Effect of exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) on mitochondrial DNA (mtDNA) copy number in rats.

Mitochondria are intracellular organelles responsible for biological oxidation and energy production. These organelles are susceptible to damage from oxidative stress and compensate for damage by increasing the number of copies of their own genome, mitochondrial DNA (mtDNA). Cancer and environmental exposure to some pollutants have also been associated with altered mtDNA copy number. Since exposures to polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have been shown to increase oxidative stress, we hypothesize that mtDNA copy number will be altered with exposure to these compounds. mtDNA copy number was measured in DNA from archived frozen liver and lung specimens from the National Toxicology Program (NTP) study of female Harlan Sprague Dawley rats exposed to TCDD (3, 10, or 100 ng/kg/day), dioxin-like (DL) PCB 126 (10, 100, or 1000 ng/kg/day), non-DL PCB 153 (10, 100, or 1000 µg/kg/day), and PCB 126 + PCB 153 (10 ng/kg/day + 10 µg/kg/day, 100 ng/kg/day + 100 µg/kg/day, or 1000 ng/kg/day + 1000 µg/kg/day, respectively) for 13 and 52 weeks. An increase in mtDNA copy number was observed in the liver and lung of rats exposed to TCDD and the lung of rats exposed to the mixture of PCB 126 and PCB 153. A statistically significant positive dose-dependent trend was also observed in the lung of rats exposed to PCB 126 and a mixture of PCB 153 and PCB 126, although in neither case was the control copy number significantly exceeded at any dose level. These exposures produced a range of pathological responses in these organs in the two-year NTP studies. Conversely, there was a significant decrease or no change in mtDNA copy number in the liver and lung of rats exposed to non-DL PCB 153. This is consistent with a general lack of PCB 153 mediated liver or lung injury in the NTP study, with the exception of liver hypertrophy. Together, the results suggest that an increase in mtDNA copy number may serve as a sensitive, early biomarker of mitochondrial injury and oxidative stress that contributes to the development of the toxicity of dioxin-like compounds.

Telomeres as targets for the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) in rats.

Telomere length (TL) can be affected by various factors, including age and oxidative stress. Changes in TL have been associated with chronic disease, including a higher risk for several types of cancer. Environmental exposure of humans to PCBs and dioxins has been associated with longer or shorter leukocyte TL. Relative telomere length (RTL) may serve as a biomarker associated with neoplastic and/or non-neoplastic responses observed with chronic exposures to TCDD and PCBs. RTL was measured in DNA isolated from archived frozen liver and lung tissues from the National Toxicology Program (NTP) studies conducted in female Harlan Sprague Dawley rats exposed for 13, 30, and 52 weeks to TCDD, dioxin-like (DL) PCB 126, non-DL PCB 153, and a mixture of PCB 126 and PCB 153. RTL was assessed by quantitative polymerase chain reaction (qPCR). Consistent with literature, decreased liver and lung RTL was seen with aging. Relative to time-matched vehicle controls, RTL was increased in both the liver and lung tissues of rats exposed to TCDD, PCB 126, PCB 153, and the mixture of PCB 126 and PCB 153, which is consistent with most epidemiological studies that found PCB exposures were associated with increased leukocyte RTL. Increased RTL was observed at doses and/or time points where little to no pathology was observed. In addition to serving as a biomarker of exposure to these compounds in rats and humans, increases in RTL may be an early indicator of neoplastic and non-neoplastic responses that occur following chronic exposure to TCDD and PCBs.

Organochlorine pesticide residues in human breast tissue and their relationships with clinical and pathological characteristics of breast cancer.

Agricultural pesticides are abundant environmental contaminants worldwide, prompting interest in studying their possible detrimental health effects. We examined organochlorine residues by quadrant (n = 245) in breast adipose tissues from 51 women with various stages of breast health to determine patterns of bioaccumulation within the breast and to assess relationships with patient clinical characteristics. Three organochlorine residues-2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE), hexachlorobenzene (HCB), and mirex-assayed by high resolution gas chromatography were abundant in breast tissue. p,p'-DDE (745 ± 1054 ng/g lipid) was the most prevalent residue, comprising 97.5% of the total chemical burden. Mean levels of p,p'-DDE and HCB were significantly correlated (P < .001) with patient age at mastectomy, and levels of p,p'-DDE were correlated (P < .05) with BMI. Pesticide concentrations did not differ significantly by breast quadrant and were not different in the quadrant(s) where the primary tumor was located compared to other cancer-free quadrants. In invasive cancer patients, organochlorine levels differed significantly based on clinical characteristics of the primary carcinoma, including stage, grade, ER status, and HER2 status, indicating that body burden of organochlorines may influence the development of specific subtypes of breast cancer. Potentially carcinogenic organochlorines were present at high levels within the human breast warranting further research to determine the impact of organochlorines in the etiology of breast cancer.

Abundance and distribution of polychlorinated biphenyls (PCBs) in breast tissue.

Many environmental chemicals accumulate in human tissues and may contribute to cancer risk. Polychlorinated biphenyls (PCBs) are associated with adverse health effects, but relationships between PCB exposure and breast cancer are unclear. In this study, we sought to determine whether bioaccumulation of PCBs differs within regions of the human breast and whether PCB levels are associated with clinical and pathological characteristics in breast cancer patients. Tissue sections (n=245) were collected from breast quadrants from 51 women with a diagnosis ranging from disease-free to metastatic breast cancer. Ninety-seven PCB congeners were assayed by high resolution gas chromatography. ANOVA was used to examine PCB distribution within the breast and relationships with clinical/pathological variables. Pearson product-moment correlations assessed relationships between age at mastectomy and PCB levels. PCBs were abundant in breast tissues with a median concentration of 293.4ng/g lipid (range 15.4-1636.3ng/g). PCB levels in breast tissue were significantly different (p<0.001) among functional groupings of congeners defined by structure-activity properties: Group I (28.2ng/g), Group II (96.6ng/g), Group III (166.0ng/g). Total PCB concentration was highly correlated with age at mastectomy, but the distribution of PCBs did not differ by breast quadrant. PCB levels were not associated with patient status or tumor characteristics. In conclusion, PCB congeners with carcinogenic potential were present at high levels in the human breast, but were not associated with clinical or pathological characteristics in breast cancer patients.

Coordination chemistry may explain pharmacokinetics and clinical response of vanadyl sulfate in type 2 diabetic patients.

Vanadium, abbreviated V, is an early transition metal that readily forms coordination complexes with a variety of biological products such as proteins, metabolites, membranes and other structures. The formation of coordination complexes stabilizes metal ions, which in turn impacts the biodistribution of the metal. To understand the biodistribution of V, V in oxidation state iv in the form of vanadyl sulfate (25, 50, 100 mg V daily) was given orally for 6 weeks to 16 persons with type 2 diabetes. Elemental V was determined using Graphite Furnas Atomic Absorption Spectrometry against known concentrations of V in serum, blood or urine. Peak serum V levels were 15.4 ± 6.5, 81.7 ± 40 and 319 ± 268 ng ml(-1) respectively, and mean peak serum V was positively correlated with dose administered (r = 0.992, p = 0.079), although large inter-individual variability was found. Total serum V concentration distribution fit a one compartment open model with a first order rate constant for excretion with mean half times of 4.7 ± 1.6 days and 4.6 ± 2.5 days for the 50 and 100 mg V dose groups respectively. At steady state, 24 hour urinary V output was 0.18 ± 0.24 and 0.97 ± 0.84 mg in the 50 and 100 mg V groups respectively, consistent with absorption of 1 percent or less of the administered dose. Peak V in blood and serum were positively correlated (r = 0.971, p < 0.0005). The serum to blood V ratio for the patients receiving 100 mg V was 1.7 ± 0.45. Regression analysis showed that glycohemoglobin was a negative predictor of the natural log(ln) peak serum V (R(2) = 0.40, p = 0.009) and a positive predictor of the euglycemic-hyperinsulinemic clamp results at high insulin values (R(2) = 0.39, p = 0.010). Insulin sensitivity measured by euglycemic-hyperinsulinemic clamp was not significantly correlated with ln peak serum V. Globulin and glycohemoglobin levels taken together were negative predictors of fasting blood glucose (R(2) = 0.49, p = 0.013). Although V accumulation in serum was dose-dependent, no correlation between total serum V concentration and the insulin-like response was found in this first attempt to correlate anti-diabetic activity with total serum V. This study suggests that V pools other than total serum V are likely related to the insulin-like effect of this metal. These results, obtained in diabetic patients, document the need for consideration of the coordination chemistry of metabolites and proteins with vanadium in anti-diabetic vanadium complexes.

Developmental exposure to polychlorinated biphenyls reduces amphetamine behavioral sensitization in Long-Evans rats.

PCBs have long been known to affect dopamine (DA) function in the brain. The current study used an amphetamine behavioral sensitization paradigm in rats developmentally exposed to PCBs. Long-Evans rats were given perinatal exposure to 0, 3, or 6mg/kg/day PCBs and behavioral sensitization to d-amphetamine (AMPH) was assessed in one adult male and female/litter. Non-exposed (control) males showed increasing locomotor activity to repeated injections of 0.5mg/kg AMPH, typical of behavioral sensitization. PCB-exposed males showed greater activation to the initial acute AMPH injection, but sensitization occurred later and was blunted relative to controls. Sensitization in control females took longer to develop than in the males, but no exposure-related differences were observed. Analysis of whole brain and serum AMPH content following a final IP injection of 0.5mg/kg revealed no differences among the exposure groups. Overall, these results indicated developmental PCB exposure can alter the motor-stimulating effects of repeated AMPH injections. Males developmentally exposed to PCBs appeared to be pre-sensitized to AMPH, but quickly showed behavioral tolerance to the same drug dose. Results also revealed the behavioral effect was not due to exposure-induced alterations in AMPH metabolism following PCB exposure.

Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder.

Persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs) and polybrominated diphenylethers (PBDEs) that bioaccumulate in lipid-rich tissues are of concern as developmental neurotoxicants. Epigenetic mechanisms such as DNA methylation act at the interface of genetic and environmental factors implicated in autism-spectrum disorders. The relationship between POP levels and DNA methylation patterns in individuals with and without neurodevelopmental disorders has not been previously investigated. In this study, a total of 107 human frozen postmortem brain samples were analyzed for eight PCBs and seven PBDEs by GC-micro electron capture detector and GC/MS using negative chemical ionization. Human brain samples were grouped as neurotypical controls (n = 43), neurodevelopmental disorders with known genetic basis (n = 32, including Down, Rett, Prader-Willi, Angelman, and 15q11-q13 duplication syndromes), and autism of unknown etiology (n = 32). Unexpectedly, PCB 95 was significantly higher in the genetic neurodevelopmental group, but not idiopathic autism, as compared to neurotypical controls. Interestingly, samples with detectable PCB 95 levels were almost exclusively those with maternal 15q11-q13 duplication (Dup15q) or deletion in Prader-Willi syndrome. When sorted by birth year, Dup15q samples represented five out of six of genetic neurodevelopmental samples born after the 1976 PCB ban exhibiting detectable PCB 95 levels. Dup15q was the strongest predictor of PCB 95 exposure over age, gender, or year of birth. Dup15q brain showed lower levels of repetitive DNA methylation measured by LINE-1 pyrosequencing, but methylation levels were confounded by year of birth. These results demonstrate a novel paradigm by which specific POPs may predispose to genetic copy number variation of 15q11-q13.

The effect of prenatal and postnatal exposure to polychlorinated biphenyls and child neurodevelopment at age twenty four months.

We examined the association between prenatal and postnatal exposure to PCBs and development at age 24 months as measured by the Bayley Scales of Infant Development II. 44 (85%) of 52 children had information available. When prenatal and postnatal exposure were modeled together, we found no association between total PCB exposure and the mental development index (MDI) or the physical development index (PDI). In examining PCB 153, we found no association between PCB 153 and MDI, while higher levels of postnatal exposure was associated with a decrease in PDI after adjustment [ß for highest tertile=-24.9; 95% CI (-44.3, -5.5)]. Higher levels of prenatal PCB 153 exposure were associated with a statistically significant increased odds of screening positive for a motor delay. In sum, when prenatal and postnatal exposures were considered together, breast milk exposure to PCB 153 appears to be associated with decrements in motor development; however, we cannot rule out that the finding was due to chance.

Long-lived epigenetic interactions between perinatal PBDE exposure and Mecp2308 mutation.

The widespread use of persistent organic polybrominated diphenyl ethers (PBDEs) as commercial flame retardants has raised concern about potential long-lived effects on human health. Epigenetic mechanisms, such as DNA methylation, are responsive to environmental influences and have long-lasting consequences. Autism spectrum disorders (ASDs) have complex neurodevelopmental origins whereby both genetic and environmental factors are implicated. Rett syndrome is an X-linked ASD caused by mutations in the epigenetic factor methyl-CpG binding protein 2 (MECP2). In this study, an Mecp2 truncation mutant mouse (Mecp2(308)) with social behavioral defects was used to explore the long-lasting effects of PBDE exposure in a genetically and epigenetically susceptible model. Mecp2(308/+) dams were perinatally exposed daily to 2,2',4,4'-tetrabromodiphenyl ether 47 (BDE-47) and bred to wild-type C57BL/6J males, and the offspring of each sex and genotype were examined for developmental, behavioral and epigenetic outcomes. Perinatal BDE-47 exposure negatively impacted fertility of Mecp2(308/+) dams and preweaning weights of females. Global hypomethylation of adult brain DNA was observed specifically in female offspring perinatally exposed to BDE-47 and it coincided with reduced sociability in a genotype-independent manner. A reversing interaction of Mecp2 genotype on BDE-47 exposure was observed in a short-term memory test of social novelty that corresponded to increased Dnmt3a levels specifically in BDE-47-exposed Mecp2(308/+) offspring. In contrast, learning and long-term memory in the Morris water maze was impaired by BDE-47 exposure in female Mecp2(308/+) offspring. These results demonstrate that a genetic and environmental interaction relevant to social and cognitive behaviors shows sexual dimorphism, epigenetic dysregulation, compensatory molecular mechanisms and specific behavioral deficits.

Human hepatic cytochrome P450-specific metabolism of the organophosphorus pesticides methyl parathion and diazinon.

Organophosphorus pesticides (OPs) are a public health concern due to their worldwide use and documented human exposures. Phosphorothioate OPs are metabolized by cytochrome P450s (P450s) through either a dearylation reaction to form an inactive metabolite, or through a desulfuration reaction to form an active oxon metabolite, which is a potent cholinesterase inhibitor. This study investigated the rate of desulfuration (activation) and dearylation (detoxification) of methyl parathion and diazinon in human liver microsomes. In addition, recombinant human P450s were used to determine the P450-specific kinetic parameters (K(m) and V(max)) for each compound for future use in refining human physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models of OP exposure. The primary enzymes involved in bioactivation of methyl parathion were CYP2B6 (K(m) = 1.25 µM; V(max) = 9.78 nmol · min(-1) · nmol P450(-1)), CYP2C19 (K(m) = 1.03 µM; V(max) = 4.67 nmol · min(-1) · nmol P450(-1)), and CYP1A2 (K(m) = 1.96 µM; V(max) = 5.14 nmol · min(-1) · nmol P450(-1)), and the bioactivation of diazinon was mediated primarily by CYP1A1 (K(m) = 3.05 µM; V(max) = 2.35 nmol · min(-1) · nmol P450(-1)), CYP2C19 (K(m) = 7.74 µM; V(max) = 4.14 nmol · min(-1) · nmol P450(-1)), and CYP2B6 (K(m) = 14.83 µM; V(max) = 5.44 nmol · min(-1) · nmol P450(-1)). P450-mediated detoxification of methyl parathion only occurred to a limited extent with CYP1A2 (K(m) = 16.8 µM; V(max) = 1.38 nmol · min(-1) · nmol P450(-1)) and 3A4 (K(m) = 104 µM; V(max) = 5.15 nmol · min(-1) · nmol P450(-1)), whereas the major enzyme involved in diazinon detoxification was CYP2C19 (K(m) = 5.04 µM; V(max) = 5.58 nmol · min(-1) · nmol P450(-1)). The OP- and P450-specific kinetic values will be helpful for future use in refining human PBPK/PD models of OP exposure.

Subchronic polychlorinated biphenyl (Aroclor 1254) exposure produces oxidative damage and neuronal death of ventral midbrain dopaminergic systems.

Recent epidemiologic studies have demonstrated a link between organochlorine and pesticide exposure to an enhanced risk for neurodegenerative disorders such as Parkinson's disease (PD). A common biological phenomenon underlying cell injury associated with both polychlorinated biphenyl (PCB) exposure and dopaminergic neurodegeneration during aging is oxidative stress (OS). In this study, we tested the hypothesis that oral PCB exposure, via food ingestion, impairs dopamine systems in the adult murine brain. We determined whether PCB exposure was associated with OS in dopaminergic neurons, a population of cells that selectively degenerate in PD. After 4 weeks of oral exposure to the PCB mixture Aroclor 1254, several congeners, mostly ortho substituted, accumulated throughout the brain. Significant increases in locomotor activity were observed within 2 weeks, which persisted after cessation of PCB exposure. Stereologic analyses revealed a significant loss of dopaminergic neurons within the substantia nigra and ventral tegmental area. However, striatal dopamine levels were elevated, suggesting that compensatory mechanisms exist to maintain dopamine homeostasis, which could contribute to the observed increases in locomotor activity following PCB exposure. Biochemical experiments revealed alterations in OS markers, including increases in SOD and HO-1 levels and the presence of oxidatively modified lipids and proteins. These findings were accompanied by elevated iron levels within the striatal and midbrain regions, perhaps due to the observed dysregulation of transferrin receptors and ferritin levels following PCB exposure. In this study, we suggest that both OS and the uncoupling of iron regulation contribute to dopamine neuron degeneration and hyperactivity following PCB exposure.

Persistent Organochlorine Exposure and Pregnancy Loss: A Prospective Cohort Study.

Polychlorinated biphenyls (PCBs) and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) are suspected reproductive toxicants. We assessed serum concentration of 76 PCB congeners, DDE, and risk of human chorionic gonadotropin confirmed pregnancy loss among 79 women followed for up to 12 menstrual cycles or until pregnancy. 55 women had live births, 14 experienced pregnancy losses, and 10 did not achieve pregnancy. PCBs and DDE were quantified using gas chromatography with electron capture. PCBs were grouped a priori by biologic activity. Cox proportional hazard regression adjusting for age (categorized 24 - 29, 30 - 34) and average standardized alcohol and cigarette intake (continuous) was used to estimate hazard ratios (HR) of pregnancy loss. Estrogenic PCBs (HR = 1.66, 95% CI: 0.68, 4.02), anti-estrogenic PCBs (HR = 0.10, 95% CI: <0.01, 67.07) and DDE (HR = 1.43, 95% CI: 0.45, 4.52) were not statistically significantly associated with pregnancy loss. Our results provide some signal that estrogenic and antiestrogenic PCBs may be differentially associated with pregnancy loss. Further research is needed to elucidate these associations.

Persistent organochlorine pollutants and menstrual cycle characteristics.

An evolving body of evidence suggests an adverse relation between persistent organochlorine pollutants (POPs) and menstruation, though prospective longitudinal measurement of menses is limited and served as the impetus for study. We prospectively assessed the relation between a mixture of persistent organochlorine compounds and menstrual cycle length and duration of bleeding in a cohort of women attempting to become pregnant. Eighty-three (83%) women contributing 447 cycles for analysis provided a blood specimen for the quantification of 76 polychlorinated biphenyls and seven organochlorine pesticides, and completed daily diaries on menstruation until a human chorionic gonadotropin confirmed pregnancy or 12 menstrual cycles without conception. Gas chromatography with electron capture detection was used to quantify concentrations (ng g(-1)serum); enzymatic methods were used to quantify serum lipids (mg dL(-1)). A linear regression model with a mixture distribution was used to identify chemicals grouped by purported biologic activity that significantly affected menstrual cycle length and duration of bleeding adjusting for age at menarche and enrollment, body mass index, and cigarette smoking. A significant 3-d increase in cycle length was observed for women in the highest tertile of estrogenic PCB congeners relative to the lowest tertile (ß=3.20; 95% CI 0.36, 6.04). A significant reduction in bleeding (<1 d) was observed among women in the highest versus lowest tertile of aromatic fungicide exposure (γ=-0.15; 95% CI -0.29, -0.00). Select POPs were associated with changes in menstruation underscoring the importance of assessing chemical mixtures for female fecundity.

Associations between blood metals and fecundity among women residing in New York State.

Trace exposures to metals may affect female reproductive health. To assess the relation between trace concentrations of blood metals and female fecundity, 99 non-pregnant women discontinuing contraception for the purpose of becoming pregnant were prospectively followed. Participants completed a baseline interview and daily diaries until pregnant, or up to 12 menstrual cycles at risk for pregnancy; home pregnancy test kits were used. For 80 women, whole blood specimens were analyzed for arsenic, cadmium, lead, magnesium, nickel, selenium and zinc using inductively coupled plasma mass spectrometry (ICP-MS). Time to pregnancy was estimated using Cox proportional hazards models for discrete time. Metal concentrations were generally within population reference intervals. Adjusted models suggest a 51.5% increase in the probability for pregnancy per 3.60 µg/L increase in Mg (P=0.062), and a 27.7% decrease per 0.54 µg/L increase in Zn (P=0.114). Findings indicate that Mg and Zn may impact female fecundity, but in varying directions.

Anti-diabetic effects of a series of vanadium dipicolinate complexes in rats with streptozotocin-induced diabetes.

The effects of oral treatment of rats with streptozotocin-induced diabetes with a range of vanadium dipicolinate complexes (Vdipic) and derivatives are reviewed. Structure-reactivity relationships are explored aiming to correlate properties such as stability, to their insulin-enhancing effects. Three types of modifications are investigated; first, substitutions on the aromatic ring, second, coordination of a hydroxylamido group to the vanadium, and third, changes in the oxidation state of the vanadium ion. These studies allowed us to address the importance of coordination chemistry, and redox chemistry, as modes of action. Dipicolinate was originally chosen as a ligand because the dipicolinatooxovanadium(V) complex (V5dipic), is a potent inhibitor of phosphatases. The effect of vanadium oxidation state (3, 4 or 5), on the insulin-enhancing properties was studied in both the Vdipic and VdipicCl series. Effects on blood glucose, body weight, serum lipids, alkaline phosphatase and aspartate transaminase were selectively monitored. Statistically distinct differences in activity were found, however, the trends observed were not the same in the Vdipic and VdipicCl series. Interperitoneal administration of the Vdipic series was used to compare the effect of administration mode. Correlations were observed for blood vanadium and plasma glucose levels after V5dipic treatment, but not after treatment with corresponding V4dipic and V3dipic complexes. Modifications of the aromatic ring structure with chloride, amine or hydroxyl groups had limited effects. Global gene expression was measured using Affymetrix oligonucleotide chips. All diabetic animals treated with hydroxyl substituted V5dipic (V5dipicOH) and some diabetic rats treated with vanadyl sulfate had normalized hyperlipidemia yet uncontrolled hyperglycemia and showed abnormal gene expression patterns. In contrast to the normal gene expression profiles previously reported for some diabetic rats treated with vanadyl sulfate, where both hyperlipidemia and hyperglycemia were normalized. Modification of the metal, changing the coordination chemistry to form a hydroxylamine ternary complex, had the most influence on the anti-diabetic action. Vanadium absorption into serum was determined by atomic absorption spectroscopy for selected vanadium complexes. Only diabetic rats treated with the ternary V5dipicOH hydroxylamine complex showed statistically significant increases in accumulation of vanadium into serum compared to diabetic rats treated with vanadyl sulfate. The chemistry and physical properties of the Vdipic complexes correlated with their anti-diabetic properties. Here, we propose that compound stability and ability to interact with cellular redox reactions are key components for the insulin-enhancing activity of vanadium compounds. Specifically, we found that the most overall effective anti-diabetic Vdipic compounds were obtained when the compound administered had an increased coordination number in the vanadium complex.

Organochlorine pesticides and endometriosis.

Limited study of persistent organochlorine pesticides (OCPs) and endometriosis has been conducted. One hundred women aged 18-40 years who were undergoing laparoscopy provided 20 cm(3) of blood for toxicologic analysis and surgeons completed operative reports regarding the presence of endometriosis. Gas chromatography with electron capture was used to quantify (ng/g serum) six OCPs. Logistic regression was utilized to estimate the adjusted odds ratios (aOR) and 95% confidence intervals (CI) for individual pesticides and groups based on chemical structure adjusting for current cigarette smoking and lipids. The highest tertile of aromatic fungicide was associated with a fivefold risk of endometriosis (aOR=5.3; 95% CI, 1.2-23.6) compared to the lowest tertile. Similar results were found for t-nonachlor and HCB. These are the first such findings in a laproscopic cohort that suggest an association between OCP exposure and endometriosis. More prospective studies are necessary to ensure temporal ordering and confirm these findings.

Maternal serum preconception polychlorinated biphenyl concentrations and infant birth weight.

BACKGROUND: Prenatal and postnatal polychlorinated biphenyl (PCBs) exposure has been associated with decrements in fetal and infant growth and development, although exposures during the preconception window have not been examined despite recent evidence suggesting that this window may correspond with the highest serum concentrations. OBJECTIVES: We assessed maternal serum PCB concentrations at two sensitive developmental windows in relation to birth weight. METHODS: Serum samples were collected from 99 women as they began trying to become pregnant (preconception) and after a positive pregnancy test (prenatal); 52 (53%) women gave birth and represent the study cohort. Using daily diaries, women recorded sexual intercourse, menstruation, and home pregnancy test results until pregnant or up to 12 menstrual cycles with intercourse during the estimated fertile window. With gas chromatography with electron capture, 76 PCB congeners were quantified (nanograms per gram serum) and subsequently categorized by purported biologic activity. Serum PCBs were log-transformed and entered both as continuous and categorized exposures along with birth weight (grams) and covariates [smoking (yes/no), height (inches), and infant sex (male/female)] into linear regression. RESULTS: A substantial reduction in birth weight (grams) was observed for women in the highest versus the lowest tertile of preconception antiestrogenic PCB concentration (beta; = 429.3 g, p = 0.038) even after adjusting for covariates (beta; = 470.8, p = 0.04). CONCLUSIONS: These data reflect the potential developmental toxicity of antiestrogenic PCBs, particularly during the sensitive preconception critical window among women with environmentally relevant chemical exposures, and underscore the importance of PCB congener-specific investigation.

Prenatal and postnatal exposure to polychlorinated biphenyls and child size at 24 months of age.

Research suggests that exposure to polychlorinated biphenyls (PCBs) may result in decreased child growth, though the critical window(s) are unclear. We investigated the association between PCBs and child size at age 24 months (n=44). PCBs were measured in first trimester serum, breast milk, and child serum at age 24 months, and dichotomized at the median. Age- and gender-specific z-scores were calculated for anthropometric measures. Using linear regression, we observed no significant changes in z-scores with prenatal or postnatal serum PCB concentrations. PCB-77 in breast milk was associated with a significant decrease in z-score for length. To our knowledge, this study is the first to examine child size in relation to PCBs measured early in pregnancy, as well as quantifying a far greater number of congeners. Further research is needed to clarify critical windows, congener-specific effects, and effect modification by sex in relation to PCBs and child anthropometric measures.

Contaminant profiles in Southeast Asian immigrants consuming fish from polluted waters in northeastern Wisconsin.

Recent immigrants to the USA from Southeast Asia may be at higher risk of exposure to fish-borne contaminants including polychlorinated biphenyls (PCBs), p, p'-dichlorodiphenyldichloroethene (DDE) and methylmercury (MeHg) because of their propensity to engage in subsistence fishing. Exposure to contaminants was assessed in men and women of Hmong descent living in Green Bay, Wisconsin, where the Fox River and lower Green Bay are contaminated with PCBs, and to a lesser extent with mercury. Serum samples from 142 people were analyzed for PCBs and p,p'-DDE by capillary column gas chromatography with electron capture detection (ECD). Whole blood was analyzed for total mercury by cold vapor atomic absorption spectrometry and atomic fluorescence spectroscopy. Lipid-adjusted total PCB concentrations ranged from 8.7 to 3,091ng/g (full range of the data), with a geometric mean of 183.6ng/g (estimated after eliminating one outlier). DDE ranged from 0.3 to 7,083 (full range of the data) with a geometric mean of 449.8ng/g (estimated after eliminating two outliers). Men had higher PCB and DDE concentrations than women. Serum PCB concentrations were significantly correlated with fish consumption (r=0.43, p<0.0001), whereas DDE concentrations were not (r=0.09,p=0.29). Instead, serum DDE was strongly associated with the number of years spent in a Thai refugee camp before immigrating to the USA (r=0.60;p<0.0001). PCB congeners 138, 153, 118 and 180 accounted for a smaller percentage of the total PCBs than has been reported in other fish-eating populations, and several lightly chlorinated congeners were present in relatively large amounts. Mercury exposure was low in this population. In conclusion, Hmong immigrants in northeastern Wisconsin are at risk of elevated PCB exposure from consumption of locally caught fish. The pattern of exposure is somewhat different than patterns in other fish-eating populations, possibly due to use of Aroclor 1242 by the paper industry in this region.

Assessment of polychlorinated biphenyl congeners, thyroid stimulating hormone, and free thyroxine among New York state anglers.

Experimental literature suggests that polychlorinated biphenyls (PCBs) alter thyroid function however studies of non-occupational or acute exposures in human populations have presented equivocal results. This study considered associations between PCBs and thyroid function biomarkers in a specially selected subsample of participants from the New York State Angler Cohort Study, with the goal of hypotheses generation. Between 1995 and 1997, 38 subjects donated a blood specimen and completed a questionnaire. Sera were analyzed for 77 PCB congeners, beta-HCH, DDE, HCB, mirex, oxychlordane, and trans-nonachlor using GC-ECD, as well as for lipids components, thyroid stimulating hormone (TSH) and free thyroxine (FT(4)). A priori, the sum of all 77 measured PCB congeners, 27 individual PCB congeners with literature evidence for thyroid effects, their sum, DDE, and HCB were chosen as potential predictors for thyroid function. Age, body mass index, cigarette smoking, gender, and use of thyroid relevant medications were considered as important covariates. Adjusted for log total serum lipids, significant (P<0.05) bivariate correlations were demonstrated for log PCB IUPAC #s 153 (r=0.33), 170 (r=0.38), 171+156 (r=0.36), and 180 (r=0.35) with FT(4); however none were observed for log TSH. Using a forward stepwise selection procedure and confounder evaluation algorithm, log PCB #170 was a significant positive predictor of serum FT(4) (beta=1.55 95%CI 0.04-3.07), adjusted for mean centered log PCB #187 and log serum total lipids. This association may be explained by competitive binding to serum thyroid binding proteins by PCB #170, its hydroxylated metabolite 4'-OH-PCB172, or other related but unconsidered compounds. However, bias due to the use of a competitive analog assay for free hormone measurement, random error, or uncontrolled confounding cannot be excluded. The results of this study suggest that Lake Ontario sportfish consumers may comprise a high risk population for PCB related thyroid function alteration and warrant a larger confirmatory investigation.