Faculty Bibliography

ABSTRACT/UNASSIGNED:The human brain dose from radon-222 (222Rn) exposure is calculated here using 222Rn tissue solubility data. A fraction of 222Rn inhaled dissolves in blood and cellular fluids and circulates to brain and all organs. Radon-222 has a relatively high solubility in blood and body fluids based on human inhalation experiments. The brain dose uses calculated concentrations of 222Rn in blood and cellular fluids from exhaled breath measurements following human exposure in a 222Rn chamber. The annual brain dose from continuous inhalation of a concentration of 100 Bq m-3 is about 450 times less than the dose to bronchial epithelium from inhalation of the same 222Rn concentration. Based on the 222Rn dosimetry here, it is highly unlikely that brain cancer is related to even high 222Rn exposures. Any functional or neurodegenerative issues from exposure to very small doses of 222Rn alpha particles are, at present, unknown.

The validation of human biological models for inhaled radionuclides is nearly impossible. Requirements for validation are: (1) the measurement of the relevant human tissue data and (2) valid exposure measurements over the interval known to apply to tissue uptake. Two lung models, ICRP 30(( 1)) and ICRP 66(( 2)), are widely used to estimate lung doses following acute occupational or environmental exposure. Both ICRP 30 and 66 lung models are structured to estimate acute rather than chronic exposure. Two sets of human tissue measurements are available: (210)Po accumulated in tissue from inhaled cigarettes and ingested in diet and airborne global fallout (239,240)Pu accumulated in the lungs from inhalation. The human tissue measurements include pulmonary and bronchial tissue in smokers, ex-smokers and non-smokers analysed radiochemically for (210)Po, and pulmonary, bronchial and lymph nodes analysed for (239,240)Pu in lung tissue collected by the New York City Medical Examiner from 1972 to 1974. Both ICRP 30 and 66 models were included in a programme to accommodate chronic uptake. Neither lung model accurately described the estimated tissue concentrations but was within a factor of 2 from measurements. ICRP 66 was the exception and consistently overestimated the bronchial concentrations probably because of its assumption of an overly long 23-d clearance half-time in the bronchi and bronchioles.

An epidemiologic study of childhood leukemia in Denmark (2,400 cases; 6,697 controls) from 1968 to 1994 suggested a weak, but statistically significant, association of residential radon exposure and acute childhood lymphoblastic leukemia (ALL). The Danish study estimated a relative risk (RR) = 1.56 (95% CI, 1.05-2.30) for a cumulative exposure of 1,000 Bq m-3 y. For an exposure duration of 10 y their RR corresponds to a radon concentration of 100 Bq m-3. There are two dose pathways of interest where alpha particles could damage potential stem cells for ALL. One is the alpha dose to bone marrow, and two is the dose to bronchial mucosa where an abundance of circulating lymphocytes is found. Compared with an exposure of about 1 mSv y-1 from natural external background, radon and decay products contribute an additional 10 to 60% to the bone marrow equivalent dose. The other pathway for exposure of T (or B) lymphocytes is within the tracheobronchial epithelium (BE). Inhaled radon decay products deposit on the relatively small area of airway surfaces and deliver a significant dose to the nearby basal or mucous cells implicated in human lung cancer. Lymphocytes are co-located with basal cells and are half as abundant. Using a 10-y exposure to 100 Bq m-3, our dose estimates suggest that the equivalent dose to these lymphocytes could approach 1 Sv. The relatively high dose estimate to lymphocytes circulating through the BE, potential precursor cells for ALL, provides a dose pathway for an association

Apoptosis is induced by caspases, which are members of the cysteine protease family. Caspases are synthesized as inactive zymogens and initiator caspases first gain activity by associating with an oligomeric complex of their adaptor proteins, such as the apoptosome. Activated initiator caspases subsequently cleave and activate effector caspases. Although such a proteolytic cascade would predict that a small number of active caspases could irreversibly amplify caspase activity and trigger apoptosis, many cells can maintain moderate levels of caspase activity to perform non-apoptotic roles in cellular differentiation, shape change and migration. Here we show that the Drosophila melanogaster apoptosome engages in a feedback inhibitory loop, which moderates its activation level in vivo. Specifically, the adaptor protein Apaf-1 lowers the level of its associated initiator caspase Dronc, without triggering apoptosis. Conversely, Dronc lowers Apaf-1 protein levels. This mutual suppression depends on the catalytic site of Dronc and a caspase cleavage site within Apaf-1. Moreover, the Drosophila inhibitor of apoptosis protein 1 (Diap1) is required for this process. We speculate that this feedback inhibition allows cells to regulate the degree of caspase activation for apoptotic and non-apoptotic purposes

Abundant epidemiological data are now available (2008) on the human lung cancer response for lifetime radon gas exposure to residential concentrations of 100 Bq m(-3), equal to 22 working level months over 40 y. We combined published pooled epidemiological data and dosimetric calculations of alpha particle hits to target basal or mucous cell nuclei in bronchial epithelium. This yields an estimate that about 10,000 basal nuclei (target) cell hits per cm2 per person over a lifetime are involved in radon-related lung cancer. The DNA target cell area (cross section) for a hit is about 2 bp. The present epidemiology indicates that 1000 persons need to be exposed to this hit rate for observable cancers to be detected. The mechanism proposed is that the extensive prior DNA damage in smokers, followed by alpha particle damage to a critical site in checkpoint genes, accounts for the greater lung cancer response in smokers

The apical surface of mouse urothelium is covered by two-dimensional crystals (plaques) of uroplakin (UP) particles. To study uroplakin function, we ablated the mouse UPII gene. A comparison of the phenotypes of UPII- and UPIII-deficient mice yielded new insights into the mechanism of plaque formation and some fundamental features of urothelial differentiation. Although UPIII knockout yielded small plaques, UPII knockout abolished plaque formation, indicating that both uroplakin heterodimers (UPIa/II and UPIb/III or IIIb) are required for plaque assembly. Both knockouts had elevated UPIb gene expression, suggesting that this is a general response to defective plaque assembly. Both knockouts also had small superficial cells, suggesting that continued fusion of uroplakin-delivering vesicles with the apical surface may contribute to umbrella cell enlargement. Both knockouts experienced vesicoureteral reflux, hydronephrosis, renal dysfunction, and, in the offspring of some breeding pairs, renal failure and neonatal death. These results highlight the functional importance of uroplakins and establish uroplakin defects as a possible cause of major urinary tract anomalies and death

FGF-2 and VEGF are potent angiogenesis inducers in vivo and in vitro. Here we show that FGF-2 induces VEGF expression in vascular endothelial cells through autocrine and paracrine mechanisms. Addition of recombinant FGF-2 to cultured endothelial cells or upregulation of endogenous FGF-2 results in increased VEGF expression. Neutralizing monoclonal antibody to VEGF inhibits FGF-2-induced endothelial cell proliferation. Endogenous 18-kD FGF-2 production upregulates VEGF expression through extracellular interaction with cell membrane receptors; high-Mr FGF-2 (22-24-kD) acts via intracellular mechanism(s). During angiogenesis induced by FGF-2 in the mouse cornea, the endothelial cells of forming capillaries express VEGF mRNA and protein. Systemic administration of neutralizing VEGF antibody dramatically reduces FGF-2-induced angiogenesis. Because occasional fibroblasts or other cell types present in the corneal stroma show no significant expression of VEGF mRNA, these findings demonstrate that endothelial cell-derived VEGF is an important autocrine mediator of FGF-2-induced angiogenesis. Thus, angiogenesis in vivo can be modulated by a novel mechanism that involves the autocrine action of vascular endothelial cell-derived FGF-2 and VEGF

Our understanding of selective neuronal vulnerability as well as etiopathogenesis of sporadic neurodegenerative diseases is extremely limited. In ALS, altered calcium homeostasis appears to contribute significantly to selective neuronal injury. Further in ALS, the absence of calcium binding proteins (calbindin-D28K, parvalbumin, and calretinin) correlates with selective vulnerability and cell loss. In motoneuron cell culture models an ALS IgG-triggered and calcium-mediated destruction can be reversed by increased expression of calbindin-D28K following retroviral infection with calbindin-D28K cDNA. To increase calcium binding protein expression in motoneurons in vitro and in vivo, we have employed vitamin D3. Forty-eight hr treatment of differentiated VSC 4.1 cells with 0.1-30 nM 1,25 dihydroxyvitamin D3 induced a two-fold increase in the immunoreactivity for calbindin-D28K and parvalbumin. Injection of 80-120 ng, 1,25 dihydroxyvitamin D3 in the cerebral ventricles of adult rats also induced positive immunoreactivity for calcium binding proteins in ventral motoneurons which are completely devoid of such reactivity in the adult stage. These data suggest that analogs of 1,25 dihydroxyvitamin D3 may be useful tools in enhancing the expression of calcium binding proteins in the motor system and may have possible therapeutic value in neurodegenerative disease