The impact of sociodemographic factors and PSA screening among low-income Black and White men: data from the Southern Community Cohort Study.

BACKGROUND: Variation in PSA screening is a potential source of disparity in prostate cancer survival, particularly among underserved populations. We sought to examine the impact of race and socioeconomic status (SES) on receipt of PSA testing among low-income men. METHODS: Black (n=22 167) and White (n=9588) men aged ⩾40 years completed a baseline questionnaire from 2002 to 2009 as part of the Southern Community Cohort Study. Men reported whether they had ever received PSA testing and had testing within the prior 12 months. To evaluate the associations between SES, race and receipt of PSA testing, odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from the multivariable logistic models where age, household income, insurance status, marital status, body mass index and educational level were adjusted. RESULTS: Black men were younger, had a lower income, less attained education and were more likely to be unmarried and uninsured (all P<0.001). Percentages of men having ever received PSA testing rose from <40% under the age of 45 years to ~90% above the age of 65 years, with Whites >50 more likely than Blacks to have received testing. Lower SES was significantly associated with less receipt of PSA testing in both groups. After adjustment for SES, White men had significantly lower odds of PSA testing (OR 0.81; 95% CI: 0.76-0.87). CONCLUSIONS: Greater PSA testing among White than Black men over the age of 50 years in this low-income population appears to be mainly a consequence of SES. Strategies for PSA screening may benefit from tailoring to the social circumstances of the men being screened.

Association between prostate-specific antigen and leptin, adiponectin, HbA1c or C-peptide among African-American and Caucasian men.

Prior studies report slightly lower prostate-specific antigen (PSA) levels among obese men. To understand this effect, we investigated the association between PSA and blood HbA1c, C-peptide, leptin and adiponectin levels in African-American (AA) (n=121) and Caucasian (CA) (n=121) men. Among AA men, PSA levels decreased with increasing C-peptide levels (PSA=0.99, 0.93, 0.75 and 0.53 ng ml(-1) across quartiles of C-peptide, respectively; P(trend)=0.005). Among CA men, PSA levels decreased with increasing HbA1c (PSA=0.84, 0.73, 0.77 and 0.45 ng ml(-1) across quartiles of HbA1c, respectively; P(trend)=0.005). This may suggest that metabolic disturbances related to metabolic syndrome or diabetes affect the ability to detect early-stage prostate cancer.

The association between body size, prostate volume and prostate-specific antigen.

Increasing prostate volume contributes to urinary tract symptoms and may obscure prostate cancer detection. We investigated the association between obesity and prostate volume, prostate-specific antigen (PSA) and PSA density among 753 men referred for prostate biopsy. Among men with a negative biopsy, prostate volume significantly increased approximately 25% from the lowest to highest body mass index (BMI), waist or hip circumference or height categories. PSA was 0.7 ng/ml lower with a high waist-to-hip ratio. These associations were less consistent among subjects diagnosed with high-grade prostatic intraepithelial neoplasia or cancer. Our data suggest that obesity and height are independently associated with prostate volume..

Using isothiocyanate excretion as a biological marker of Brassica vegetable consumption in epidemiological studies: evaluating the sources of variability.

OBJECTIVE: Brassica vegetable consumption (e.g. broccoli) leads to excretion of isothiocyanates (ITC) in urine. We evaluated the consistency of ITC as a biomarker for dietary Brassica vegetable consumption across the types of vegetables and methods of preparation used in Western societies, and across consumption levels. DESIGN: A single-armed behavioural intervention with duplicate baseline assessment and post-intervention assessment. Urinary ITC excretion and estrogen metabolites were measured from 24-hour urine samples. Dietary intake was measured by a 24-hour recall. SETTING: The behavioural intervention facilitated daily Brassica intake among participants by providing peer support, food preparation instruction, guided practice in a teaching kitchen, and other information. SUBJECTS: Thirty-four healthy free-living postmenopausal women who recently had a negative screening mammogram at the University of Massachusetts Medical Center. RESULTS: Urinary ITC excretion and total Brassica intake followed the same pattern over the intervention. The ITC biomarker significantly predicted Brassica intake when Brassica consumption averaged about 100 g day-1, but not when Brassica consumption averaged about 200 g day-1. Urinary ITC levels were somewhat higher when more raw vegetables were consumed as compared to lightly cooked vegetables, while the types of Brassica consumed appeared to have only a small, non-significant effect on urinary ITC levels. CONCLUSION: Urinary ITC excretion would be a good exposure biomarker among populations regularly consuming a vegetable serving/day, but may be less accurate among populations with greater intake levels or a wide range of cooking practices.

Macronutrient intake and estrogen metabolism in healthy postmenopausal women.

The purpose of this study was to determine if dietary factors could bias estimates of the relationships between estrogen metabolites and breast cancer risk factors. A lower ratio of urinary 2-hydroxyestrone/16alpha-hydroxyestrone (2/16) has been associated with breast cancer diagnosis. However, both estrogen metabolism and breast cancer risk have been associated with dietary intake, and breast cancer patients may have different dietary patterns than healthy controls. An association between urinary 2/16 levels and breast cancer risk may be due to transitory dietary change after diagnosis, or due to other breast cancer risk factors which have been associated to steroid hormone metabolism. Thirty-seven healthy postmenopausal women provided two 24-h urine samples at a two-week interval. Six 24-h diet recalls were administered in this same time period. In linear regression analysis, dietary fat-to-fiber ratio (fat/fiber) and the saturated fat/soluble fiber ratio was inversely associated with urinary 2/16 values (b = -0.22, 95% CI (-0.43, -0.01); b= -0.26, 95% CI (-0.43, -0.09), respectively). The effects of these dietary factors on 2/16 were independent of body mass index or other breast cancer risk factors. These study results suggest that some of the variation in estrogen metabolite levels among postmenopausal Caucasian women may be due to dietary intake, and that dietary factors should be carefully measured and evaluated when investigating the relationship between estrogen metabolites and breast cancer risk.

Brassica vegetable consumption shifts estrogen metabolism in healthy postmenopausal women.

Previous studies suggest that the estrogen metabolite 16alpha-hydroxyestrone acts as a breast tumor promoter. The alternative product of estrogen metabolism, 2-hydroxyestrone, does not exhibit estrogenic properties in breast tissue, and lower values of the ratio 2-hydroxyestrone:16alpha-hydroxyestrone (2:16) in urine may be an endocrine biomarker for greater breast cancer risk. Vegetables of the Brassica genus, such as broccoli, contain a phytochemical, which may shift estrogen metabolism and increase the 2:16 ratio. Adding 500 g/day of broccoli to a standard diet shifts 2:16 values upward in humans; however, it is unknown as to whether healthy women are able to consume a sufficient quantity of Brassica to affect breast cancer risk through this mechanism. In this study, 34 healthy postmenopausal women participated in an intensive intervention designed to facilitate the addition of Brassica to the daily diet. The diet was measured by repeated 24-h recall, and estrogen metabolites were measured by enzyme immunoassay in 24-h urine samples. In a crude analysis, there was a nonsignificant increase in the urinary 2:16 ratio associated with greater Brassica consumption. With adjustment for other dietary parameters, Brassica vegetable consumption was associated with a statistically significant increase in 2:16 values, such that for each 10-g/day increase in Brassica consumption, there was an increase in the 2:16 ratio of 0.08 (95% confidence interval, 0.02-0.15). To the extent that the 2:16 ratio, as measured in urine, is associated with breast cancer risk, future research should consider Brassica vegetable consumption as a potentially effective and acceptable dietary strategy to prevent breast cancer.

Regioselective binding of 2,5-hexanedione to high-molecular-weight rat neurofilament proteins in vitro.

Previous studies have shown selective binding of the neurotoxicant 2,5-hexanedione (2,5-HD) to carboxyl-terminal domains of rat neurofilament (NF) M and H proteins in vitro. The present study was designed to further localize this binding in native rat NF preparations exposed to [14C]2,5-HD. Purified M and H proteins from 2,5-HD-treated NFs were subjected to cyanogen bromide (CNBr) cleavage, and the resultant peptides were separated by Tris-tricine SDS-PAGE and electroblotted to PVDF membranes. Peptides were identified by direct sequencing of stained bands and the relative radiolabeling of each peptide was determined by comparing band intensities in fluorographed blots. For NF-M, the highest label was found in CNBr 10, a peptide corresponding to residues 678-846 at the extreme carboxyl terminus. This region of the protein includes three highly conserved lysine-containing sequences believed to be critical to its function. For NF-H, the greatest binding was localized in CNBr 7 + 8, representing an incomplete cleavage product of residues 390-810. This peptide contains essentially all of the phosphorylation sites in the carboxyl terminus of NF-H, a domain believed to control NF interactions in the axon. Only minor radiolabeling was observed in other M or H peptides. Extensive dephosphorylation of NFs prior to 2,5-HD exposure had no effect on relative adduct levels in each protein. These results provide additional support for limited and specific binding of 2,5-HD to neurofilaments and indicate that the phosphorylation state of the protein may not substantially influence this binding.

Inhibition of hen brain acetylcholinesterase and neurotoxic esterase by chlorpyrifos in vivo and kinetics of inhibition by chlorpyrifos oxon in vitro: application to assessment of neuropathic risk.

Chlorpyrifos (CPS; O,O-diethyl 3,5,6-trichloro-2-pyridyl phosphorothionate; Dursban) is a widely used broad-spectrum organophosphorus (OP) insecticide. Because some OP compounds can cause a sensory-motor distal axonopathy called OP compound-induced delayed neurotoxicity (OPIDN), CPS has been evaluated for this paralytic effect. Early studies of the neurotoxicity of CPS in young and adult hens reported reversible leg weakness but failed to detect OPIDN. More recently, a human case of mild OPIDN was reported to result from ingestion of a massive dose (about 300 mg/kg) in a suicide attempt. Subsequent experiments in adult hens (the currently accepted animal model of choice for studies of OPIDN) showed that doses of CPS in excess of the LD50 in atropine-treated animals inhibited brain neurotoxic esterase (NTE) and produced mild to moderate ataxia. Considering the extensive use of CPS and its demonstrated potential for causing OPIDN at supralethal doses, additional data are needed to enable quantitative estimates to be made of the neuropathic risk of this compound. Previous work has shown that the ability of OP insecticides to cause acute cholinergic toxicity versus OPIDN can be predicted from their relative tendency to inhibit the intended target, acetylcholinesterase (AChE), versus the putative neuropathic target, NTE, in brain tissue. The present study was designed to clarify the magnitude of neuropathic risk associated with CPS exposures by measuring hen brain AChE and NTE inhibition following dosing in vivo and determining the bimolecular rate constant of inhibition (ki) for each enzyme by the active metabolite, CPS oxon (CPO), in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Limited and selective adduction of carboxyl-terminal lysines in the high molecular weight neurofilament proteins by 2,5-hexanedione in vitro.

2,5-Hexanedione (2,5-HD) induces a toxic neuropathy characterized by massive, focal axonal neurofilament (NF) accumulation. Covalent interaction of 2,5-HD with NF protein amines, resulting in pyrrole adduct formation, has been proposed as a critical step in its mechanism. The present study was undertaken to evaluate the hypothesis of selective 2,5-HD/lysine modification, by quantitating in vitro adduction in the NF proteins and in specific polypeptide domains of each protein. Native rat spinal cord NFs were exposed to 0-212.5 mM [14C]2,5-HD for 2-16 h (37 degrees C under argon), followed by removal of non-covalently bound radioactivity. Incorporation of radioactivity and pyrrole formation in NFs increased linearly with 2,5-HD concentration and biphasically with time. SDS-PAGE and fluorography demonstrated prominent labeling of the three NF subunit proteins (H, M, and L), in addition to high-MW, crosslinked material derived from NF-H and -M. Mild chymotryptic cleavage was employed to isolate the carboxyl-terminal 'tail' domains of NF-H and -M, and the pooled amino-terminal NF 'rod' regions, all of which were radiolabeled. Specific activity (mol adduct/mol protein) of adducted NF proteins and polypeptide domains was determined by scintillation counting of electroeluted proteins. Stable binding in the NF-H and -M proteins was 4- to 6-fold higher than in the NF-L protein at all 2,5-HD concentrations, with specific activities of approximately 6.9, 4.7, and 1.3 mol/mol protein, respectively, at 212.5 mM. Approximately 70-80% of NF-H and -M binding was localized to the tail domains. In contrast, NF-L and pooled rod domain adduction did not substantially exceed 1 mol/mol protein. These findings provide the first direct evidence for limited and selective pyrrole adduction in the NF proteins following 2,5-HD exposure.

Characterization of isothiocyanates, thioureas, and other lysine adduction products in carbon disulfide-treated peptides and protein.

Carbon disulfide (CS2) is an industrial solvent used in rayon production and as an organic synthetic precursor. It is also a member of the class of neuropathy-inducing xenobiotics known as the "neurofilament (NF) neurotoxicants". Current hypotheses propose direct reaction of CS2 with NF lysine epsilon-amine moieties as a step in the mechanism of this neuropathy. In this study, covalent CS2 binding in a lysine-containing dipeptide and in bovine serum albumin (BSA) in vitro was characterized. Dipeptide and BSA, incubated with 14CS2, exhibited stable incorporation of radioactivity after removal of unbound CS2 and reincubation in physiological buffer for up to 10 days. In contrast, free thiol levels decreased from a maximum immediately following CS2 exposure to near-base-line levels after 10 days, consistent with time-dependent conversion of initially formed N-substituted dithiocarbamate adducts into secondary products. HPLC/thermospray-MS and HPLC/UV photodiode-array analysis of CS2-dipeptide adducts confirmed dithiocarbamate formation and demonstrated their conversion into N-alkylisothiocyanates and, ultimately, N,N'-disubstituted thioureas and ureas. The results of UV spectrophotometry of CS2-treated BSA were also consistent with loss of dithiocarbamate and appearance of thioureas. Similar time-dependent formation of these products, in addition to N,N'-disubstituted thiuram disulfides, was demonstrated in CS2-treated BSA by means of 13C-NMR spectroscopy. SDS-PAGE analysis of adducted protein revealed a discrete, higher mobility band, likely representing a specific intramolecular cross-link. In contrast, no evidence for intermolecular protein cross-linking was obtained. Identical results were obtained with cysteinyl-blocked BSA, indicating the lack of formation of N,S-dialkyldithiocarbamate (dithiourethane) cross-links in these preparations.(ABSTRACT TRUNCATED AT 250 WORDS)