Larry D. Anderson

Health Effects of Depleted Uranium on Exposed Gulf War Veterans: A 10-Year Follow-Up

Medical surveillance of a group of U.S. Gulf War veterans who were victims of depleted uranium (DU) “friendly fire” has been carried out since the early 1990s. Findings to date reveal a persistent elevation of urine uranium, more than 10 yr after exposure, in those veterans with retained shrapnel fragments. The excretion is presumably from ongoing mobilization of DU from fragments oxidizing in situ. Other clinical outcomes related to urine uranium measures have revealed few abnormalities. Renal function is normal despite the kidneys expected involvement as the “critical” target organ of uranium toxicity. Subtle perturbations in some proximal tubular parameters may suggest early although not clinically significant effects of uranium exposure. A mixed picture of genotoxic outcomes is also observed, including an association of hypoxanthine-guanine phosphoribosyl transferase (HPRT) mutation frequency with high urine uranium levels. Findings observed in this chronically exposed cohort offer guidance for predicting future health effects in other potentially exposed populations and provide helpful data for hazard communication for future deployed personnel.

The Role of Nonsteroidal Regulators in Control of Oocyte and Follicular Maturation

Publisher Summary This chapter discusses the role of nonsteroidal regulators in control of oocyte and follicular maturation. The ovarian follicle is bathed in a fluid rich in steroid hormones as well as nonsteroidal regulators which interact to serve to control its maturation, responsiveness to gonadotropins, as well as to lead to control of the maturation of its oocyte. The orderly maturation of an ovarian follicle and its oocyte is controlled by pituitary LH and FSH in concert with local intrafollicular regulators. The principal nonsteroidal follicular regulators are an oocyte maturation inhibitor, a luteinization inhibitor, a luteinization stimulator, FSH receptor binding inhibitor, and inhibin-F. OMI is a polypeptide

Surveillance of depleted uranium exposed Gulf War veterans: Health effects observed in an enlarged friendly fire cohort

To determine clinical health effects in a small group of US Gulf War veterans (n = 50) who were victims of depleted uranium (DU) “friendly fire,” we performed periodic medical surveillance examinations. We obtained urine uranium determinations, clinical laboratory values, reproductive health measures, neurocognitive assessments, and genotoxicity measures. DU-exposed Gulf War veterans with retained metal shrapnel fragments were excreting elevated levels of urine uranium 8 years after their first exposure (range, 0.018 to 39.1 &mgr;g/g creatinine for DU-exposed Gulf War veterans with retained fragments vs 0.002 to 0.231 &mgr;g/g creatinine in DU exposed but without fragments). The persistence of the elevated urine uranium suggests ongoing mobilization from the DU fragments and results in chronic systemic exposure. Clinical laboratory outcomes, including renal functioning, were essentially normal. Neurocognitive measures showing subtle differences between high and low uranium exposure groups, seen previously, have since diminished. Sister chromatid exchange frequency, a measure of mutation in peripheral lymphocytes, was related to urine uranium level (6.35 sister chromatid exchanges/cell in the high uranium exposure group vs 5.52 sister chromatid exchanges/cell in the low uranium exposure group;P = 0.03). Observed health effects were related to subtle but biologically plausible perturbations in central nervous system function and a general measure of mutagen exposure. The findings related to uranium’s chemical rather than radiologic toxicity. Observations in this group of veterans prompt speculation about the health effects of DU in other exposure scenarios.

Surveillance results of depleted uranium-exposed Gulf War I veterans: sixteen years of follow-up.

As part of a longitudinal surveillance program, 35 members of a larger cohort of 77 Gulf War I veterans who were victims of depleted uranium (DU) “friendly fire” during combat underwent a 3-day clinical assessment at the Baltimore Veterans Administration Medical Center (VAMC). The assessment included a detailed medical history, exposure history, physical examination, and laboratory studies. Spot and 24-h urine collections were obtained for renal function parameters and for urine uranium (U) measures. Blood U measures were also performed. Urine U excretion was significantly associated with DU retained shrapnel burden (8.821 μg U/g creatinine [creat.] vs. 0.005 μg U/g creat., p = .04). Blood as a U sampling matrix revealed satisfactory results for measures of total U with a high correlation with urine U results (r = .84) when urine U concentrations were ≥0.1 μg/g creatinine. However, isotopic results in blood detected DU in only half of the subcohort who had isotopic signatures for DU detectable in urine. After stratifying the cohort based on urine U concentration, the high-U group showed a trend toward higher concentrations of urine β2 microglobulin compared to the low-U group (81.7 v. 69.0 μg/g creat.; p = .11 respectively) and retinol binding protein (48.1 vs. 31.0 μg/g creat.; p = .07 respectively). Bone metabolism parameters showed only subtle differences between groups. Sixteen years after first exposure, this cohort continues to excrete elevated concentrations of urine U as a function of DU shrapnel burden. Although subtle trends emerge in renal proximal tubular function and bone formation, the cohort exhibits few clinically significant U-related health effects.

Health surveillance of Gulf War I veterans exposed to depleted uranium: Updating the cohort

A cohort of seventy-four 1991 Gulf War soldiers with known exposure to depleted uranium (DU) resulting from their involvement in friendly-fire incidents with DU munitions is being followed by the Baltimore Veterans Affairs Medical Center. Biennial medical surveillance visits designed to identify uranium-related changes in health have been conducted since 1993. On-going systemic exposure to DU in veterans with embedded metal fragments is indicated by elevated urine uranium (U) excretion at concentrations up to 1,000-fold higher than that seen in the normal population. Health outcome results from the subcohort of this group of veterans attending the 2005 surveillance visit were examined based on two measures of U exposure. As in previous years, current U exposure is measured by determining urine U concentration at the time of their surveillance visit. A cumulative measure of U exposure was also calculated based on each veterans past urine U concentrations since first exposure in 1991. Using either exposure metric, results continued to show no evidence of clinically significant DU-related health effects. Urine concentrations of retinol binding protein (RBP), a biomarker of renal proximal tubule function, were not significantly different between the low vs. high U groups based on either the current or cumulative exposure metric. Continued evidence of a weak genotoxic effect from the on-going DU exposure as measured at the HPRT (hypoxanthine-guanine phosphoribosyl transferase) locus and suggested by the fluorescent in-situ hybridization (FISH) results in peripheral blood recommends the need for continued surveillance of this population.

Lead effects on protamine–DNA binding

BACKGROUND Lead impairs male fertility and may affect offspring of exposed males, but the mechanisms for this impairment are not completely clear. Protamine P1 and P2 families pack and protect mammalian sperm DNA. Human HP2 is a zinc-protein and may have an important role in fertility. As lead has affinity for zinc-containing proteins, we evaluated its ability in vitro to bind to HP2 and its effects on HP2-DNA binding. Methods and Results UV/VIS spectroscopic data indicated that HP2 binds both Pb(2+) and Zn(2+)(as chloride salts). They also provided evidence that thiol groups mainly participate for Zn(2+)-binding; however, HP2 has additional binding sites for Pb(2+). The mobility shift assay showed that lead interaction with HP2 caused a dose-dependent decrease on HP2 binding to DNA, suggesting that lead may alter chromatin stability. CONCLUSIONS These in vitro results demonstrate that lead can interact with HP2 altering the DNA-protamine binding. This chemical interaction of lead with protamines may result in chromatin alterations, which in turn may lead to male fertility problems and eventually to DNA damage.

Porcine granulosa and cumulus cell properties LH/hCG receptors, ability to secrete progesterone and ability to respond to LH☆

In order to compare the properties of isolated cumulus and granulosa cells, granulosa cells and cumulus cells surrounding oocytes were harvested from small (1-2 mm), medium (3-5 mm) and large (6-12 mm) porcine antral follicles and the number of LH/hCG receptors was measured by the binding of [125I]hCG. The ability of the cells to secrete progesterone in culture was examined in the presence and absence of hCG and LH. In 3 separate experiments of 1-h incubations at 37 degrees C using cells harvested from medium-sized follicles, granulosa cells bound 10--15-fold more iodinated hCG than an equivalent number of cumulus cells. During a 2-day culture period, cumulus cells secreted less progesterone than granulosa cells from medium- and large-sized antral follicles (p less than 0.01). The potential of both cumulus and granulosa cells to secrete progesterone in culture increased as the follicle progressed from small to large size. Also, the ability of the oocyte to mature in culture increased with antral follicle size. Concurrently the ability of cumulus-oocyte complexes to form monolayers in culture decreased as the follicle matured. Cumulus and granulosa cells harvested from small- and medium-sized follicles responded similarly to LH and hCG with a stimulation in progesterone secretion after 2-6 days in culture.

Coupled physical and digital cadaver dissection followed by a visual test protocol provides insights into the nature of anatomical knowledge and its evaluation

This research effort compared and contrasted two conceptually different methods for the exploration of human anatomy in the first‐year dissection laboratory by accomplished students: “physical” dissection using an embalmed cadaver and “digital” dissection using three‐dimensional volume modeling of whole‐body CT and MRI image sets acquired using the same cadaver. The goal was to understand the relative contributions each method makes toward student acquisition of intuitive sense of practical anatomical knowledge gained during “hands‐on” structural exploration tasks. The main instruments for measuring anatomical knowledge under this conceptual model were questions generated using a classification system designed to assess both visual presentation manner and the corresponding response information required. Students were randomly divided into groups based on exploration method (physical or digital dissection) and then anatomical region. The physical dissectors proceeded with their direct methods, whereas the digital dissectors generated and manipulated indirect 3D digital models. After 6 weeks, corresponding student anatomical assignment teams compared their results using photography and animated digital visualizations. Finally, to see whether each method provided unique advantages, a visual test protocol of new visualizations based on the classification schema was administered. Results indicated that all students, regardless of gender, dissection method, and anatomical region dissected performed significantly better on questions presented as rotating models requiring spatial ordering or viewpoint determination responses in contrast to requests for specific lexical feature identifications. Additional results provided evidence of trends showing significant differences in gender and dissection method scores. These trends will be explored with further trials with larger populations. Anat Sci Ed 1:27–40, 2008.

Inhibitory Effect of Charcoal-Treated Porcine Follicular Fluid upon Serum FSH Levels and Follicular Development in the Rhesus Monkey

Injection of charcoal treated porcine follicular fluid into 4 intact, 4 long term castrate and 2 postmenopausal rhesus monkeys brought about a selective decline in serum FSH levels. Luteinizing hormone levels were not significantly decreased. Intraperitoneal injection of 4 ml porcine follicular fluid every 8 hours for the first 4 days of the menstrual cycle led to a decrease in follicle and granulosa cell growth observed at that midcycle. Treatment with porcine serum did not exert this effect.

Effects of Follicular Development on the Ability of Cultured Porcine Granulosa Cells to Convert Androgens to Estrogens

Porcine granulosa cells from different stages of follicular development were examined for their ability to convert androgens to estrogens and their ability to secrete progesterone. Granulosa cells from all stages of follicular development can convert androgens to estrogens, and the addition of exogenous androgen is required for estrogen secretion. Granulosa cells obtained from medium and large follicles have a greater capacity to convert androgens to estrogens than do granulosa cells obtained from small follicles. The addition of FSH brought about an increase in estrogen secretion in the presence of androgen only in granulosa cells from large follicles. LH attenuated estrogen secretion in granulosa cells from medium follicles treated with testosterone. Granulosa cells from medium follicles were unable to secrete estrogen from days two to four irrespective of treatment. Androgens augment FSH stimulated progesterone secretion in granulosa cells from medium follicles from days two to four, and the addition of follicular fluid from small follicles stimulates progesterone secretion in the presence of FSH and androgens.