Exposure to DDT from indoor residual spraying and biomarkers of inflammation among reproductive-aged women from South Africa.

BACKGROUND: Evidence from animal studies suggests that DDT and DDE can adversely affect immuno-competence while human data are less conclusive. We aimed to assess the association of plasma concentrations of DDT and DDE with biomarkers of inflammation among reproductive-aged women residing in homes sprayed with DDT through Indoor Residual Spraying (IRS). METHODS: This study included 416 women from the Study of Women and Babies, South Africa (2010-2011). DDT, DDE, and biomarkers of inflammation (immunoglobulins A, G and M, interleukins 1ß, 6, and 8, tumor necrosis factor-α, C-reactive protein, serum amyloid-A, intercellular adhesion molecule-1, vascular cell adhesion molecule-1) were quantified in plasma. Linear regression was used to assess associations of DDT and DDE with each natural log-transformed biomarker. Models were adjusted for age, body mass index, parity, income, and season; beta estimates were expressed as percent differences. RESULTS: Compared to women with the lowest plasma concentrations of DDT and DDE, those with the highest concentrations of both compounds had higher levels IL-1ß, IL6, and TNF- α. While associations were statistically significant for both DDT and DDE, the magnitude of the associations was slightly stronger for DDT. Compared to women in the lowest quintile of DDT, women in the highest quintile were estimated to have 53.0% (95%CI: 21.7%, 84.4%), 28.1% (95%CI: 6.4%, 49.8%), and 26.6% (95%CI: 12.0%, 41.1%) higher levels of IL-1ß, IL6, and TNF- α, respectively. CONCLUSIONS: Our results suggest that increased plasma concentrations of DDT and DDE resulting from exposure to IRS may increase concentrations of pro-inflammatory biomarkers among reproductive-aged women in South Africa.

Hepatic Transcriptomic Patterns in the Neonatal Rat After Pentabromodiphenyl Ether Exposure.

Human exposure to pentabromodiphenyl ether (PBDE) mixture (DE-71) and its PBDE-47 congener can occur both in utero and during lactation. Here, we tested the hypothesis that PBDE-induced neonatal hepatic transcriptomic alterations in Wistar Han rat pups can inform on potential toxicity and carcinogenicity after longer term PBDE exposures. Wistar Han rat dams were exposed to either DE-71 or PBDE-47 daily from gestation day (GD 6) through postnatal day 4 (PND 4). Total plasma thyroxine (T4) was decreased in PND 4 pups. In liver, transcripts for CYPs and conjugation enzymes, Nrf2, and ABC transporters were upregulated. In general, the hepatic transcriptomic alterations after exposure to DE-71 or PBDE-47 were similar and provided early indicators of oxidative stress and metabolic alterations, key characteristics of toxicity processes. The transcriptional benchmark dose lower confidence limits of the most sensitive biological processes were lower for PBDE-47 than for the PBDE mixture. Neonatal rat liver transcriptomic data provide early indicators on molecular pathway alterations that may lead to toxicity and/or carcinogenicity if the exposures continue for longer durations. These early toxicogenomic indicators may be used to help prioritize chemicals for a more complete toxicity and cancer risk evaluation.

An Evaluation of Neurotoxicity Following Fluoride Exposure from Gestational Through Adult Ages in Long-Evans Hooded Rats.

At elevated levels, fluoride (F-) exposure has been associated with adverse human health effects. In rodents, F- exposure has been reported to induce deficits in motor performance and learning and memory. In this study, we examined Long-Evans hooded male rats maintained on a standard diet (20.5 ppm F-) or a low F- diet (3.24 ppm F-) with drinking water exposure to 0, 10, or 20 ppm F- from gestational day 6 through adulthood. At postnatal day 25, brain F- levels were 0.048 or 0.081 µg/g and femur 235 or 379.8 µg/g for 10 and 20 ppm F-, respectively. Levels increase with age and in adults, levels for plasma were 0.036 or 0.025 µg/ml; for the brain 0.266 or 0.850 µg/g; and for the femur, 681.2 or 993.4 µg/g. At these exposure levels, we observed no exposure-related differences in motor, sensory, or learning and memory performance on running wheel, open-field activity, light/dark place preference, elevated plus maze, pre-pulse startle inhibition, passive avoidance, hot-plate latency, Morris water maze acquisition, probe test, reversal learning, and Y-maze. Serum triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH) levels were not altered as a function of 10 or 20 ppm F- in the drinking water. No exposure-related pathology was observed in the heart, liver, kidney, testes, seminal vesicles, or epididymides. Mild inflammation in the prostate gland was observed at 20 ppm F-. No evidence of neuronal death or glial activation was observed in the hippocampus at 20 ppm F-.

A Black Cohosh Extract Causes Hematologic and Biochemical Changes Consistent with a Functional Cobalamin Deficiency in Female B6C3F1/N Mice.

Black cohosh rhizome, available as a dietary supplement, is most commonly marketed as a remedy for dysmenorrhea and menopausal symptoms. A previous subchronic toxicity study of black cohosh dried ethanolic extract (BCE) in female mice revealed a dose-dependent ineffective erythropoiesis with a macrocytosis consistent with the condition known as megaloblastic anemia. The purpose of this study was to investigate potential mechanisms by which BCE induces these particular hematological changes. B6C3F1/N female mice (32/group) were exposed by gavage to vehicle or 1,000 mg/kg BCE for 92 days. Blood samples were analyzed for hematology, renal and hepatic clinical chemistry, serum folate and cobalamin, red blood cell (RBC) folate, and plasma homocysteine and methylmalonic acid (MMA). Folate levels were measured in liver and kidney. Hematological changes included decreased RBC count; increased mean corpuscular volume; and decreased reticulocyte, white blood cell, neutrophil, and lymphocyte counts. Blood smear evaluation revealed increased Howell-Jolly bodies and occasional basophilic stippling in treated animals. Plasma homocysteine and MMA concentrations were increased in treated animals. Under the conditions of our study, BCE administration caused hematological and clinical chemistry changes consistent with a functional cobalamin, and possibly folate, deficiency. Further studies are needed to elucidate the mechanism by which BCE causes increases in homocysteine and MMA.

Correction: Maternal Glomerular Filtration Rate in Pregnancy and Fetal Size.

[This corrects the article DOI: 10.1371/journal.pone.0101897.].

Anti-Müllerian hormone and lifestyle, reproductive, and environmental factors among women in rural South Africa.

BACKGROUND: Few data exist regarding anti-Müllerian hormone, a marker of ovarian reserve, in relation to environmental factors with potential ovarian toxicity. METHODS: This analysis included 420 women from Limpopo, South Africa studied in 2010-2011. Women were administered comprehensive questionnaires, and plasma concentrations of anti-Müllerian hormone and dichlorodiphenyltrichloroethane were determined. We used separate multivariable models to examine the associations between natural log-transformed anti-Müllerian hormone concentration (ng/ml) and each of the lifestyle, reproductive, and environmental factors of interest, adjusted for age, body mass index, education, and parity. RESULTS: The median age of women was 24 years (interquartile range [IQR] = 22 to 26); the median anti-Müllerian hormone concentration was 3.1 ng/ml (IQR = 2.0 to 6.0). Women who reported indoor residual spraying in homes with painted walls (indicative of exposure to pyrethroids) had 25% lower (95% confidence interval [CI] = -39%, -8%) anti-Müllerian hormone concentrations compared with women who reported no spraying. Little evidence of decreased anti-Müllerian hormone concentrations was observed among women with the highest dichlorodiphenyltrichloroethane levels. Compared with women who used an electric stove, no association was observed among women who cooked indoors over open wood fires. The findings also suggested lower anti-Müllerian hormone concentrations among women who drank coffee (-19% [95% CI = -31%, -5%]) or alcohol (-21% [95% CI = -36%, -3%]). CONCLUSIONS: These are among the first data regarding anti-Müllerian hormone concentrations relative to pesticides and indoor air pollution. Our results are suggestive of decreased ovarian reserve associated with exposure to pyrethroid pesticides, which is consistent with laboratory animal data.

Recreational Exercise Before and During Pregnancy in Relation to Plasma C-Reactive Protein Concentrations in Pregnant Women.

BACKGROUND: Pregnant women who are physically active have a lower risk of preeclampsia and gestational diabetes than women who are less active. One possible mechanism is a reduction in low-grade inflammation, as measured by plasma concentrations of C-reactive protein (CRP). The association between exercise and CRP in pregnant women, however, has not been adequately investigated. METHODS: A total of 537 pregnant women, enrolled around the 17th week of gestation in the Norwegian Mother and Child Cohort Study in 2003 to 2004, were studied. Self-reported recreational exercise was recalled for both 3 months before pregnancy and early pregnancy. The total energy expenditure from recreational exercise (total recreational exercise, metabolic equivalent of task [MET]-hr/week) was estimated, and low-, moderate- and vigorous-intensity exercise was defined. Plasma CRP concentrations were measured during pregnancy. RESULTS: In adjusted linear regression models, mean CRP concentration was 1.0% lower [95% CI = -1.9% to 0.2%] with each 1 MET-hr/week of total recreational exercise before pregnancy. In addition, vigorous-intensity exercise before pregnancy was more strongly related to a reduction in CRP levels than low- or moderate-intensity exercise. However, we observed no association between recreational exercise during pregnancy and plasma CRP levels. CONCLUSIONS: Recreational exercise before pregnancy, especially vigorous exercise, may reduce the risk of maternal inflammation during pregnancy.

Maternal glomerular filtration rate in pregnancy and fetal size.

BACKGROUND: The relationship of maternal glomerular filtration rate (GFR) in pregnancy to fetal size needs to be better characterized as it impacts an ongoing debate about confounding effect of maternal GFR in investigations of important environmental contaminants. We aimed to characterize the size of the association between maternal GFR and infant birth weight. MATERIALS AND METHODS: A sub-cohort of 953 selected women (470 women with and 483 women without preeclampsia) in the Norwegian Mother and Child Cohort (MoBa), recruited during 2003-2007 were analyzed. GFR in the second trimester was estimated based on plasma creatinine. Birth weight was ascertained from the Medical Birth Registry of Norway. Multivariate linear regression was used to evaluate the association between maternal GFR in second trimester (estimated by the Cockroft-Gault [GFR-CG] and the modification of diet in renal disease [GFR-MDRD] formulas) and infant birth weight. Partial correlation coefficients were also calculated. RESULTS: Maternal GFR-CG (ß: 0.73 g/ml/min, p = 0.04) and GFR-MDRD (ß: 0.83 g/ml/min, p = 0.04) were associated with infant birth weight in models adjusted for maternal weight in kilograms, preeclampsia, and gestational age at delivery (days). Partial correlation coefficients for the association between infant birth weight and GFR were 0.07 for both formulas. Although the birth weight-GFR association was stronger among the women with preeclampsia, the difference from women without preeclampsia was not statistically significant. CONCLUSION: These data support an association between GFR during pregnancy and infant birth weight, and indicate that GFR may confound selected epidemiologic associations.

Predictors of plasma DDT and DDE concentrations among women exposed to indoor residual spraying for malaria control in the South African Study of Women and Babies (SOWB).

BACKGROUND: Few studies have examined predictors of DDT (dichlorodiphenyltrichloroethane) and DDE (dichlorodiphenyldichloroethylene) levels among residents in homes sprayed with DDT for malaria control with the aim of identifying exposure-reduction strategies. METHODS: The present analysis included 381 women enrolled in the Study of Women and Babies (SOWB) during 2010-2011, from eight South African villages in the Limpopo Province, South Africa. Indoor residual spraying (IRS) occurred in half of the villages. Questionnaires regarding various demographic and medical factors were administered and blood samples were obtained. We classified the women into three exposure groups by type of residence: unsprayed village (n = 175), IRS village in household with a low likelihood of DDT use (non-DDT IRS household, n = 106), IRS village in household with a high likelihood of DDT use (DDT IRS household, n = 100). We used multivariable models of natural log-transformed DDT plasma levels (in micrograms per liter) and DDE (in micrograms per liter) to identify predictors for each group. RESULTS: Median levels of DDT and DDE among women in unsprayed villages were 0.3 [interquartile range (IQR): 0.1-0.9] and 1.7 (IQR: 0.7-5.5), respectively. Median levels of DDT and DDE among women in DDT IRS households were 2.6 (IQR: 1.1-6.6) and 8.5 (IQR: 4.7-18.0), respectively. In unsprayed villages, women with water piped to the yard, rather than a public tap, had 73% lower DDT (95% CI: -83, -57%) and 61% lower DDE (95% CI: -74, -40%) levels. In DDT IRS households, women who reported taking more than six actions to prepare their home before IRS (e.g., covering water and food) had 40% lower DDT levels (95% CI: -63, -0.3%) than women who took fewer than four actions. CONCLUSION: The predictors of DDT and DDE plasma levels identified in the present study may inform interventions aimed at decreasing exposure. Among households where DDT is likely to be used for IRS, education regarding home preparations may provide an interventional target.

Perfluoroalkyl substances during pregnancy and validated preeclampsia among nulliparous women in the Norwegian Mother and Child Cohort Study.

Perfluoroalkyl substances (PFAS) are persistent and ubiquitous environmental contaminants, and human exposure to these substances may be related to preeclampsia, a common pregnancy complication. Previous studies have found serum concentrations of PFAS to be positively associated with pregnancy-induced hypertension and preeclampsia in a population with high levels of exposure to perfluorooctanoate. Whether this association exists among pregnant women with background levels of PFAS exposure is unknown. Using data from the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health, we carried out a study of nulliparous pregnant women enrolled in 2003-2007 (466 cases, 510 noncases) to estimate associations between PFAS concentrations and an independently validated diagnosis of preeclampsia. We measured levels of 9 PFAS in maternal plasma extracted midpregnancy; statistical analyses were restricted to 7 PFAS that were quantifiable in more than 50% of samples. In proportional hazards models adjusted for maternal age, prepregnancy body mass index (weight (kg)/height (m)(2)), educational level, and smoking status, we observed no strongly positive associations between PFAS levels and preeclampsia. We found an inverse association between preeclampsia and the highest quartile of perfluoroundecanoic acid concentration relative to the lowest quartile (hazard ratio = 0.55, 95% confidence interval: 0.38, 0.81). Overall, our findings do not support an increased risk of preeclampsia among nulliparous Norwegian women with background levels of PFAS exposure.

Perfluoroalkyl substances and lipid concentrations in plasma during pregnancy among women in the Norwegian Mother and Child Cohort Study.

BACKGROUND: Perfluoroalkyl substances (PFASs) are widespread and persistent environmental pollutants. Previous studies, primarily among non-pregnant individuals, suggest positive associations between PFAS levels and certain blood lipids. If there is a causal link between PFAS concentrations and elevated lipids during pregnancy, this may suggest a mechanism by which PFAS exposure leads to certain adverse pregnancy outcomes, including preeclampsia. METHODS: This cross-sectional analysis included 891 pregnant women enrolled in the Norwegian Mother and Child (MoBa) Cohort Study in 2003-2004. Non-fasting plasma samples were obtained at mid-pregnancy and analyzed for nineteen PFASs. Total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured in plasma. Linear regression was used to quantify associations between each PFAS exposure and each lipid outcome. A multiple PFAS model was also fitted. RESULTS: Seven PFASs were quantifiable in >50% of samples. Perfluorooctane sulfonate (PFOS) concentration was associated with total cholesterol, which increased 4.2mg/dL per inter-quartile shift (95% CI=0.8, 7.7) in adjusted models. Five of the seven PFASs studied were positively associated with HDL cholesterol, and all seven had elevated HDL associated with the highest quartile of exposure. Perfluoroundecanoic acid showed the strongest association with HDL: HDL increased 3.7 mg/dL per inter-quartile shift (95% CI=2.5, 4.9). CONCLUSION: Plasma concentrations of PFASs were positively associated with HDL cholesterol, and PFOS was positively associated with total cholesterol in this sample of pregnant Norwegian women. While elevated HDL is not an adverse outcome per se, elevated total cholesterol associated with PFASs during pregnancy could be of concern if causal.

Exposure to tobacco smoke in utero and subsequent plasma lipids, ApoB, and CRP among adult women in the MoBa cohort.

BACKGROUND: Recent findings suggest that maternal smoking during pregnancy may play a role in the development of metabolic alterations in offspring during childhood. However, whether such exposure increases the risk of developing similar metabolic alterations during adulthood is uncertain. OBJECTIVE: We evaluated the association of in utero exposure to maternal tobacco smoke with plasma lipids, apolipoprotein B (apoB), and C-reactive protein (CRP) in adulthood. METHODS: The study was based on a subsample of the Norwegian Mother and Child Cohort Study (MoBa) and included 479 pregnant women with plasma lipids, apoB, and CRP measurements. Information on in utero exposure to tobacco smoke, personal smoking, and other factors were obtained from the women by a self-completed questionnaire at enrollment, at approximately 17 weeks of gestation. RESULTS: Women exposed to tobacco smoke in utero had higher triglycerides [10.7% higher; 95% confidence interval (CI): 3.9, 17.9] and lower high-density lipoprotein cholesterol (HDL) (-1.9 mg/dL; 95% CI: -4.3, 0.5) compared with unexposed women, after adjusting for age, physical activity, education, personal smoking, and current body mass index (BMI). Exposed women were also more likely to have triglycerides ≥ 200 mg/dL [adjusted odds ratio (aOR) = 2.5; 95% CI: 1.3, 5.1] and HDL < 50 mg/dL (aOR = 2.3; 95% CI: 1.1, 5.0). Low-density lipoprotein cholesterol, total cholesterol, and apoB were not associated with the exposure. CRP was increased among exposed women; however, after adjustment for BMI, the association was completely attenuated. CONCLUSIONS: In this population, in utero exposure to tobacco smoke was associated with high triglycerides and low HDL in adulthood, 18-44 years after exposure.

Molecular and organismal changes in offspring of male mice treated with chemical stressors.

Both gene methylation changes and genetic instability have been noted in offspring of male rodents exposed to radiation or chemicals, but few specific gene targets have been established. Previously, we identified the gene for ribosomal RNA, rDNA, as showing methylation change in sperm of mice treated with the preconceptional carcinogen, chromium(III) chloride. rDNA is a critical cell growth regulator. Here, we investigated the effects of paternal treatments on rDNA in offspring tissue. A total of 93 litters and 758 offspring were obtained, permitting rigorous mixed-effects models statistical analysis of the results. We show that the offspring of male mice treated with Cr(III) presented increased methylation in a promoter sequence of the rDNA gene, specifically in lung. Furthermore polymorphic variants of the multi-copy rDNA genes displayed altered frequencies indicative of structural changes, as a function of both tissue type and paternal treatments. Organismal effects also occurred: some groups of offspring of male mice treated with either Cr(III) or its vehicle, acidic saline, compared with those of untreated mice, had altered average body and liver weights and levels of serum glucose and leptin. Males treated directly with Cr(III) or acidic saline presented serum hormone changes consistent with a stress response. These results establish for the first time epigenetic and genetic instability effects in a gene of central physiological importance, in offspring of male mice exposed preconceptionally to chemicals, possibly related to a stress response in these males.

Perfluorinated compounds in relation to birth weight in the Norwegian Mother and Child Cohort Study.

Perfluorooctane sulfonate and perfluorooctanoic acid are perfluorinated compounds (PFCs) widely distributed in the environment. Previous studies of PFCs and birth weight are equivocal. The authors examined this association in the Norwegian Mother and Child Cohort Study (MoBa), using data from 901 women enrolled from 2003 to 2004 and selected for a prior case-based study of PFCs and subfecundity. Maternal plasma samples were obtained around 17 weeks of gestation. Outcomes included birth weight z scores, preterm birth, small for gestational age, and large for gestational age. The adjusted birth weight z scores were slightly lower among infants born to mothers in the highest quartiles of PFCs compared with infants born to mothers in the lowest quartiles: for perfluorooctane sulfonate, ß = -0.18 (95% confidence interval: -0.41, 0.05) and, for perfluorooctanoic acid, ß = -0.21 (95% confidence interval: -0.45, 0.04). No clear evidence of an association with small for gestational age or large for gestational age was observed. Perfluorooctane sulfonate and perfluorooctanoic acid were each associated with decreased adjusted odds of preterm birth, although the cell counts were small. Whether some of the associations suggested by these findings may be due to a noncausal pharmacokinetic mechanism remains unclear.

Artifactual changes in Sprague-Dawley rat hematologic parameters after storage of samples at 3 °C and 21 °C.

Circumstances can occur that prevent timely analysis of blood samples. The purpose of this study was to characterize artifactual changes in rat hematologic parameters after storage of samples at 3 and 21 °C and to document the effects of storage on peripheral blood smear findings. EDTA-treated blood samples were collected from 12 male Sprague-Dawley rats. Samples were analyzed on an impedance hematology analyzer within 5 min after collection and then at 6, 24, 48, and 72 h after storage at 3 °C or 21 °C. Corresponding blood smears were examined microscopically. RBC count and hemoglobin concentration had not changed after 72 h at either temperature. At 3 °C, the instrument-derived hematocrit and manually measured PCV remained unchanged for 72 h. Compared with 0-h values, platelet counts and MCV at 6 h and MPV at 24 h were higher at either temperature. In general, WBC count and neutrophil and lymphocyte percentages were unchanged for at least 48 h at either temperature. Prominent blood smear findings were smudge cells, pyknotic leukocytes, echinocytes, and spheroechinocytes. Although some observed changes were within analytic variability or clinically negligible, the best practice likely is to measure hematologic parameters within 6 h after collection. In the event of delayed analysis, specimens should be stored in the refrigerator, and care must be taken not to misinterpret artifactual changes as pathologic findings.

Perfluorinated compounds and subfecundity in pregnant women.

BACKGROUND: Perfluorinated compounds are ubiquitous pollutants; epidemiologic data suggest they may be associated with adverse health outcomes, including subfecundity. We examined subfecundity in relation to 2 perfluorinated compounds-perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). METHODS: This case-control analysis included 910 women enrolled in the Norwegian Mother and Child Cohort Study in 2003 and 2004. Around gestational week 17, women reported their time to pregnancy and provided blood samples. Cases consisted of 416 women with a time to pregnancy greater than 12 months, considered subfecund. Plasma concentrations of perfluorinated compounds were analyzed using liquid chromatography-mass spectrometry. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for each pollutant quartile using logistic regression. Estimates were further stratified by parity. RESULTS: The median plasma concentration of PFOS was 13.0 ng/mL (interquartile range [IQR] = 10.3-16.6 ng/mL) and of PFOA was 2.2 ng/mL (IQR = 1.7-3.0 ng/mL). The relative odds of subfecundity among parous women was 2.1 (95% CI = 1.2-3.8) for the highest PFOS quartile and 2.1 (1.0-4.0) for the highest PFOA quartile. Among nulliparous women, the respective relative odds were 0.7 (0.4-1.3) and 0.5 (0.2-1.2). CONCLUSION: Previous studies suggest that the body burden of perfluorinated compounds decreases during pregnancy and lactation through transfer to the fetus and to breast milk. Afterward, the body burden may increase again. Among parous women, increased body burden may be due to a long interpregnancy interval rather than the cause of a long time to pregnancy. Therefore, data from nulliparous women may be more informative regarding toxic effects of perfluorinated compounds. Our results among nulliparous women did not support an association with subfecundity.

Ontogeny-driven rDNA rearrangement, methylation, and transcription, and paternal influence.

Gene rearrangement occurs during development in some cell types and this genome dynamics is modulated by intrinsic and extrinsic factors, including growth stimulants and nutrients. This raises a possibility that such structural change in the genome and its subsequent epigenetic modifications may also take place during mammalian ontogeny, a process undergoing finely orchestrated cell division and differentiation. We tested this hypothesis by comparing single nucleotide polymorphism-defined haplotype frequencies and DNA methylation of the rDNA multicopy gene between two mouse ontogenic stages and among three adult tissues of individual mice. Possible influences to the genetic and epigenetic dynamics by paternal exposures were also examined for Cr(III) and acid saline extrinsic factors. Variables derived from litters, individuals, and duplicate assays in large mouse populations were examined using linear mixed-effects model. We report here that active rDNA rearrangement, represented by changes of haplotype frequencies, arises during ontogenic progression from day 8 embryos to 6-week adult mice as well as in different tissue lineages and is modifiable by paternal exposures. The rDNA methylation levels were also altered in concordance with this ontogenic progression and were associated with rDNA haplotypes. Sperm showed highest level of methylation, followed by lungs and livers, and preferentially selected haplotypes that are positively associated with methylation. Livers, maintaining lower levels of rDNA methylation compared with lungs, expressed more rRNA transcript. In vitro transcription demonstrated haplotype-dependent rRNA expression. Thus, the genome is also dynamic during mammalian ontogeny and its rearrangement may trigger epigenetic changes and subsequent transcriptional controls, that are further influenced by paternal exposures.

Diet-induced obesity is associated with hyperleptinemia, hyperinsulinemia, hepatic steatosis, and glomerulopathy in C57Bl/6J mice.

Obesity and obesity-related illnesses are global epidemics impacting the health of adults and children. The purpose of the present work is to evaluate a genetically intact obese mouse model that more accurately reflects the impact of aging on diet-induced obesity and type 2 diabetes in humans. Male C57Bl/6J mice consumed either a control diet or one in which 60% kcal were due to lard beginning at 5-6 weeks of age. Body weight and fat measurements were obtained and necropsy performed at 15, 20, 30, and 40 weeks of age. Serum chemistry, histopathology, gene expression of the liver, and renal and hepatic function were also evaluated. In concert with significant increases in percent body fat and weight, mice fed the high-fat versus control diet had significantly increased levels of serum cholesterol. At ages 20 and 30 weeks, serum glucose was significantly higher in obese versus controls, while serum insulin levels were >/=4-fold higher in obese mice at ages 30 and 40 weeks. The effect of age exacerbated the effects of consuming a high-fat diet. In addition to being hyperinsulinemic and leptin resistant, older obese mice exhibited elevated hepatic PAI-1 and downregulation of GLUT4, G6PC, IGFBP-1, and leptin receptor mRNA in the liver, steatosis with subsequent inflammation, glomerular mesangial proliferation, elevated serum ALT, AST, and BUN, and increased numbers of pancreatic islets.

Orally administered H-Dmt-Tic-Lys-NH-CH2-Ph (MZ-2), a potent mu/delta-opioid receptor antagonist, regulates obese-related factors in mice.

Orally active dual mu-/delta-opioid receptor antagonist, H-Dmt-Tic-Lys-NH-CH(2)-Ph (MZ-2) was applied to study body weight gain, fat content, bone mineral density, serum insulin, cholesterol and glucose levels in female ob/ob (B6.V-Lep/J homozygous) and lean wild mice with or without voluntary exercise on wheels for three weeks, and during a two week post-treatment period under the same conditions. MZ-2 (10mg/kg/day, p.o.) exhibited the following actions: (1) reduced body weight gain in sedentary obese mice that persisted beyond the treatment period without effect on lean mice; (2) stimulated voluntary running on exercise wheels of both groups of mice; (3) decreased fat content, enhanced bone mineral density (BMD), and decreased serum insulin and glucose levels in obese mice; and (4) MZ-2 (30 microM) increased BMD in human osteoblast cells (MG-63) comparable to naltrexone, while morphine inhibited mineral nodule formation. Thus, MZ-2 has potential application in the clinical management of obesity, insulin and glucose levels, and the amelioration of osteoporosis.

Uterine leiomyomata in relation to insulin-like growth factor-I, insulin, and diabetes.

BACKGROUND: Insulin-like growth factor-I (IGF-I) and insulin stimulate cell proliferation in uterine leiomyoma (fibroid) tissue. We hypothesized that circulating levels of these proteins would be associated with increased prevalence and size of uterine fibroids. METHODS: Participants were 35-49-year-old, randomly selected members of an urban health plan who were enrolled in the study in 1996-1999. Premenopausal participants were screened for fibroids with ultrasound. Fasting blood samples were collected. Associations between fibroids and diabetes, plasma IGF-I, IGF binding protein 3 (BP3), and insulin were evaluated for blacks (n = 585) and whites (n = 403) by using multiple logistic regression. RESULTS: IGF-I showed no association with fibroids in blacks, but in whites the adjusted odds ratios (aORs) for both mid and upper tertiles compared with the lowest tertile were 0.6 (95% confidence intervals [CI] = 0.3-1.0 and 0.4-1.1, respectively). Insulin and diabetes both tended to be inversely associated with fibroids in blacks. The insulin association was with large fibroids; aOR for the upper insulin tertile relative to the lowest was 0.4 (0.2-0.9). The aOR for diabetes was 0.5 (0.2-1.0). Associations of insulin and diabetes with fibroids were weak for whites. Binding protein 3 showed no association with fibroids. CONCLUSIONS: Contrary to our hypothesis, high circulating IGF-I and insulin were not related to increased fibroid prevalence. Instead, there was suggestion of the opposite. The inverse association with diabetes, although based on small numbers, is consistent with previously reported findings. Future studies might investigate vascular dysfunction as a mediator between hyperinsulinemia or diabetes and possible reduced risk of fibroids.