Evaluation of urinary trans-3′-hydroxycotinine as a biomarker of children's environmental tobacco smoke exposure

Abstract

The utility of urinary trans-3′-hydroxy cotinine (3HC) as a biomarker of environmental tobacco smoke (ETS) exposure was investigated in comparison with urinary cotinine (COT), the sum (3HC?+?COT), and ratio of the two nicotine metabolites (3HC/COT). Participants were 150 ETS exposed children (aged 1–44 months) and their parents. Child urine samples were collected during 3weekly baseline assessments and at interviews administered 3, 6, 12, and 18 months after baseline. Findings indicate that 3HC and COT can be measured reliably (rho?=?0.96, 0.88) and show equivalent levels of repeated measures stability (rho?=?0.71, 0.75). COT, 3HC, and 3HC?+?COT showed equally strong associations with air nicotine levels, reported ETS contamination, and reported ETS exposure (r=0.60–0.70). The intraclass correlations of 3HC/COT were lower than those for COT or 3HC. Older children had a higher 3HC/COT ratio than younger children (3.5 versus 2.2), and non-Hispanic White children had a higher ratio than African-American children (3.2 versus 1.9). These findings suggest that COT, 3HC, and 3HC?+?COT are approximately equivalent and equally strong biomarkers of ETS exposure in children. Moreover, 3HC/COT may provide a useful indicator to investigate age- and race-related differences in the metabolism of COT and 3HC.     

Do biomarkers of exposure and effect correlate with internal exposure to PAHs in swine?

Humans are commonly exposed to polycyclic aromatic hydrocarbons (PAHs), a family of compounds present as mixtures in the environment. This study exposed swine to PAH mixtures in single and subacute dose regimens and collected liver and ileum tissue to measure cytochrome P450 mRNA expression and enzyme activity as biomarkers of exposure and DNA adducts and oxidized proteins as biomarkers of effect. Micronucleated reticulocytes were measured as systemic biomarkers of effect. Duration of exposure did not influence biomarkers of exposure, though exposure duration produced significant increases in DNA adducts and oxidative stress. Micronucleated reticulocyte numbers were not affected by exposure length.     

Age-dependent association of KIBRA gene polymorphism with Alzheimer’s disease in Han Chinese

Genetic factors play an important role in the Alzheimer’s disease (AD) development and memory impairment is a cardinal clinical feature of AD. Kidney and brain expressed protein (KIBRA), owing to its connection with human episodic memory, became an interesting candidate gene for AD. Recently, KIBRA (rs17070145) was reported to be associated with AD in the genetic and functional levels in Caucasian and African-American, and the association might be different across age groups. To investigate the possibility of age-dependent association of KIBRA with AD in Asian, we conducted an independent replication study in a cohort of 1,586 subjects from Han Chinese (including 790 LOAD patients and 796 healthy controls). The results revealed no significant differences in the distributions of genotype or allele between LOAD and control groups in the total sample. However, when these data were stratified by their age, we observed a significant difference in the genotypes and alleles frequencies (genotype: p = 0.004, allele: p = 0.035) in the young subgroup. Moreover, the association was further demonstrated in logistic regression analysis (rs17070145: p = 0.045, OR = 0.428). Our data suggested that KIBRA might associate with younger AD patients (≤74 years) in a Northern Han Chinese population.     

Are modifications of melatonin circadian rhythm in the middle years of life related to habitual patterns of light exposure?

The mechanisms underlying age-related changes in the signal from the biological clock have yet to be determined. The authors sought to determine if the phase advance of circadian melatonin rhythm during the middle years of life is related to different patterns of habitual light exposure. Forty-one healthy subjects between the ages of 22 and 58 y were studied. Habitual light exposure was measured by a wrist monitor for 7 days. Participants underwent a 25-h constant routine. They provided saliva samples every 30 min, and melatonin concentration was determined by radioimmunoassay to assess salivary dim light melatonin onset (S-DLMO(1.3)). Aging was associated with earlier S-DLMO(1.3). Increasing age was not related to the time spent at different light intensities. However, it was associated with lower percentage of light exposure during the night (between 0200-0400, 0600-0700, and 2300-2400 h) and with higher percentage of light exposure in the morning (between 0800-1100 h). Earlier S-DLMO(1.3) was associated with lower percentage of light exposure early on in the night (between 2200-0000, 0000-0100, and 0200-0300 h) as well as in the afternoon (between 1500-1600 h) and with higher percentage of light exposure in the morning (between 0800-1100 h). When the effects of age were controlled, there was no significant relationship between S-DLMO(1.3) and percentages of light exposure. Yet increasing age was associated with earlier S-DLMO(1.3) regardless of light exposure patterns. Earlier habitual wake time explained the earlier light exposure patterns of older subjects. Both habitual wake time and age contributed to the prediction of S-DLMO(1.3). The results suggest a phase advance of circadian rhythms in the middle years of life. Whereas a clear change in habitual light exposure patterns was associated with aging and with shifts in S-DLMO(1.3), it did not explain entirely the age-related advance of melatonin circadian phase.     

Excretion of urinary cadmium, copper, and zinc in cadmium-exposed and nonexposed subjects, with special reference to urinary excretion of β2-microglobulin and metallothioneinand metallothionein

The objectives of this study were to examine the association between urinary excretion of cadmium (U-Cd), copper (U-Cu), and zinc (U-Zn) and the severity of two different indicators of renal toxicity (urinary excretion of beta2-microglobulin [U-beta2-MG] and metallothionein [U-MT]) in Cd-exposed subjects compared to controls, and to assess the physiologic mechanisms by which the exposure to environmental Cd affects U-Cd, U-Cu, and U-Zn. The target population included 3508 Cd-exposed and 294 nonexposed participants who received a health survey conducted among the population of the Kakehashi River basin. Increases of U-Cd, U-beta2-MG, and U-MT in the Cd-exposed population were observed relative to excretion of these substances in controls. Regression analysis using a general linear model revealed that the correlations between U-Cd or U-Cu, and U-beta2-MG and between U-Cd, U-Cu or U-Zn, and U-MT were statistically significant in both sexes, but the correlation between U-Zn and U-beta2-MG excretion was significant only in men. These results suggest U-Cd and U-Cu is affected by dysfunction in renal tubular absorption (indicated by U-beta2-MG), whereas not only U-Cd and U-Cu but also U-Zn appear to be a function of renal cellular desquamation (indicated by U-MT).     

Is urinary flow rate a major regulator of prostaglandin E excretion in man?

Urinary PGE₂ excretion is enhanced in several polyuric states in man suggesting that PGE₂ synthesis could be a mediator of diuresis. To explore the alternate hypothesis that polyuria is the cause of the increased PGE₂ excretion, we increased urine flow rate by intravenous administration of dextrose and water with different magnesium, calcium and potassium solutions in four normal males. Urinary PGE excretion rose in parallel with urine volume (r = 0.65 p < 0.01) independently of the electrolyte solution. To determine the effects of chronic alterations in water balance in 5 female subjects, we sequentially regulated oral water intake to induce 1, 2, 4 and 8 liters of urine volume/day. During low (40 mEq) sodium diets, PGE increased from 540 ± 50 to 4880 ± 1240 ng/d with increasing urinary volume (r = 0.81, p < 7.01). Similarly, for 200 mEq sodium intake PGE paralleled urinary volume (from 630 ± 100 to 4740 ± 800 ng/d, r = 0.61, p <0.01). In vitro sample dilution studies demonstrated no interference from method blank, and the addition of thin layer chromatography prior to Sephadex chromatography failed to alter assay measurements. We conclude that extreme increases in urinary flow rate may directly enhance PGE excretion in man.     

Increased urinary excretion of nephrin, podocalyxin, and βig-h3 in women with preeclampsia

Emerging evidence has shown that podocyte injury and reduced specific podocyte protein expressions contribute to proteinuria in preeclampsia. We collected urine specimens from women with preeclampsia to study whether podocyte-specific protein shedding is associated with renal barrier dysfunction. Urine specimens from women with normal pregnancies and from pregnant women complicated by chronic hypertension were used for comparison. We determined soluble podocyte slit protein nephrin levels in the urine specimens. Podocalyxin, βig-h3, and VEGF concentrations were also measured. We found that nephrin and podocalyxin were barely detectable in the urine specimens from normal pregnant women and from women with chronic hypertension. In preeclampsia, urinary nephrin and podocalyxin concentrations were significantly increased and highly correlated to each other, r(2) = 0.595. Nephrin and podocalyxin were also correlated with urine protein concentrations. βig-h3 was detected in the urine specimens from women with preeclampsia, and it is highly correlated with nephrin and podocalyxin concentrations in preeclampsia. βig-h3 was undetectable in normal pregnancy and pregnancy complicated by chronic hypertension. Elevated VEGF levels were also found in women with preeclampsia compared with those of normal pregnancy and pregnancy complicated by chronic hypertension. These results provide strong evidence that podocyte protein shedding occurs in preeclampsia, and their levels are associated with proteinuria. The finding of urinary βig-h3 excretion in preeclampsia suggests that increased transforming growth factor activity might also be involved in the kidney lesion in this pregnancy disorder.     

To screen or not to screen for pre-type 1 diabetes?

The incidence of type 1 diabetes is increasing worldwide and the disease is an onerous burden both to the individual and to society. There are thus important reasons to screen for the disease before it becomes manifest: (1) to improve understanding of the natural history of the prediabetic period; (2) to gain further insights into the immunopathogenesis of the disease; (3) to identify individuals for prevention trials; (4) to make an earlier diagnosis in order to reduce morbidity and mortality. Great strides have been made, yet there is still a great deal to be learned. Opponents of screening argue that screening tests for the disease have a low positive predictive value and that predicting the disease without a primary prevention capability raises ethical considerations because of induced stress, lifestyle changes, cost and potential effects on insurability. The greatest single barrier against large-scale population screening and prevention of the disease remains the lack of an effective intervention. However, screening in the context of well-designed research studies must continue - ultimately the benefit to the individual and to society will be immense.     

Comparison of mouse urinary metabolic profiles after exposure to the inflammatory stressors γ radiation and lipopolysaccharide

Metabolomics on easily accessible biofluids has the potential to provide rapid identification and distinction between stressors and inflammatory states. In the event of a radiological event, individuals with underlying medical conditions could present with similar symptoms to radiation poisoning, prominently nausea, diarrhea, vomiting and fever. Metabolomics of radiation exposure in mice has provided valuable biomarkers, and in this study we aimed to identify biomarkers of lipopolysaccharide (LPS) exposure to compare and contrast with ionizing radiation. LPS treatment leads to a severe inflammatory response and a cytokine storm, events similar to radiation exposure, and LPS exposure can recapitulate many of the responses seen in sepsis. Urine from control mice, LPS-treated mice, and mice irradiated with 3, 8 and 15 Gy of γ rays was analyzed by LCMS, and markers were extracted using SIMCA-P(+) and Random Forests. Markers were validated through tandem mass spectrometry against pure chemicals. Five metabolites, cytosine, cortisol, adenine, O-propanoylcarnitine and isethionic acid, showed increased excretion at 24 h after LPS treatment (P < 0.0001, 0.0393, 0.0393, <0.0001 and 0.0004, respectively). Of these, cytosine, adenine and O-propanoylcarnitine showed specificity to LPS treatment when compared to radiation. On the other hand, increased excretion of cortisol after LPS and radiation treatments indicated a rapid systemic response to inflammatory agents. Isethionic acid excretion, however, showed elevated levels not only after LPS treatment but also after a very high dose of radiation (15 Gy), while additional metabolites showed responsiveness to radiation but not LPS. Metabolomics therefore has the potential to distinguish between different inflammatory responses based on differential ion signatures. It can also provide quick and reliable assessment of medical conditions in a mass casualty radiological scenario and aid in effective triaging.     

Is acetylcholinesterase a pertinent biomarker to detect exposure of pyrethroids? A study case with deltamethrin

The possibility to use acetylcholinesterase as biomarker of exposure to deltamethrin insecticide in the honeybee, Apis mellifera were considered. Joined actions of deltamethrin and pirimicarb (carbamate), alone or in association (dual treatment), were investigated on AChE activity in surviving and dead honeybees in order to test its reliability as biomarker. All treatments induced a reduction in tissue AChE activity in dead bees. In surviving bees, deltamethrin treatment induced an important increase of AChE activity that is not abolished by pirimicarb treatment. The analysis of AChE forms revealed an increase in the soluble form in surviving and dead bees and an increase of the membrane form in surviving bees. No direct effect of deltamethrin on soluble and membrane AChE was observed in vitro. The important increase in AChE activity in response to deltamethrin, not altered by pirimicarb treatment, suggests that AChE activity could represent a robust biomarker specific to deltamethrin exposure in living bees.     

Study of the urinary and faecal excretion of N ε-carboxymethyllysine in young human volunteers

The dietary habits of the adolescent population with a high intake of snack and fast foods mean that they consume a high rate of which in turn leads to the development of different degenerative disorders. There are few studies available on MRP absorption and metabolism. We investigated the effects of a MRP-high and a MRP-low diet on carboxymethyllysine (CML) intake and excretion in 11-14 years adolescent males. In a 2-period crossover trial, 20 healthy subjects were randomly assigned to two groups. The first group consumed the MRP-low diet for 2 weeks, observed a 40-day washout period, and then consumed the MRP-high diet for 2 weeks. The second group received the diets in the reverse order. Subjects collected urine and faeces on the last 3 days of each dietary period. The consumption of the MRP-high diet led to a higher CML input (P < 0.05) (11.28 vs. 5.36 mg/day CML for MRP-high and -low diet, respectively). In parallel, the faecal excretion was also greater (P < 0.05) (3.52 vs. 1.23 mg/day CML, respectively) and proportional to the dietary intake. The urinary elimination of CML was not increased significantly when the MRP-high diet was consumed compared to consumption of the MRP-low diet, and was not proportional to the dietary exposure of CML. In conclusion it was shown that CML absorption and faecal excretion were highly influenced by dietary CML levels. Since the compound has long-term effects on health, an excessive intake deserves attention, especially in a population nutritionally at risk as adolescents.     

Longitudinal urinary excretion of some “trace” acids in a human male

Conjugated and unconjugated urinary levels of phenylacetic acid (PAA), m-hydroxyphenylacetic acid (m-HPA) and p-hydroxyphenylacetic acid have been determined for 24-h urine samples obtained from a single healthy male over a 28-day period. Gas chromatographic—electron-capture and mass spectrometric—integrated ion current techniques incorporating appropriate internal standards were used. The average urinary excretion values obtained were (in mg/24 h): PAA unconjugated 0.67, conjugated 96.6; m-HPA unconjugated 7.3, conjugated < 0.1; p-HPA unconjugated 22.4, conjugated < 1.2. Following the ingestion of appropriate deuterated amino acid precursors the expected urinary deuterated trace acids were identified and quantitated; in the case of deuterated phenylethylamine, m-HPA and p-HPA as well as PAA were identified and quantitated. This is the first evidence of phenylethylamine hydroxylation in the human. The longitudinal excretion of the trace acids was compared with that of the trace amines.     

Evaluation of urinary dihydrocodeine excretion in human by gas chromatography–mass spectrometry

Urinary metabolic pattern after the therapeutic peroral dose of dihydrocodeine tartrate to six human volunteers has been explored. Using the GC–MS analytical method, we have found that the major part of the dose administered is eliminated via urine within the first 24 h. However, the analytical monitoring of dihydrocodeine and its metabolites in urine was still possible 72 h after the dose was administered. The dihydrocodeine equivalent amounts excreted in urine in 72 h ranged between 32 and 108% of the dose, on average 62% in all individuals. The major metabolite excreted into urine was a 6-conjugate of dihydrocodeine, then in a lesser amount a 6-conjugate of nordihydrocodeine (both conjugated to approximately 65%). The O-demethylated metabolite dihydromorphine was of a minor amount and was 3,6-conjugated in 85%. Traces of nordihydromorphine and hydrocodone were confirmed as other metabolites of dihydrocodeine in our study. This information can be useful in interpretation of toxicological findings in forensic practice.     

Turkish-language ability of children of immigrants in Germany: which contexts of exposure influence preschool children's acquisition of their heritage language?

A lot of research has been devoted to explaining immigrants' acquisition of the language of the receiving country. However, less attention has been paid to explaining the acquisition of the heritage language among children of immigrants. The most important determinant for young children is exposure to the language. Language exposure can occur in various contexts, such as within the family, during preschool, through peers or via media. Our empirical analysis therefore explores which of these contexts is most statistically significant for the acquisition of the heritage language among children of Turkish immigrants. Using data from the project Preschool Education and Educational Careers among Migrant Children, we show that all contexts are important at different age levels but the acquisition of the heritage language is mainly determined by the exposure to it within the family.     

Is plasticity in mating preferences adapted to perceived exposure to pathogens?

Humans are unique among primates due to a lack of typical thermally insulating fur. The ectoparasite avoidance mediated by the mate choice hypothesis suggests that the loss of body hair reduces the risk of infection by ectoparasites and that the movement toward nudity may have been enforced by parasite-mediated sexual selection. In this study, we investigated two possible predictions of this hypothesis: (1) that preferences for hairless bodies increase with exposure to environmental pathogens and (2) that disgust sensitivity to the pathogens’ threat predicts the degree to which a woman will prefer hairless bodies. Using an experiment comparing the preferences of 88 women for shaved vs. hairy pictured versions of 20 male torsos, we found that exposure to the visual cues of pathogens does not predict preferences for a male chest nor does the individual disgust sensitivity to disease-related invertebrates. Overall, the results suggest that female perception of male trunk hair is not associated with a risk of contamination, which questions the salience of the ectoparasite avoidance hypothesis in explaining the loss of body hair in humans.