A systematic review and meta-analysis of murine models of uremic cardiomyopathy.

Chronic kidney disease (CKD) triggers the risk of developing uremic cardiomyopathy as characterized by cardiac hypertrophy, fibrosis and functional impairment. Traditionally, animal studies are used to reveal the underlying pathological mechanism, although variable CKD models, mouse strains and readouts may reveal diverse results. Here, we systematically reviewed 88 studies and performed meta-analyses of 52 to support finding suitable animal models for future experimental studies on pathological kidney-heart crosstalk during uremic cardiomyopathy. We compared different mouse strains and the direct effect of CKD on cardiac hypertrophy, fibrosis and cardiac function in "single hit" strategies as well as cardiac effects of kidney injury combined with additional cardiovascular risk factors in "multifactorial hit" strategies. In C57BL/6 mice, CKD was associated with a mild increase in cardiac hypertrophy and fibrosis and marginal systolic dysfunction. Studies revealed high variability in results, especially regarding hypertrophy and systolic function. Cardiac hypertrophy in CKD was more consistently observed in 129/Sv mice, which express two instead of one renin gene and more consistently develop increased blood pressure upon CKD induction. Overall, "multifactorial hit" models more consistently induced cardiac hypertrophy and fibrosis compared to "single hit" kidney injury models. Thus, genetic factors and additional cardiovascular risk factors can "prime" for susceptibility to organ damage, with increased blood pressure, cardiac hypertrophy and early cardiac fibrosis more consistently observed in 129/Sv compared to C57BL/6 strains.

Native, Intact Glucagon-Like Peptide 1 Is a Natural Suppressor of Thrombus Growth Under Physiological Flow Conditions.

OBJECTIVE: In patients with diabetes mellitus, increased platelet reactivity predicts cardiac events. Limited evidence suggests that DPP-4 (dipeptidyl peptidase 4) influences platelets via GLP-1 (glucagon-like peptide 1)-dependent effects. Because DPP-4 inhibitors are frequently used in diabetes mellitus to improve the GLP-1-regulated glucose metabolism, we characterized the role of DPP-4 inhibition and of native intact versus DPP-4-cleaved GLP-1 on flow-dependent thrombus formation in mouse and human blood. Approach and Results: An ex vivo whole blood microfluidics model was applied to approach in vivo thrombosis and study collagen-dependent platelet adhesion, activation, and thrombus formation under shear-flow conditions by multiparameter analyses. In mice, in vivo inhibition or genetic deficiency of DPP-4 (Dpp4-/-), but not of GLP-1-receptors (Glp1r-/-), suppressed flow-dependent platelet aggregation. In human blood, GLP-1(7-36), but not DPP-4-cleaved GLP-1(9-36), reduced thrombus volume by 32% and impaired whole blood thrombus formation at both low/venous and high/arterial wall-shear rates. These effects were enforced upon ADP costimulation and occurred independently of plasma factors and leukocytes. Human platelets did not contain detectable levels of GLP-1-receptor transcripts. Also, GLP-1(7-36) did not inhibit collagen-induced aggregation under conditions of stirring or stasis of platelets, pointing to a marked flow-dependent role. CONCLUSIONS: Native, intact GLP-1 is a natural suppressor of thrombus growth under physiological flow conditions, with DPP-4 inhibition and increased intact GLP-1 suppressing platelet aggregation under flow without a main relevance of GLP-1-receptor on platelets.

Gene expression in archived newborn blood spots distinguishes infants who will later develop cerebral palsy from matched controls.

BACKGROUND: Gene expression in archived newborn blood spots remaining from newborn screening may reflect pathophysiological disturbances useful in understanding the etiology of cerebral palsy (CP). METHODS: We quantified the expression of gene sets representing four physiological pathways hypothesized to contribute to CP in archived unfrozen residual newborn blood spot specimens from 53 children with CP and 53 age-, gender-, and gestational age-matched controls. We selected four empirical and three canonical gene sets representing the inflammatory, hypoxic, coagulative, and thyroidal pathways and examined mRNA expression using an 8 × 60,000 oligonucleotide microarray. The log2 fold change of gene expression between matched cases and controls was analyzed using the generally applicable gene set enrichment method. RESULTS: The empirical inflammatory and empirical hypoxic gene sets were significantly downregulated in term-born CP cases (n = 33) as compared with matched controls (P = 0.0007 and 0.0009, respectively), whereas both gene sets were significantly upregulated (P =0.0055 and 0.0223, respectively) in preterm-born CP cases (n = 20). The empirical thyroidal gene set was significantly upregulated in preterm-born CP cases (P = 0.0023). CONCLUSION: The newborn blood spot transcriptome can serve as a platform for investigating distinctive gene expression patterns in children who later develop CP.

Air pollutant exposure and preterm and term small-for-gestational-age births in Detroit, Michigan: long-term trends and associations.

Studies in a number of countries have reported associations between exposure to ambient air pollutants and adverse birth outcomes, including low birth weight, preterm birth (PTB) and, less commonly, small for gestational age (SGA). Despite their growing number, the available studies have significant limitations, e.g., incomplete control of temporal trends in exposure, modest sample sizes, and a lack of information regarding individual risk factors such as smoking. No study has yet examined large numbers of susceptible individuals. We investigated the association between ambient air pollutant concentrations and term SGA and PTB outcomes among 164,905 singleton births in Detroit, Michigan occurring between 1990 and 2001. SO(2), CO, NO(2), O(3) and PM(10) exposures were used in single and multiple pollutant logistic regression models to estimate odds ratios (OR) for these outcomes, adjusted for the infant's sex and gestational age, the mother's race, age group, education level, smoking status and prenatal care, birth season, site of residence, and long-term exposure trends. Term SGA was associated with CO levels exceeding 0.75ppm (OR=1.14, 95% confidence interval=1.02-1.27) and NO(2) exceeding 6.8ppb (1.11, 1.03-1.21) exposures in the first month, and with PM(10) exceeding 35µg/m(3) (1.22, 1.03-1.46) and O(3) (1.11, 1.02-1.20) exposure in the third trimester. PTB was associated with SO(2) (1.07, 1.01-1.14) exposure in the last month, and with (hourly) O(3) exceeding 92ppb (1.08, 1.02-1.14) exposure in the first month. Exposure to several air pollutants at modest concentrations was associated with adverse birth outcomes. This study, which included a large Black population, suggests the importance of the early period of pregnancy for associations between term SGA with CO and NO(2), and between O(3) with PTB; and the late pregnancy period for associations between term SGA and O(3) and PM(10), and between SO(2) with PTB. It also highlights the importance of accounting for individual risk factors such as maternal smoking, maternal race, and long-term trends in air pollutant levels and adverse birth outcomes in evaluating relationships between pollutant exposures and adverse birth outcomes.

Innate immune system gene polymorphisms in maternal and child genotype and risk of preterm delivery.

OBJECTIVE: There is little information about the combination of genetic variability in pregnant women and their children in relation to the risk of preterm delivery (PTD). In a sub-cohort of 487 non-Hispanic white and 288 African-American mother/child pairs, the Pregnancy Outcomes and Community Health Study assessed 10 functional polymorphisms in 9 genes involved in innate immune function. METHODS: Race-stratified weighted logistic regression models were used to calculate odds ratios for genotype and PTD/PTD subtypes. Polymorphisms significantly associated with PTD/PTD subtypes were tested for mother/child genotype interactions. RESULTS: Three maternal polymorphisms (IL-1 receptor antagonist intron two repeat (IL-1RN), matrix metalloproteinase- -C1562T, and TNF receptor two M196R (TNFR2)) and three child polymorphisms (IL1-RN, tumor necrosis factor-alpha -G308A, and TNFR2) were associated with PTD, but associations varied by PTD subtype and race. Two interactions were detected for maternal and child genotype. Among non-Hispanic white women, the odds of PTD was higher when both mother and child carried the IL-1RN allele two (additive interaction p < 0.05). Among African-American women, the odds of PTD were higher when both mother and child carried the TNFR2 R allele (multiplicative interaction p < 0.05). CONCLUSION: These results highlight the importance of assessing both maternal and child genotype in relation to PTD risk.

Interplay of cytokine polymorphisms and bacterial vaginosis in the etiology of preterm delivery.

Recent findings suggest that the association between inflammation-related genes and preterm delivery may be stronger in the presence of bacterial vaginosis (BV). Tumor necrosis factor-alpha (TNFα) and interleukin 1-beta (IL-1ß) are pro-inflammatory cytokines capable of inducing preterm labor in non-human primates. In this study the authors tested associations among two TNFα promoter polymorphisms (-G308A and -G238A), a single IL-1ß polymorphism (+C3954T), vaginal microbial findings, and risk of preterm delivery. Data were from the Pregnancy Outcomes and Community Health (POUCH) Study (n=777 term and n=230 preterm deliveries). Vaginal smears collected at mid-pregnancy (15-27 weeks gestation) were scored according to Nugent's criteria. A Nugent score of ≥ 4 was modeled as the cut-point for intermediate and positive BV. Logistic regression was used to estimate odds ratios for associations among independent covariates (vaginal flora, genotype) and preterm delivery. Results showed that women with a Nugent score of≥ 4 and the TNFα -238 A/G or A/A were at increased risk of delivering preterm (race/ethnicity adjusted OR 2.6, 95% CI 1.2, 5.8). The p-value for the genotype and Nugent score interaction=0.02. This study points to one more example of a potential gene-environment interaction in a preterm delivery pathway. Future tests of this finding will determine the robustness of these results.

Adverse effects of low level heavy metal exposure on male reproductive function.

Lead, cadmium, mercury, and arsenic, often referred to as "heavy metals", are toxic for wildlife, experimental animals, and humans. While experimental animal and human occupational studies with high exposure levels generally support an adverse role for these metals in human reproductive outcomes, information on the effects of low, environmentally-realistic exposure levels of these metals on male reproductive outcomes is limited. We review the literature on effects of exposure to low levels of these metals on measures of male fertility (semen quality and reproductive hormone levels) and provide supporting evidence from experimental and occupational studies. Potentially modifying effects of genetic polymorphisms on these associations are discussed. A brief review of the literature on the effects of three trace metals, copper, manganese, and molybdenum, that are required for human health, yet may also cause adverse reproductive effects, follows. Overall, there were few studies examining the effects of exposure to low levels of these metals on male reproductive health. For all metals, there were several well-designed studies with sufficient populations appropriately adjusted for potential confounders and many of these reported harmful effects. However, many studies lacked sufficient numbers of participants to be able to detect differences in outcomes between exposed and non-exposed individuals, did not clearly identify the source and characteristics of the participants, and did not control for other exposures that could alter or contribute to the outcomes. The evidence for the effects of low exposure was strongest for cadmium, lead, and mercury and less certain for arsenic. The potential modifying effects of genetic polymorphisms has not been fully explored. Additional studies on the reproductive effects of these toxic ubiquitous metals on male reproduction are required to expand the knowledge base and to resolve inconsistencies.

Environmental exposure to metals and male reproductive hormones: circulating testosterone is inversely associated with blood molybdenum.

OBJECTIVE: To explore associations between exposure to metals and male reproductive hormone levels. DESIGN: Cross-sectional epidemiology study with adjustment for potential confounders. SETTING: University Medical Center. PATIENT(S): Men recruited through two infertility clinics in Michigan. INTERVENTION(S): Metal concentrations and reproductive hormone levels were measured in blood samples collected from 219 men. MAIN OUTCOME MEASURE(S): Serum FSH, LH, inhibin B, T, and sex hormone-binding globulin levels. RESULT(S): Cadmium, copper, and lead were all significantly or suggestively positively associated with T when modeled individually, findings that are consistent with limited previous human and animal studies. Conversely, molybdenum was associated with reduced T. A significant inverse trend between molybdenum and T remained when additionally considering other metals in the model, and a positive association between T and zinc was also found. Finally, in exploratory analysis there was evidence for an interaction between molybdenum and zinc, whereby high molybdenum was associated with a 37% reduction in T (relative to the population median level) among men with low zinc. CONCLUSION(S): Although reductions in T and reproductive toxicity after molybdenum exposure have been previously demonstrated in animal studies, more research is needed to determine whether molybdenum poses a risk to human reproductive health.

Multiple metals predict prolactin and thyrotropin (TSH) levels in men.

Exposure to a number of metals can affect neuroendocrine and thyroid signaling, which can result in adverse effects on development, behavior, metabolism, reproduction, and other functions. The present study assessed the relationship between metal concentrations in blood and serum prolactin (PRL) and thyrotropin (TSH) levels, markers of dopaminergic, and thyroid function, respectively, among men participating in a study of environmental influences on male reproductive health. Blood samples from 219 men were analyzed for concentrations of 11 metals and serum levels of PRL and TSH. In multiple linear regression models adjusted for age, BMI and smoking, PRL was inversely associated with arsenic, cadmium, copper, lead, manganese, molybdenum, and zinc, but positively associated with chromium. Several of these associations (Cd, Pb, Mo) are consistent with limited studies in humans or animals, and a number of the relationships (Cr, Cu, Pb, Mo) remained when additionally considering multiple metals in the model. Lead and copper were associated with non-monotonic decrease in TSH, while arsenic was associated with a dose-dependent increase in TSH. For arsenic these findings were consistent with recent experimental studies where arsenic inhibited enzymes involved in thyroid hormone synthesis and signaling. More research is needed for a better understanding of the role of metals in neuroendocrine and thyroid function and related health implications.

Negative effects of serum p,p'-DDE on sperm parameters and modification by genetic polymorphisms.

OBJECTIVE: Effects of ambient exposure to DDT and its metabolites (DDE-DDT) on human sperm parameters and the role of genetic polymorphisms in modifying the association were investigated. METHODS: Demographics, medical history data, blood and semen samples were obtained from the first 336 male partners of couples presenting to 2 infertility clinics. Serum was analyzed for organochlorines (OC) and DNA for polymorphisms in GSTM1, GSTT1, GSTP1 and CYP1A1. Men with each sperm parameter considered low by WHO criteria (concentration <20million/mL, motility <50%, morphology <4%) were compared to men with all normal sperm parameters in logistic regression models, controlling for sum of other OC pesticides. RESULTS: High DDE-DDT level was associated with significantly increased odds for all 3 low sperm parameters. The risk of low motility with high DDE-DDT exposure was increased in men with the GSTT1 null genotype compared to those with GSTT1 intact (odds ratio (OR)=4.19, 95% confidence interval (CI) 1.05-16.78 and OR=3.57, 1.43-8.93, respectively). Risk for low morphology in men with high DDE-DDT and one or both CYP1A1*2A alleles was lower compared to men with the common CYP1A1 alleles (OR=2.18, 0.78-6.07 vs. OR=3.45, 1.32-9.03, respectively). Similar results were obtained for men with low DDE-DDT exposure. Effects of high DDE-DDT on low sperm concentration (OR=2.53, 1.0-6.31) was unaffected by the presence of the polymorphisms. CONCLUSION: High DDE-DDT exposure adversely affected all 3 sperm parameters and its effects were exacerbated by the GSTT1 null polymorphism and by the CYP1A1 common alleles.

Cadmium, lead, and other metals in relation to semen quality: human evidence for molybdenum as a male reproductive toxicant.

BACKGROUND: Evidence on human semen quality as it relates to exposure to various metals, both essential (e.g., zinc, copper) and nonessential (e.g., cadmium, lead), is inconsistent. Most studies to date used small sample sizes and were unable to account for important covariates. OBJECTIVES: Our goal in this study was to assess relationships between exposure to multiple metals at environmental levels and human semen-quality parameters. METHODS: We measured semen quality and metals in blood (arsenic, Cd, chromium, Cu, Pb, manganese, mercury, molybdenum, selenium, and Zn) among 219 men recruited through two infertility clinics. We used multiple statistical approaches to assess relationships between metals and semen quality while accounting for important covariates and various metals. RESULTS: Among a number of notable findings, the associations involving Mo were the most consistent over the various statistical approaches. We found dose-dependent trends between Mo and declined sperm concentration and normal morphology, even when considering potential confounders and other metals. For example, adjusted odds ratios (ORs) for below-reference semen-quality parameters in the low, medium, and high Mo groups were 1.0 (reference), 1.4 [95% confidence interval (CI), 0.5-3.7], and 3.5 (95% CI, 1.1-11) for sperm concentration and 1.0 (reference), 0.8 (95% CI, 0.3-1.9), and 2.6 (95% CI, 1.0-7.0) for morphology. We also found preliminary evidence for interactions between Mo and low Cu or Zn. In stratified analyses, the adjusted ORs in the high Mo/low Cu group were 14.4 (1.6, 132) and 13.7 (1.6, 114) for below-reference sperm concentration and morphology, respectively. CONCLUSIONS: Our findings represent the first human evidence for an inverse association between Mo and semen quality. These relationships are consistent with animal data, but additional human and mechanistic studies are needed.

A pilot study associating urinary concentrations of phthalate metabolites and semen quality.

Phthalates are ubiquitous industrial chemicals that are reported to adversely affect human reproductive outcomes. Divergent effects on semen quality have been reported in a limited number of studies. To assess the possible contribution of regional differences in phthalate exposure to these results, we wished to determine if ambient phthalate exposure of men from the Great Lakes region was associated with human sperm parameters. Male partners (N=45) of subfertile couples presenting to a Michigan infertility clinic were recruited. Urinary concentrations of several phthalate metabolites were measured in these men. Semen parameters, measured according to the World Health Organization [WHO 1999] protocols, were divided into those at or above WHO cutoffs for motility (50% motile), concentration (20 million/mL) and morphology (4% normal) and those below. Phthalate metabolite concentrations were divided into those concentrations above the median and those at or below the median. Specific gravity was used as a covariate in the regression models to adjust for urine dilution. Low sperm concentration was significantly associated with above median concentrations of monoethyl phthalate (MEP) (OR=6.5, 95% CI: 1.0-43.6) and low morphology with above median concentrations of mono-3-carboxypropyl phthalate (OR=7.6, 95% CI: 1.7-33.3). Increased odds for low concentration and above median concentrations of metabolites of di(2-ethylhexyl) phthalate (DEHP) (OR=5.4, 95% CI: 0.9-30.8) and low morphology and above median concentrations of MEP (OR=3.4, 95% CI: 0.9-13.8) were also found. A significant trend was observed for tertiles of MEP and low sperm concentration (p=0.05). Results suggest that ambient phthalate metabolite concentrations may adversely affect human semen quality.

Ambient manganese exposure is negatively associated with human sperm motility and concentration.

BACKGROUND: Occupational and experimental animal studies indicate that exposure to high levels of manganese impairs male fertility, but the effects of ambient manganese in humans are not known. METHODS: We measured blood levels of manganese and selenium in 200 infertility clinic clients in a cross-sectional study. Correlations between metals and semen variables were determined, adjusting for other risk factors. Outcomes were low motility (<50% motile), low concentration (<20 million/mL), or low morphology (<4% normal). We also investigated dose-response relationships between quartiles of manganese exposure and sperm parameters. RESULTS: High manganese level was associated with increased risk of low sperm motility (odds ratio = 5.4; 95% confidence interval = 1.6-17.6) and low sperm concentration (2.4; 1.2-4.9). We saw a U-shaped dose-response pattern between quartiles of manganese exposure and all 3 sperm parameters. CONCLUSION: Ambient exposure to manganese levels is associated with a reduction in sperm motility and concentration. No adverse effects were seen for high selenium.