Effects of chronic exposure to low-level cadmium on renal tubular function and CYP2A6-mediated coumarin metabolism in healthy human subjects

Relationships between cadmium (Cd) body burden, kidney function and coumarin metabolism were investigated using two groups of 197 and 200 healthy Thais with men and women in nearly equal numbers. A mean age of one group was 30.5 years and it was 39.3 years for the other group. Of 397, 20 subjects (5%) excreted urine Cd between 1.4 mug/g and 3.8 mug/g creatinine and these subjects faced 10-15% increase in the probability of having abnormal urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG-uria). The prevalence of NAG-uria varied with Cd body burden in a dose-dependent manner (chi(2) = 22, P < 0.008). Also NAG-nuria was one of the three kidney effect markers tested that showed the greatest strength of correlation with urine Cd in both men and women (r = 0.48 P < 0.001). In addition, urine Cd excretion of men and women showed a positive correlation (r = 0.46 to 0.54. P < 0.001) with urine 7-hydroxycoumarin (7-OHC) excretion which was used as a marker of liver cytochrome P450 2A6 (CYP2A6) enzyme activity. Urinary CA excretion accounted for 25% of the total variation in urine 7-OHC excretion (P < 0.001). These data suggest that Cd may increase the expression of CYP2A6 in liver, resulting in enhanced coumarin metabolism in subjects with high Cd body burden. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

Effects of cigarette smoking and exposure to cadmium and lead on phenotypic variability of hepatic CYP2A6 and renal function biomarkers in men

Effects of cigarette smoking and exposure to dietary cadmium (Cd) and lead (Pb) on urinary biomarkers of renal function and phenotypic variability of cytochrome P450 2A6 (CYP2A6) were investigated in a group of 96 healthy Thai men with mean age of 36.7 year (19-57 years). In non-smokers, Cd burden increased with age (r = 0.47, P < 0.001). In current smokers, Cd burden increased with both age (r = 0.45, P = 0.01) and number of cigarettes smoked per day (r = 0.32, P = 0.05). Cd-linked renal tubular dysfunction was seen in both smokers and non-smokers, but Pb-linked glomerular dysfunction was seen in smokers only, possibly due to more recent exposure to high levels of Cd and Pb, as reflected by 30-50% higher serum Cd and Pb levels in smokers than non-smokers (P < 0.05). Exposure to dietary Cd and Pb appeared to be associated with mild tubular dysfunction whereas dietary exposure plus cigarette smoking was associated with tubular plus glomerular dysfunction. Hepatic CYP2A6 activity in non-smokers showed a positive association with Cd burden (adjusted P = 0.38, P = 0.006), but it showed an inverse correlation with Pb (adjusted beta = -0.29, P = 0.003), suggesting opposing effects of Cd and Pb on hepatic CYP2A6 phenotype. In contrast, CYP2A6 activity in current smokers did not correlate with Cd or Pb, but it showed a positive correlation with serum ferritin levels (r = 0.45, P = 0.01). These finding suggest that Pb concentrations in the liver probably were too low to inhibit hepatic synthesis of heme and CYP2A6 and that the concurrent induction of hepatic CYP2A6 and ferritin was probably due to cigarette smoke constituents other than the Cd and Pb. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

Evidence for Concurrent Effects of Exposure to Environmental Cadmium and Lead on Hepatic CYP2A6 Phenotype and Renal Function Biomarkers in Non Smokers

We examined the interrelationships between phenotype of hepatic cytochrome P450 2A6 (CYP2A6), nephropathy, and exposure to cadmium and lead in a group of 118 healthy Thai men and women who had never smoked. Their urinary Cd excretion ranged from 0.05 to 2.36 mug/g creatinine, whereas their urinary Pb excretion ranged from 0.1 to 12 mug/g creatinine. Average age and Cd burden of women and men did not differ. Women, however, on average showed a 46% higher urinary Pb excretion (p < 0.001) and lower zinc status, suggested by lower average serum Zn and urinary Zn excretion compared with those in men. Cd-linked nephropathy was detected in both men and women. However, Pb-linked nephropathy was seen only in women, possibly because of higher Pb burden coupled with lower protective factors, notably of Zn (P < 0.001), in women compared with men. In men, Pb burden showed a negative association with CYP2A6 activity (adjusted beta = -0.29, p = 0.003), whereas Cd burden showed a positive association with CYP2A6 activity (adjusted beta = 0.38, p = 0.001), suggesting opposing effects of Cd and Pb on hepatic CYP2A6 phenotype. The weaker correlation between Cd burden CYP2A6 activity in women despite similarity in Cd burden between men and women is consistent with opposing effects of Pb and Cd on hepatic CYP2A6 phenotypic expression. A positive correlation between Cd-linked nephropathy (urinary N-acetyl-beta-D-glucosaminidase excretion) and CYP2A6 activity in men (r = 0.39, p = 0.002) and women (r = 0.37, p = 0.001) suggests that Cd induction of hepatic CYP2A6 expression and Cd-linked nephropathy occurred simultaneously.

Maternal alcohol use disorder and offspring ADHD: disentangling genetic and environmental effects using a children-of-twins design

Background. Children of alcoholics are significantly more likely to experience high-risk environmental exposures, including prenatal substance exposure, and are more likely to exhibit externalizing problems [e.g. attention deficit hyperactivity disorder (ADHD)]. While there is evidence that genetic influences and prenatal nicotine and/or alcohol exposure play separate roles in determining risk of ADHD, little has been done on determining the joint roles that genetic risk associated with maternal alcohol use disorder (AUD) and prenatal risk factors play in determining risk of ADHD. Method. Using a children-of-twins design, diagnostic telephone interview data from high-risk families (female monozygotic and dizygotic twins concordant or discordant for AUD as parents) and control families targeted from a large Australian twin cohort were analyzed using logistic regression models. Results. Offspring of twins with a history of AUD, as well as offspring of non-AUD monozygotic twins whose co-twin had AUD, were significantly more likely to exhibit ADHD than offspring of controls. This pattern is consistent with a genetic explanation for the association between maternal AUD and increased offspring risk of ADHD. Adjustment for prenatal smoking, which remained significantly predictive, did not remove the significant genetic association between maternal AUD and offspring ADHD. Conclusions. While maternal smoking during pregnancy probably contributes to the association between maternal AUD and offspring ADHD risk, the evidence for a significant genetic correlation suggests: (i) pleiotropic genetic effects, with some genes that influence risk of AUD also influencing vulnerability to ADHD; or (ii) ADHD is a direct risk-factor for AUD.

An examination of the effects of print media exposure and contact on subjective social reality and acculturation attitudes

This study draws upon cultivation theory, acculturation theory, and works on intergroup relations to examine the effects of print media exposure and contact on subjective social reality and acculturation attitudes of Chinese immigrants in Australia. Data was gathered via a survey administered to 265 respondents with Chinese origin. Results indicate that exposure to mainstream newspapers is only positively related to one indicator of subjective reality, namely, outgroup perception whereas exposure to ethnic newspapers was not significantly related to any of the indicators of subjective reality. Acculturation attitudes, on the other hand, are more closely related to group perception and contact but not closely associated with exposure to print media. These findings have again challenged the direct effect assumption of cultivation theory, paved the ground for combining mediated communication variables with interpersonal communication variables in acculturation research and suggested policy implications for interethnic coexistence. (c) 2005 Elsevier Ltd. All rights reserved.

Effects of memory load and distraction on performance and event-related slow potentials in a visuospatial working memory task

Brain electrical activity related to working memory was recorded at 15 scalp electrodes during a visuospatial delayed response task. Participants (N = 18) touched the remembered position of a target on a computer screen after either a 1 or 8 sec delay. These memory trials were compared to sensory trials in which the target remained present throughout the delay and response periods. Distracter stimuli identical to the target were briefly presented during the delay on 30% of trials. Responses were less accurate in memory than sensory trials, especially after the long delay. During the delay slow potentials developed that were significantly more negative in memory than sensory trials. The difference between memory and sensory trials was greater at anterior than posterior electrodes. On trials with distracters, the slow potentials generated by memory trials showed further enhancement of negativity whereas there were minimal effects on accuracy of performance. The results provide evidence that engagement of visuospatial working memory generates slow wave negativity with a timing and distribution consistent with frontal activation. Enhanced brain activity associated with working memory is required to maintain performance in the presence of distraction. © 1997 by the Massachusetts Institute of Technology

Coronary events and exposure to environmental tobacco smoke: a case-control study from Australia and New Zealand

Objectives-To estimate the relative risk of coronary heart disease (CHD) associated with exposure to environmental tobacco smoke (ETS). Design-Population-based case-control study. Subjects-Cases were 953 people identified in a population register of coronary events, and controls were 3189 participants in independent community-based risk factor prevalence surveys from the same study populations. Setting-Newcastle, Australia and Auckland, New Zealand. Main outcome measures-Acute myocardial infarction or coronary death. Results-After adjusting for the effects of age, education, history of heart disease, and body mass index, women had a statistically significant increased risk of a coronary event associated with exposure to ETS (relative risk (RR) = 1.99; 95% confidence interval (CI)= 1.40-2.81). There was little statistical evidence of increased risk found in men (RR = 1.02, 95% CI = 0.81-1.28). Conclusion-Our study found evidence for the adverse effects of exposure to ETS on risk of coronary heart disease among women, especially at home. For men the issue is unclear according to the data from our study. Additional studies with detailed information on possible confounders and adequate statistical power are needed. Most importantly, they should use methods for measuring exposure to ETS that are sufficiently accurate to permit the investigation of dose-response relationships.

Chronic ethanol exposure and withdrawal influence NMDA receptor subunit and splice variant mRNA expression in the rat cerebral cortex

Chronic ethanol exposure and subsequent withdrawal are known to change NMDA receptor activity. This study examined the effects of chronic ethanol administration and withdrawal on the expression of several NMDA receptor subunit and splice variant mRNAs in the rat cerebral cortex. Ethanol dependence was induced by ethanol vapour exposure. To delineate between seizure-induced changes in expression during withdrawal and those due to withdrawal per se, another group of naive rats was treated with pentylenetetrazol (PTZ) injection (30 mg/kg, i.p.). RNA samples from the cortices of chronically treated and withdrawing animals were compared to those from pairfed controls. Changes in NMDA receptor mRNA expression were determined using ribonuclease protection assays targetting the NR2A, -2B, -2C and NR1-pan subunits as well as the three alternatively spliced NR1 inserts (NR1-pan describes all the known NR1 splice variants generated from the 5' insert and the two 3' inserts). The ratio of NR1 mRNA incorporating the 5' insert vs, that lacking it was decreased during ethanol exposure and up to 48 h after withdrawal. NR2B mRNA expression was elevated during exposure, but returned to control levels 18 h after withdrawal. Levels of NR2A, NR2C, NR1-pan and both 3' NR1 insert mRNAs from the ethanol-treated groups did not alter compared with the pair-fed control group. No changes in the level of any NMDA receptor subunit mRNA was detected in the PTZ-treated animals. These data support the hypothesis that changes in NMDA receptor subunit composition may underlie a neuronal adaptation to the chronic ethanol-inhibition and may therefore be important in the precipitation of withdrawal hyperactivity. (C) 1999 Elsevier Science B.V. All rights reserved.

Effects of cyanide on coral photosynthesis: implications for identifying the cause of coral bleaching and for assessing the environmental effects of cyanide fishing

Modulated chlorophyll fluorescence techniques were used to examine the effects of cyanide (NaCN) from cyanide fishing on photosynthesis of the symbiotic algae (zooxanthellae) located within the tissues of the zooxanthellate hard coral Plesiastrea versipora. Incubating corals for 3 h in a cyanide concentration of >10(-5) M NaCN under a saturating light intensity (photosynthetically active radiation [PAR] intensity of 250 mu mol quanta m(-2) s(-1)) caused a long-term decrease in the ratio of variable to maximal fluorescence (dark-adapted F-v/F-m). The effect of cyanide on dark-adapted F-v/F-m was Light dependent; thus F-v/F-m only decreased in corals exposed to 10(-4) M NaCN for 3 h under PAR of 250 mu mol quanta m(-2) s(-1). In corals where dark-adapted F-v/F-m was significantly lowered by cyanide exposure, we observed significant loss of zooxanthellae from the tissues. causing the corals to discolour (bleach). To further examine the light-dependent effect of cyanide and its relation to loss of zooxanthellae, corals were exposed to 10-4 M NaCN or seawater only (control), either in darkness or under 250 mu mol quanta m(-2) s(-1). ill significant decrease in dark-adapted F-v/F-m and loss of zooxanthellae only occurred in corals exposed to cyanide in the light. These results suggest cyanide causes the dissociation of the symbiosis (bleaching) by affecting photosynthesis of the zooxanthellae. Quenching analysis using the saturation-pulse technique revealed the development of high levels of non-photochemical quenching in cyanide-exposed coral. This result is consistent with the known property of cyanide as an inhibitor of the dark reactions of the Calvin cycle, specifically as an inhibitor of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). Therefore, chronic photoinhibition and an impairment of photosynthesis of zooxanthellae provides an important 'signal' to examine the environmental effects of cyanide fishing during controlled releases in situ.

Effects of beta-escin and saponin on the transverse-tubular system and sarcoplasmic reticulum membranes of rat and toad skeletal muscle

Mechanically skinned skeletal muscle fibres from rat and toad were exposed to the permeabilizing agents beta-escin and saponin. The effects of these agents on the sealed transverse tubular system (t-system) and sarcoplasmic reticulum (SR) were examined by looking at changes in the magnitude of the force responses to t-system depolarization, the time course of the fluorescence of fura-2 trapped in the sealed t-system, and changes in the magnitude of caffeine-induced contractures following SR loading with Ca2+ under defined conditions. In the presence of 2 mu g ml(-1) beta-escin and saponin, the response to t-system depolarization was not completely abolished, decreasing to a plateau, and a large proportion of fura-2 remained in the sealed t-system. At 10 mu g ml(-1), both agents abolished the ability of both rat and toad preparations to respond to t-system depolarization after 3 min of exposure, but a significant amount of fura-2 remained in sealed t-tubules even after exposure to 100 mu g ml(-1) beta-escin and saponin for 10 min. beta-Escin took longer than saponin to reduce the t-system depolarizations and fura-2 content of the sealed t-system to a similar level. The ability of the SR to load Ca2+ was reduced to a lower level after treatment with beta-escin than saponin. This direct effect on the SR occurred at much lower concentrations for rat (2 mu g ml(-1) beta-escin and 10 mu g ml(-1) saponin) than toad (10 mu g ml(-1) beta-escin and 150 mu g ml(-1) saponin). The reverse order in sensitivities to beta-escin and saponin of t-system and SR membranes indicates that the mechanisms of action of beta-escin and saponin are different in the two types of membrane. In conclusion, this study shows that: (1) beta-escin has a milder action on the surface membrane than saponin; (2) beta-escin is a more potent modifier of SR function; (3) simple permeabilization of membranes is not sufficient to explain the effects of beta-escin and saponin on muscle membranes; and (4) the t-system network within muscle fibres is not a homogeneous compartment.

The effects of salbutamol, beclomethasone, and dexamethasone on fibronectin expression by cultured airway smooth muscle cells

Possible mechanisms of adverse drug effects in asthma include worsening of cellular hyperplasia and stimulation of extracellular matrix deposition. In this study, salbutamol, dexamethasone and beclomethasone were investigated to ascertain their ability to induce mitogenesis and stimulate fibronectin expression in cultured canine airway smooth muscle cells. In cells maintained in serum-free media for 72 h, salbutamol(1 nM-10 mu M) caused mitogenesis. The control cells had 2.57 +/- 0.34 x 10(5) cells per mi (mean +/- SEM, N = 13), while salbutamol (1 mu M) caused a maximal increase in cell number to 3.57 +/- 0.23 x 10(5) cells/ml (P < 0.01). In cells stimulated to replicate by addition of either fetal bovine serum or canine serum, no additional mitogenic effect of salbutamol was seen. Salbutamol did not have a detectable quantitative effect on fibronectin matrix expression. The glucocorticoids, beclomethasone and dexamethasone, significantly altered fibronectin expression by cultured airway smooth muscle cells. Beclomethasone increased fibronectin expression, while dexamethasone decreased expression.