated by sex and the levels of 4-ABP:DNA adducts in liver determined using 32P-postlabeling. DNA adduct profiles were similar between male and female pups with total adduct levels of 332 and 338 fmol of adducts/mg of DNA, respectively. These results indicate that the genotoxic effects of 4-ABP can be transmitted from exposed dams to the nursing offspring.

Functional outcome of closed head injury in children and young adults.

A comprehensive questionnaire which measured gross and fine motor function in the area of cognition, communication, and social development was completed by parents of children and young adults who had suffered severe closed head injuries between the years 1967 and 1978. The final sample included 42 returned questionnaires. Of these patients, 15 (37%) were considered independent, 20 (49%) dependent, and 6 (14%) had died. The area of cognition and communication dysfunction seemed to contribute most to dependency. The younger age group and the patients who were comatose for a shorter period of time tended to do the best functionally. While severe closed head injury can result in significant disability, many patients can achieve functional independence.

The training of coordination.

The training of coordination is generally considered a volitional activity, during which, by trial and perception of results, an individual selects the muscular activity resulting in the desired performance. This concept of volitionally directed complex coordination of multiple muscles with speed, skill, and strength does not stand the test of thorough evaluation. Attention is limited to 1 activity at a time, with the ability to shift attention not more frequently than 3 times per second. Only under special conditions can activity be limited to specific muscles during an untrained contraction without cocontraction of other muscles. However, with repeated practice of the desired activity, a pattern of performance is developed which can be carried out rapidly and forcefully without activation of other muscles. At that time, the consciousness is no longer directing the components of the activity but merely starting, maintaining, and stopping the performance. The development of these patterns, or engrams, by practice develops the capacity to automatically inhibit muscles that do not contribute to the performance of the desired pattern. The capacity for inhibition results in coordinated activation of the muscles contributing to the performance desired. Investigation of the development of coordination in many types of normal activities, as well as in neuromuscularly impaired patients, shows that engrams develop progressively by slow, precise practice of simple patterns, combined as they develop into more and more complex patterns, until the final skill is attained.