MCS
Psychoneuroendocrinology. 2007 Dec 11 [Epub ahead of print]
Smith AK, Dimulescu I, Falkenberg
VR, Narasimhan S, Heim C, Vernon SD, Rajeevan MS.
Division of Viral and Rickettsial Diseases,
National Center for Infectious Diseases, Centers for Disease Control and
Prevention, 1600 Clifton Road, MSG41, Atlanta, GA 30333, USA.
Chronic
fatigue syndrome (CFS) is a debilitating disorder of unknown etiology with no
known lesions, diagnostic markers or therapeutic intervention. The pathophysiology of CFS remains elusive, although
abnormalities in the central nervous system (CNS) have been implicated,
particularly hyperactivity of the serotonergic
(5-hydroxytryptamine; 5-HT) system and hypoactivity
of the hypothalamic-pituitary-adrenal (HPA) axis. Since alterations in 5-HT
signaling can lead to physiologic and behavioral changes, a genetic evaluation
of the 5-HT system was undertaken to identify serotonergic
markers associated with CFS and potential mechanisms for CNS abnormality. A
total of 77 polymorphisms in genes related to serotonin synthesis (TPH2),
signaling (HTR1A, HTR1E, HTR2A, HTR2B, HTR2C, HTR3A, HTR3B, HTR4, HTR5A, HTR6,
and HTR7), transport (SLC6A4), and catabolism (MAOA) were examined in 137
clinically evaluated subjects (40 CFS, 55 with insufficient fatigue, and 42
non-fatigued, NF, controls) derived from a population-based CFS surveillance
study in Wichita, Kansas. Of the polymorphisms examined, three markers
(-1438G/A, C102T, and rs1923884) all located in the 5-HT receptor subtype HTR2A
were associated with CFS when compared to NF controls. Additionally, consistent
associations were observed between HTR2A variants and quantitative measures of
disability and fatigue in all subjects. The most compelling of these
associations was with the A allele of -1438G/A (rs6311) which is suggested to
have increased promoter activity in functional studies. Further, in silico analysis revealed that the -1438 A allele creates a
consensus binding site for Th1/E47, a transcription factor implicated in the
development of the nervous system. Electrophoretic
mobility shift assay supports allele-specific binding of E47 to the A allele
but not the G allele at this locus. These data indicate that sequence variation
in HTR2A, potentially resulting in its enhanced activity, may be involved in
the pathophysiology of CFS.
PMID: 18079067 [PubMed
- as supplied by publisher]
TJ Med Toxicol. 2007
Sep;3(3):89-93.
Meggs WJ, Brewer
KL.
Department of Emergency Medicine, Brody School of Medicine at East Carolina
University, Greenville, NC 27858, USA. meggsw@ecu.edu <meggsw@ecu.edu>
OBJECTIVE:
This work exposed rats to low levels of the organophosphate insecticide chlorpyrifos and monitored for toxic effects, including
weight gain. METHODS: Rats received either a subcutaneous injection of chlorpyrifos, 5 mg/kg/day, or an equal volume of vehicle
daily for 4 months. Subjects were observed for 30 minutes after injection for
signs of acute toxicity. Body weights were recorded at baseline, 2 months, 3
months, and 4 months. At the end of the experiment, the weights of hearts, medial
lobe of the livers, peri-nephric fat pads, and gastrocnemius muscles were recorded. Effects of chlorpyrifos on adipocyte
differentiation in culture were studied. Results were compared using RMANOVA.
RESULTS: No signs of acute cholinergic toxicity were observed after injections
in any subject. Rats in the 5 mg/kg group were significantly heavier than those
in the control group by 2 months (335.7 +/- 16.7 g vs. 318.6 +/- 15.8 g; p =
0.034). This difference increased at 3 months (350.1 +/- 16.4 g vs. 322.3 +/-
21.3 g p = 0.006) and 4 months (374.4 +/- 22.2 g vs. 340.2 +/- 25.2 g p =
0.006). At 4 months, the weights of the perinephric
fat pads were significantly increased in the chlorpyrifos
group relative to controls (2.867 + 0.516 vs. 1.130 + 0.171, p = 0.0039). The
two groups showed no weight differences between hearts, livers, and gastrocnemius muscles. Chlorpyrifos
did not affect adipocyte differentiation in tissue
culture. CONCLUSIONS: Chronic exposure to chlorpyrifos
at 5 mg/kg/day caused an increase in rat body weight when compared to controls.
This increase was in adipose tissue. Chlorpyrifos did
not induce differentiation of adipocytes in culture.
PMID:
18072142 [PubMed - in process]
J Chromatogr B Analyt Technol Biomed Life Sci. 2007
Nov 23
Development and validation of a chemical hydrolysis
method for dextromethorphan and dextrophan
determination in urine samples: Application to the assessment of CYP2D6
activity in fibromyalgia patients.
Daali Y, Cherkaoui S, Doffey-Lazeyras F, Dayer P, Desmeules JA.
Clinical Pharmacology and Toxicology,
Dextromethorphan (DEM)
is a widely used probe drug for human cytochrome P450 2D6 isozyme
activity assessment by measuring the ratio between DEM and its N-demethylated metabolite dextrorphan
(DOR). DOR is excreted in urine mainly conjugated to glucuronic
acid. Prior to quantification, DOR must be deconjugated
to avoid variability caused by the polymorphic glucuronosyltransferase
enzyme. A chemical hydrolysis method was optimized using a chemometric
approach. Three factors (acid concentration, hydrolysis time and temperature)
were selected and simultaneously varied to study their effect on conjugated DOR
hydrolysis. Hydrolysis conditions that maximize DOR release without significant
degradation of both DEM and DOR were chosen and results were compared to those
obtained by enzymatic method using beta-glucuronidase.
An HPLC method with fluorescence detection was developed for the simultaneous quantitation of DEM, DOR and levallorphan,
used as an internal standard. Separation was performed on a phenyl analytical
column (150mmx4.6mm i.d., 5mum) with a mobile phase
consisting of 18% acetonitrile and 50mM phosphoric
acid (pH 3). The overall analytical procedure was validated and showed good
performances in terms of selectivity, linearity, sensitivity, precision and
accuracy. Finally, this assay was used to determine DEM/DOR molar ratios in
fibromyalgia patients for the purpose of determining phenotype status for the
CYP2D6.
PMID: 18065299 [PubMed
- as supplied by publisher]
Int J Androl. 2007 Dec 6
Hauser R
Department of Environmental Health, Harvard School of Public Health,
Boston, MA, USA.
Phthalates
are a class of chemicals with widespread general population exposure. Some
phthalates are reproductive and developmental toxicants in laboratory animals.
Advances in the field of phthalate research in humans are dependent on the
development and implementation of biomarkers to assess exposure and outcome, as
well as potential markers that may be indicative of increased susceptibility.
Recently, we incorporated a novel biomarker of potential 'susceptibility' into
our study on the relationship of phthalates with semen quality and sperm DNA
damage among men recruited from an infertility clinic. We measured urinary concentrations
of three di(2-ethylhexyl) phthalate (DEHP)
metabolites, mono(2-ethylhexyl) phthalate (MEHP) and two oxidative metabolites,
mono-(2-ethyl-5-hydroxylhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-oxohexyl)
phthalate (MEOHP). We calculated the percent of DEHP excreted as the hydrolytic
monoester (i.e., MEHP). We referred to this as %MEHP and considered it a
phenotypic marker of the proportion of DEHP excreted in the urine as MEHP. In
our sperm DNA study, we found novel results for the DEHP metabolites. Although
MEHP was positively correlated with the oxidative metabolites, the association
of sperm DNA damage with MEHP, as compared to MEHHP and MEOHP, were in opposite
directions. We hypothesized that MEHP is the bioactive toxicant and further
metabolism to MEHHP/MEOHP may lower internal burden of MEHP and thus be
protective from sperm DNA damage. An alternative explanation may include that
the relative percentage of DEHP excreted as MEHP was a surrogate for the
function of phase I enzymes. Men with high %MEHP may have higher levels of
sperm DNA damage because of poor metabolism (detoxification) of other genotoxic chemicals. Our hypothesis that %MEHP may
represent a phenotypic marker of metabolism is novel but requires further
exploration to confirm.
PMID: 18067563 [PubMed
- as supplied by publisher]
Indoor Air. 2007 Aug;17(4):328-33
Department of Medicine,
Self-reported
non-allergic nasal symptom triggers in non-allergic ('vasomotor') rhinitis
overlap with commonly identified environmental exposures in non-specific
building-related illness. These include extremes of temperature and humidity,
cleaning products, fragrances, and tobacco smoke. Some individuals with
allergic rhinitis also report non-allergic triggers. We wished to explore the
phenotypic overlap between allergic and non-allergic rhinitis by ascertaining
self-reported non-allergic nasal symptom triggers among allergic rhinitics. Sixty subjects without work-related respiratory
exposures or symptoms, aged 19-68 years, stratified by age, gender and (skin
test-proven) allergic rhinitis status, were queried with regard to self-reported
non-allergic nasal symptom triggers (aggregate score 0-8). In this sample, the
number of self-reported non-allergic triggers was bimodal, with peaks at 1 and
5. Forty-two percent of seasonal allergic rhinitic
subjects reported more than three non-allergic triggers, compared with only 3%
of non-allergic non-rhinitics (P < 0.01). Subjects
over 35 years were more likely to report one or more non-allergic triggers,
particularly tobacco smoke (P < 0.05). Allergic rhinitics
reported more non-allergic symptom triggers than did non-allergic, non-rhinitics. As indexed by self-reported reactivity to
non-specific physical and chemical triggers, both non-allergic rhinitics and a subset of allergic rhinitics
may constitute susceptible populations for non-specific building-related
illness. PRACTICAL IMPLICATIONS: Judging by self-report, a substantial subset
of individuals with allergic rhinitis--along with all individuals with nonallergic rhinitis (by definition)--are hyperreactive to non-allergic triggers. There is overlap
between these triggers (elicited in the process of obtaining a clinical
diagnosis) and environmental characteristics associated with ''problem
buildings.'' Since individuals with self-identified rhinitis report an excess
of symptoms in most epidemiologic studies of problem buildings (even in the
absence of unusual aeroallergen levels), rhintics may
be acting as a ''sentinel'' subgroup when indoor air quality is suboptimal.
Together, non-allergic rhinitics plus allergic rhinitics with prominent non-allergic triggers, are thought
to constitute approximately one-sixth of the
PMID:
17661929 [PubMed - indexed for MEDLINE
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