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1.
Ecotoxicol Environ Saf ; 284: 116962, 2024 Oct 01.
Article in English | MEDLINE | ID: mdl-39208573

ABSTRACT

PURPOSE: Glyphosate and glyphosate-based herbicides (GBH), widely used globally, were initially considered harmless to humans. Experimental studies have suggested that these substances can disrupt iron homeostasis by interfering with iron uptake or triggering inflammatory responses. However, their potential impact on human iron homeostasis remains underexplored. APPROACH AND RESULTS: We analyzed data from 5812 participants aged three and older from the 2013 to 2018 NHANES. We investigated the relationships between urinary glyphosate levels, oral iron intake, and markers of iron homeostasis, including serum iron, unsaturated iron-binding capacity (UIBC), total iron-binding capacity (TIBC), transferrin saturation, ferritin, and transferrin receptor. Higher urinary glyphosate levels were positively associated with oral iron intake (ß = 1.310, S.E. = 0.382, P = 0.001). A one-unit increase in the natural logarithm (ln)-glyphosate was associated with lower serum iron (ß = - 4.236, 95 % CI = - 6.432 to - 2.039, P < 0.001) and ferritin (ß = - 9.994, 95 % CI = - 17.342 to - 2.647, P = 0.009), and higher UIBC (ß = 5.431, 95 % CI = 1.061-9.800, P = 0.018) and transferrin receptor levels (ß = 0.139, 95 % CI = 0.015-0.263, P = 0.029). Increasing glyphosate exposure was associated with significant decreases in serum iron and ferritin across exposure quintiles (trend P-values = 0.003 and 0.018, respectively). CONCLUSIONS: Higher glyphosate exposure is associated with reduced iron availability, suggesting potential disruptions in iron absorption. These findings underscore the need for further research into the health implications of glyphosate exposure on iron homeostasis.


Subject(s)
Glycine , Glyphosate , Herbicides , Homeostasis , Iron , Nutrition Surveys , Humans , Glycine/analogs & derivatives , Glycine/urine , Iron/blood , Iron/urine , Homeostasis/drug effects , Male , Adult , Female , Middle Aged , United States , Young Adult , Adolescent , Aged , Child , Child, Preschool , Ferritins/blood , Transferrin/metabolism
2.
Am J Physiol Renal Physiol ; 324(1): F30-F42, 2023 01 01.
Article in English | MEDLINE | ID: mdl-36264884

ABSTRACT

Collectrin (Tmem27), an angiotensin-converting enzyme 2 homologue, is a chaperone of amino acid transporters in the kidney and endothelium. Global collectrin knockout (KO) mice have hypertension, endothelial dysfunction, exaggerated salt sensitivity, and diminished renal blood flow. This phenotype is associated with altered nitric oxide and superoxide balance and increased proximal tubule (PT) Na+/H+ exchanger isoform 3 (NHE3) expression. Collectrin is located on the X chromosome where genome-wide association population studies have largely been excluded. In the present study, we generated PT-specific collectrin KO (PT KO) mice to determine the precise contribution of PT collectrin in blood pressure homeostasis. We also examined the association of human TMEM27 single-nucleotide polymorphisms with blood pressure traits in 11,926 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Hispanic/Latino participants. PT KO mice exhibited hypertension, and this was associated with increased baseline NHE3 expression and diminished lithium excretion. However, PT KO mice did not display exaggerated salt sensitivity or a reduction in renal blood flow compared with control mice. Furthermore, PT KO mice exhibited enhanced endothelium-mediated dilation, suggesting a compensatory response to systemic hypertension induced by deficiency of collectrin in the PT. In HCHS/SOL participants, we observed sex-specific single-nucleotide polymorphism associations with diastolic blood pressure. In conclusion, loss of collectrin in the PT is sufficient to induce hypertension, at least in part, through activation of NHE3. Importantly, our model supports the notion that altered renal blood flow may be a determining factor for salt sensitivity. Further studies are needed to investigate the role of the TMEM27 locus on blood pressure and salt sensitivity in humans.NEW & NOTEWORTHY The findings of our study are significant in several ways: 1) loss of an amino acid chaperone in the proximal tubule is sufficient to cause hypertension, 2) the results in global and proximal tubule-specific collectrin knockout mice support the notion that vascular dysfunction is required for salt sensitivity or that impaired renal tubule function causes hypertension but is not sufficient to cause salt sensitivity, and 3) our study is the first to implicate a role of collectrin in human hypertension.


Subject(s)
Blood Pressure , Hypertension , Kidney Tubules, Proximal , Membrane Glycoproteins , Animals , Female , Humans , Male , Mice , Blood Pressure/physiology , Genome-Wide Association Study , Hispanic or Latino/genetics , Hypertension/genetics , Kidney Tubules, Proximal/metabolism , Mice, Knockout , Sodium Chloride, Dietary/metabolism , Sodium-Hydrogen Exchanger 3/genetics , Sodium-Hydrogen Exchanger 3/metabolism , Membrane Glycoproteins/deficiency , Membrane Glycoproteins/genetics
3.
J Formos Med Assoc ; 121 Suppl 1: S30-S38, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34980550

ABSTRACT

BACKGROUND/PURPOSE: The burden of end-stage kidney disease (ESKD) continues to grow globally. Information on medication prescribed to advanced chronic kidney disease (CKD) patients can help formulate further CKD prevention policies. This study aimed to review and assess several major medications routinely prescribed to pre-ESKD patients. METHODS: Medication information of advanced CKD patients one year before regular dialysis was collected from the National Health Insurance Research Database from 2000 to 2018 in Taiwan. Usages of major medication were comprehensively analyzed. RESULTS: During 2000-2018, trends in medication usage evolved gradually in the pre-ESKD population in Taiwan. The use of erythropoietin had increased (48.3% in 2000 to 71.0% in 2018) with decreased blood transfusion rate (70.9% in 2003 to 52.1% in 2018). The use of non-steroidal anti-inflammatory drugs had also dropped (43.5% in 2004 to 25.5% in 2018). These changes were more evident for patients enrolled in the pre-ESKD prevention program. The most frequently used blood pressure-lowering and glucose-lowering agents were calcium channel blockers (90.6%) and insulin (78.1%), but usage of metformin was unexpectedly high (38.4% in 2018). The most frequently used blood thinner was aspirin (49.5%), with considerably increased use of direct oral anticoagulant (16.5% in 2018). CONCLUSION: An overview of the trends of major medication usage and blood transfusion represented the continuously improving care quality in pre-ESKD patients in Taiwan. These trends were especially evident in patients enrolled in the pre-ESKD prevention program. This report also indirectly indicated the potential and long-term benefits of implementing CKD and pre-ESKD prevention programs.


Subject(s)
Kidney Failure, Chronic , Renal Insufficiency, Chronic , Humans , Kidney Failure, Chronic/drug therapy , Kidney Failure, Chronic/epidemiology , Renal Dialysis , Renal Insufficiency, Chronic/epidemiology , Taiwan
5.
Ecotoxicol Environ Saf ; 224: 112663, 2021 Aug 18.
Article in English | MEDLINE | ID: mdl-34418852

ABSTRACT

Bisphenol A (BPA) exposure is associated with atherosclerotic cardiovascular diseases. The interactions between BPA, extracellular microparticles (MPs), and atherosclerosis are unknown. A total of 103,756 young students participated in the mass urine-screening program in Taiwan between 1992 and 2000 were analyzed. After exclusion, 886 subjects were recruited to test the relationships between serum level of BPA, endothelial and platelet MPs as well as subclinical atherosclerosis represented by carotid artery intima-media thickness (CIMT). We found that an increment of one unit of log-BPA could lead to significant association between thicker CIMT and concentrations of endothelial microparticles and platelet microparticles in the cohort (odds ratio (OR) 1.23, P < 0.001). CD31 + /CD42a- (> 50%, OR 1.229, P = 0.001) and CD31 + /CD42a+ (≦ 50%, OR 1.262, P = 0.017 and > 50%, OR 1.212, P = 0.006) were significantly associated with thicker CIMT in the presence of elevated BPA. When considering the interactions between CD31 + /CD42a- and CD31 + /CD42a+ , we observed increased OR as CD31 + /CD42a- was greater than 50% (CD31 +/CD42a- > 50% and CD31 +/CD42a+ ≦ 50%, OR 1.356, P = 0.029; CD31 +/CD42a- > 50% and CD31 +/CD42a+ > 50%, OR 1.204, P = 0.014). Our study identified a higher risk of thicker CIMT associated with altered MPs in the presence of elevated BPA levels. BPA exposure is associated with endothelial dysfunction and subclinical atherosclerosis in a young population.

6.
PLoS Genet ; 13(5): e1006728, 2017 May.
Article in English | MEDLINE | ID: mdl-28498854

ABSTRACT

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.


Subject(s)
Blood Pressure/genetics , Genetic Loci , Hypertension/genetics , Multifactorial Inheritance , Black or African American/genetics , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Cadherins/genetics , Case-Control Studies , Female , Genome-Wide Association Study , Humans , Hypertension/ethnology , Male , Membrane Proteins/genetics , Mice , Polymorphism, Single Nucleotide
7.
J Lipid Res ; 60(3): 648-660, 2019 03.
Article in English | MEDLINE | ID: mdl-30642880

ABSTRACT

Studies on the effects of longitudinal lipid trajectories on end-stage renal disease (ESRD) development and deaths among patients with chronic kidney disease (CKD) are limited. We conducted a registry-based prospective study using data from a 13-year multidisciplinary pre-ESRD care program. The final study population comprised 4,647 patients with CKD. Using group-based trajectory modeling, we dichotomized longitudinal trajectories of total cholesterol (T-CHO), triglyceride (TG), LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C). Time to ESRD or death was analyzed using multiple Cox regression. At baseline, higher levels of T-CHO and LDL-C were associated with rapid progression to ESRD, whereas only HDL-C was positively associated with all-cause mortality [adjusted hazard ratio (HR), 1.20; 95% CI, 1.06-1.36; P-value, 0.005]. Compared with those with a normal T-CHO trajectory, the fully adjusted HR of patients with a high T-CHO trajectory for ESRD risk was 1.21 (P-value, 0.019). Subgroup analysis showed that a high TG trajectory was associated with a 49% increase in mortality risk in CKD patients without diabetes (P-value for interaction, 0.012). In contrast to what was observed based on baseline HDL-C, patients with a trajectory of frequent hypo-HDL cholesterolemia had higher risk of all-cause mortality (adjusted HR, 1.53; P-value, 0.014). Thus, only T-CHO, both at baseline and over the longitudinal course, demonstrated a significant potential risk of incident ESRD. The inconsistency in the observed directions of association between baseline levels and longitudinal trajectories of HDL-C warrants further research to unveil specific pathogenic mechanisms underlying the HDL-C metabolism in patients with CKD.


Subject(s)
Renal Insufficiency, Chronic/blood , Adult , Aged , Aged, 80 and over , Cohort Studies , Disease Progression , Female , Humans , Longitudinal Studies , Male , Middle Aged , Renal Dialysis , Renal Insufficiency, Chronic/mortality , Renal Insufficiency, Chronic/pathology , Renal Insufficiency, Chronic/therapy , Risk , Young Adult
8.
Am J Hum Genet ; 99(3): 636-646, 2016 Sep 01.
Article in English | MEDLINE | ID: mdl-27588450

ABSTRACT

We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.


Subject(s)
Ethnicity/genetics , Genome-Wide Association Study , Kidney/physiopathology , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/physiopathology , Sodium Chloride/pharmacology , Stress, Physiological/drug effects , Stress, Physiological/genetics , Alleles , Animals , Deoxyribonuclease I/metabolism , Diabetes Mellitus/genetics , Disease Models, Animal , Drosophila melanogaster/genetics , Female , Glomerular Filtration Rate/genetics , Humans , Kidney/pathology , Linkage Disequilibrium , Male , NFATC Transcription Factors/genetics , Polymorphism, Single Nucleotide/genetics , Quantitative Trait Loci , RGS Proteins/genetics , Racial Groups/genetics , Salt Tolerance/genetics , Sodium-Phosphate Cotransporter Proteins, Type IIa/genetics
9.
J Am Soc Nephrol ; 28(6): 1826-1837, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28062568

ABSTRACT

Collectrin, encoded by the Tmem27 gene, is a transmembrane glycoprotein with approximately 50% homology with angiotensin converting enzyme 2, but without a catalytic domain. Collectrin is most abundantly expressed in the kidney proximal tubule and collecting duct epithelia, where it has an important role in amino acid transport. Collectrin is also expressed in endothelial cells throughout the vasculature, where it regulates L-arginine uptake. We previously reported that global deletion of collectrin leads to endothelial dysfunction, augmented salt sensitivity, and hypertension. Here, we performed kidney crosstransplants between wild-type (WT) and collectrin knockout (Tmem27Y/- ) mice to delineate the specific contribution of renal versus extrarenal collectrin on BP regulation and salt sensitivity. On a high-salt diet, WT mice with Tmem27Y/- kidneys had the highest systolic BP and were the only group to exhibit glomerular mesangial hypercellularity. Additional studies showed that, on a high-salt diet, Tmem27Y/- mice had lower renal blood flow, higher abundance of renal sodium-hydrogen antiporter 3, and lower lithium clearance than WT mice. In WT mice, administration of angiotensin II for 2 weeks downregulated collectrin expression in a type 1 angiotensin II receptor-dependent manner. This downregulation coincided with the onset of hypertension, such that WT and Tmem27Y/- mice had similar levels of hypertension after 2 weeks of angiotensin II administration. Altogether, these data suggest that salt sensitivity is determined by intrarenal collectrin, and increasing the abundance or activity of collectrin may have therapeutic benefits in the treatment of hypertension and salt sensitivity.


Subject(s)
Angiotensin II/physiology , Down-Regulation , Hypertension/etiology , Membrane Glycoproteins/physiology , Sodium Chloride, Dietary/adverse effects , Animals , Kidney/metabolism , Male , Membrane Glycoproteins/biosynthesis , Mice , Mice, Knockout
10.
PLoS Genet ; 9(10): e1003807, 2013.
Article in English | MEDLINE | ID: mdl-24130503

ABSTRACT

During ischemic stroke, occlusion of the cerebrovasculature causes neuronal cell death (infarction), but naturally occurring genetic factors modulating infarction have been difficult to identify in human populations. In a surgically induced mouse model of ischemic stroke, we have previously mapped Civq1 to distal chromosome 7 as a quantitative trait locus determining infarct volume. In this study, genome-wide association mapping using 32 inbred mouse strains and an additional linkage scan for infarct volume confirmed that the size of the infarct is determined by ancestral alleles of the causative gene(s). The genetically isolated Civq1 locus in reciprocal recombinant congenic mice refined the critical interval and demonstrated that infarct size is determined by both vascular (collateral vessel anatomy) and non-vascular (neuroprotection) effects. Through the use of interval-specific SNP haplotype analysis, we further refined the Civq1 locus and identified integrin alpha L (Itgal) as one of the causative genes for Civq1. Itgal is the only gene that exhibits both strain-specific amino acid substitutions and expression differences. Coding SNPs, a 5-bp insertion in exon 30b, and increased mRNA and protein expression of a splice variant of the gene (Itgal-003, ENSMUST00000120857), all segregate with infarct volume. Mice lacking Itgal show increased neuronal cell death in both ex vivo brain slice and in vivo focal cerebral ischemia. Our data demonstrate that sequence variation in Itgal modulates ischemic brain injury, and that infarct volume is determined by both vascular and non-vascular mechanisms.


Subject(s)
Genome-Wide Association Study , Integrin alpha Chains/genetics , Stroke/genetics , Alleles , Animals , Brain Injuries/genetics , Brain Injuries/pathology , Brain Ischemia/genetics , Brain Ischemia/physiopathology , Disease Models, Animal , Genetic Linkage , Haplotypes , Humans , Integrin alpha Chains/metabolism , Mice , Polymorphism, Single Nucleotide , Quantitative Trait Loci , Stroke/physiopathology
11.
Stroke ; 45(7): 2101-6, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24876084

ABSTRACT

BACKGROUND AND PURPOSE: Endoglin deficiency causes hereditary hemorrhagic telangiectasia-1 and impairs myocardial repair. Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia-1 are associated with a high incidence of paradoxical embolism in the cerebral circulation and ischemic brain injury. We hypothesized that endoglin deficiency impairs stroke recovery. METHODS: Eng heterozygous (Eng+/-) and wild-type mice underwent permanent distal middle cerebral artery occlusion (pMCAO). Pial collateral vessels were quantified before pMCAO. Infarct/atrophic volume, vascular density, and macrophages were quantified in various days after pMCAO, and behavioral function was assessed using corner and adhesive removal tests on days 3, 15, 30, and 60 after pMCAO. The association between ENG 207G>A polymorphism and brain arteriovenous malformation rupture and surgery outcome was analyzed using logistic regression analysis in 256 ruptured and 157 unruptured patients. RESULTS: After pMCAO, Eng+/- mice showed larger infarct/atrophic volumes at all time points (P<0.05) and showed worse behavior performance (P<0.05) at 15, 30, and 60 days when compared with wild-type mice. Eng+/- mice had fewer macrophages on day 3 (P=0.009) and more macrophages on day 60 (P=0.02) in the peri-infarct region. Although Eng+/- and wild-type mice had similar numbers of pial collateral vessels before pMCAO, Eng+/- mice had lower vascular density in the peri-infarct region (P=0.05) on day 60 after pMCAO. In humans, ENG 207A allele has been associated with worse outcomes after arteriovenous malformation rupture or surgery of patients with unruptured arteriovenous malformation. CONCLUSIONS: Endoglin deficiency impairs brain injury recovery. Reduced angiogenesis, impaired macrophage homing, and delayed inflammation resolution could be the underlying mechanism.


Subject(s)
Infarction, Middle Cerebral Artery/metabolism , Intracellular Signaling Peptides and Proteins/deficiency , Intracranial Arteriovenous Malformations/metabolism , Receptors, Cell Surface/deficiency , Recovery of Function/physiology , Alleles , Animals , Antigens, CD/genetics , Antigens, CD/metabolism , Behavior, Animal/physiology , Disease Models, Animal , Endoglin , Humans , Infarction, Middle Cerebral Artery/etiology , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Intracranial Arteriovenous Malformations/genetics , Intracranial Arteriovenous Malformations/surgery , Mice , Mice, Knockout , Polymorphism, Genetic/genetics , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Recovery of Function/genetics , Time Factors
12.
Curr Hypertens Rep ; 16(11): 490, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25182162

ABSTRACT

Collectrin (Tmem27) is a transmembrane glycoprotein that is highly expressed in the kidney and vascular endothelium. It is a homologue of the angiotensin-converting enzyme 2 (ACE2) but harbors no catalytic domain. In the extravascular tissues of the kidney, collectrin is localized to the proximal tubule and collecting duct. Collectrin-deficient mice are featured with hypertension and exaggerated salt sensitivity. These phenotypes are associated with impaired uptake of the nitric oxide precursor L-arginine and the expression of its amino acid transporters, CAT-1 and y(+)LAT1, in endothelial cells. In addition, collectrin-deficient mice display decreased dimerization of nitric oxide synthase and decreased nitric oxide synthesis, but enhanced superoxide generation, suggesting that deletion of collectrin leads to a state of nitric oxide synthase uncoupling. These findings suggest that collectrin plays a protective role against hypertension. The collectrin knockout mouse represents a unique model for hypertension research. Furthermore, collectrin may serve as a novel therapeutic target in the treatment of hypertension.


Subject(s)
Blood Pressure/physiology , Homeostasis/physiology , Hypertension/metabolism , Membrane Glycoproteins/metabolism , Nitric Oxide/metabolism , Angiotensin-Converting Enzyme 2 , Animals , Humans , Hypertension/physiopathology , Peptidyl-Dipeptidase A/metabolism
13.
Physiol Genomics ; 45(17): 751-63, 2013 Sep 03.
Article in English | MEDLINE | ID: mdl-23800850

ABSTRACT

In the mouse model of permanent, middle cerebral artery occlusion, infarct volume varies widely across inbred strains but generally is inversely correlated with collateral vessel number. However, we also observed certain mouse strains that share similar collateral vessel anatomy but exhibit significantly different infarct volume. To identify genetic factors determining infarct volume in a collateral vessel-independent manner, we performed quantitative trait locus analysis on a F2 cross between C57BL/6J and C3H/HeJ strains. We mapped four novel loci (Civq4 through Civq7) that modulate infarct volume. Civq4, on chromosome 8, is the strongest locus (logarithm of the odds 9.8) that contributes 21% of the phenotypic variance of infarct volume in the cross. The Civq4 and Civq6 loci represent transgressive B6 alleles that render animals susceptible to larger infarcts. Based on genomic sequence and microarray analyses, we propose candidate genes for the Civq4 locus. By selecting inbred strains with similar collateral vessel anatomy but that vary significantly in infarct volume, we have mapped four loci determining infarct volume in a mouse model of ischemic stroke. Two of the loci appear to modulate infarct volume through a collateral vessel-independent mechanism. Based on strain-specific sequence variants and differences in transcript levels, Msr1 and Mtmr7 appear to be strong candidate genes for Civq4. Identifying the underlying genetic factors of these loci will elucidate the genetic architecture response to cerebral ischemia, shed new light on disease mechanisms of ischemic stroke, and identify potential therapeutic targets for clinical applications.


Subject(s)
Brain Ischemia/genetics , Brain Ischemia/pathology , Collateral Circulation/genetics , Quantitative Trait Loci , Animals , Brain Infarction/genetics , Brain Infarction/pathology , Chromosome Mapping , Disease Models, Animal , Genetic Linkage , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Polymorphism, Single Nucleotide , Protein Tyrosine Phosphatases, Non-Receptor/genetics , Scavenger Receptors, Class A/genetics
14.
Environ Sci Pollut Res Int ; 30(39): 91207-91215, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37474857

ABSTRACT

Glyphosate is the most commonly utilized herbicide globally, and a growing body of experimental research has linked its exposure to red blood cell damage. However, the potential toxicity of glyphosate exposure on erythrocytes in the general population remains poorly understood. Therefore, we analyzed data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) of 1466 adults (≥ 18 years) to explore the potential relationship between glyphosate exposure and erythrocyte profiles. Our results indicated a significant negative association between urinary glyphosate levels and hemoglobin (Hb) and hematocrit (Hct) in multiple regression analysis, with ß coefficients of -0.157 (S.E. = 0.055, P = 0.012) and -0.431 (S.E. = 0.195, P = 0.043), respectively. Additionally, the odds ratio showed a significant increase in individuals with anemia with a one-unit increase in ln-glyphosate levels (odds ratio = 1.523 (95% CI = 1.301 - 1.783), P < 0.001 in the final model). The negative correlation between glyphosate and Hb was more pronounced in subjects older than 60 years, non-Hispanic white ethnicity, lower income, and those with a body mass index (BMI) < 25 and ≥ 30. In conclusion, our results provide preliminary evidence of a plausible association between glyphosate exposure and anemia in a subset of the adult population in the United States. However, further research is necessary to understand the underlying mechanisms and clinical implications of this association.


Subject(s)
Anemia , Herbicides , Humans , Adult , United States , Nutrition Surveys , Herbicides/toxicity , Anemia/chemically induced , Anemia/epidemiology , Erythrocytes , Hemoglobins , Glyphosate
15.
Article in English | MEDLINE | ID: mdl-37674008

ABSTRACT

BACKGROUND: Glyphosate, the herbicide with the highest global usage, has been found to have links to neurological impairment in some occupational studies. Neurofilament light chain (NfL) is a protein that is released into the bloodstream following neuroaxonal damage and has emerged as a reliable biomarker for various neurological disorders. However, no research has investigated the potential link between glyphosate exposure and neurological damage or serum NfL levels in the general population. OBJECTIVE: The objective of this study was to assess the possible correlation between glyphosate exposure and serum NfL levels in a population that is representative of the United States. METHODS: We analyzed data from 597 adults (aged ≥20 years) from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) to explore the potential correlation between urinary glyphosate levels and serum NfL levels. RESULTS: We found a significant positive association between urinary glyphosate levels and serum NfL levels (ß-coefficient = 0.110; S.E. = 0.040; P = 0.015), indicating that higher levels of glyphosate exposure may be linked to higher levels of neuroaxonal damage. Furthermore, when glyphosate levels were divided into quintiles, we observed a significant trend of increasing mean NfL concentrations with increasing quintiles of glyphosate exposure (P for trend = 0.036). Notably, the association was more pronounced in certain subgroups, including those aged ≥40 years, non-Hispanic whites, and those with a BMI between 25 and 30. IMPACT STATEMENT: This is the first research to suggest an association between glyphosate exposure and biomarkers indicative of neurological damage in general U.S. adults. If the correlation observed is causal, it raises concerns about the potential effects of glyphosate exposure on neurological health among U.S. adults. The study is noteworthy due to its representation of American adults aged 20 and above, as well as the use of reliable and comprehensive data from the NHANES database.

16.
Stem Cells ; 29(11): 1763-73, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21915944

ABSTRACT

Lysophosphatidic acid (LPA), an extracellular lipid mediator, exerts multiple bioactivities through activating G protein-coupled receptors. LPA receptor 3 (LPA(3)) is a member of the endothelial differentiation gene family, which regulates differentiation and development of the circulation system. However, the relationship among the LPA receptors (LPARs) and erythropoiesis is still not clear. In this study, we found that erythroblasts expressed both LPA(1) and LPA(3), and erythropoietic defects were observed in zLPA(3) antisense morpholino oligonucleotide-injected zebrafish embryos. In human model, our results showed that LPA enhanced the erythropoiesis in the cord blood-derived human hematopoietic stem cells (hHSCs) with erythropoietin (EPO) addition in the plasma-free culture. When hHSCs were treated with Ki16425, an antagonist of LPA(1) and LPA(3), erythropoietic process of hHSCs was also blocked, as detected by mRNA and protein expressions of CD71 and GlyA. In the knockdown study, we further demonstrated that specific knockdown of LPA(3), not LPA(1), blocked the erythropoiesis. The translocation of ß-catenin into the nucleus, a downstream response of LPAR activation, was blocked by Ki16425 treatment. In addition, upregulation of erythropoiesis by LPA was also blocked by quercetin, an inhibitor of the ß-catenin/T-cell factor pathway. Furthermore, the enhancement of LPA on erythropoiesis was diminished by blocking c-Jun-activated kinase/signal transducer and activator of transcription and phosphatidylinositol 3-kinase/AKT activation, the downstream signaling pathways of EPO receptor, suggested that LPA might play a synergistic role with EPO to regulate erythropoietic process. In conclusion, we first reported that LPA participates in EPO-dependent erythropoiesis through activating LPA(3).


Subject(s)
Erythropoiesis/drug effects , Lysophospholipids/pharmacology , Receptors, Lysophosphatidic Acid/agonists , Receptors, Lysophosphatidic Acid/metabolism , AC133 Antigen , Animals , Antigens, CD/metabolism , Cells, Cultured , Embryo, Nonmammalian , Flow Cytometry , Glycoproteins/metabolism , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/metabolism , Humans , Isoxazoles/pharmacology , Peptides/metabolism , Propionates/pharmacology , Receptors, Lysophosphatidic Acid/antagonists & inhibitors , Zebrafish
17.
PLoS Genet ; 5(9): e1000647, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19763165

ABSTRACT

The Calsequestrin (Csq) transgenic mouse model of cardiomyopathy exhibits wide variation in phenotypic progression dependent on genetic background. Seven heart failure modifier (Hrtfm) loci modify disease progression and outcome. Here we report Tnni3k (cardiac Troponin I-interacting kinase) as the gene underlying Hrtfm2. Strains with the more susceptible phenotype exhibit high transcript levels while less susceptible strains show dramatically reduced transcript levels. This decrease is caused by an intronic SNP in low-transcript strains that activates a cryptic splice site leading to a frameshifted transcript, followed by nonsense-mediated decay of message and an absence of detectable protein. A transgenic animal overexpressing human TNNI3K alone exhibits no cardiac phenotype. However, TNNI3K/Csq double transgenics display severely impaired systolic function and reduced survival, indicating that TNNI3K expression modifies disease progression. TNNI3K expression also accelerates disease progression in a pressure-overload model of heart failure. These combined data demonstrate that Tnni3k plays a critical role in the modulation of different forms of heart disease, and this protein may provide a novel target for therapeutic intervention.


Subject(s)
Cardiomyopathies/enzymology , Cardiomyopathies/pathology , Disease Progression , Protein Kinases/metabolism , Alleles , Alternative Splicing/genetics , Animals , Base Sequence , Cardiomyopathies/genetics , Cardiomyopathies/physiopathology , Codon, Nonsense/genetics , Disease Models, Animal , Gene Expression Regulation, Enzymologic , Heart Function Tests , Mice , Mice, Inbred Strains , Mice, Transgenic , Myocardium/enzymology , Myocardium/pathology , Protein Kinases/genetics , Protein Serine-Threonine Kinases , RNA Stability/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Survival Analysis , Systole
18.
Sci Rep ; 11(1): 7851, 2021 04 12.
Article in English | MEDLINE | ID: mdl-33846379

ABSTRACT

The role of the difference and ratio of albuminuria (urine albumin-to-creatinine ratio, uACR) and proteinuria (urine protein-to-creatinine ratio, uPCR) has not been systematically evaluated with all-cause mortality. We retrospectively analyzed 2904 patients with concurrently measured uACR and uPCR from the same urine specimen in a tertiary hospital in Taiwan. The urinary albumin-to-protein ratio (uAPR) was derived by dividing uACR by uPCR, whereas urinary non-albumin protein (uNAP) was calculated by subtracting uACR from uPCR. Conventional severity categories of uACR and uPCR were also used to establish a concordance matrix and develop a corresponding risk matrix. The median age at enrollment was 58.6 years (interquartile range 45.4-70.8). During the 12,391 person-years of follow-up, 657 deaths occurred. For each doubling increase in uPCR, uACR, and uNAP, the adjusted hazard ratios (aHRs) of all-cause mortality were 1.29 (95% confidence interval [CI] 1.24-1.35), 1.12 (1.09-1.16), and 1.41 (1.34-1.49), respectively. For each 10% increase in uAPR, it was 1.02 (95% CI 0.98-1.06). The linear dose-response association with all-cause mortality was only observed with uPCR and uNAP. The 3 × 3 risk matrices revealed that patients with severe proteinuria and normal albuminuria had the highest risk of all-cause mortality (aHR 5.25, 95% CI 1.88, 14.63). uNAP significantly improved the discriminative performance compared to that of uPCR (c statistics: 0.834 vs. 0.828, p-value = 0.032). Our study findings advocate for simultaneous measurements of uPCR and uACR in daily practice to derive uAPR and uNAP, which can provide a better mortality prognostic assessment.


Subject(s)
Albumins/analysis , Albuminuria , Creatinine/urine , Adult , Aged , Albuminuria/etiology , Albuminuria/mortality , Female , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Taiwan/epidemiology , Tertiary Care Centers
20.
PLoS One ; 15(6): e0234622, 2020.
Article in English | MEDLINE | ID: mdl-32555690

ABSTRACT

INTRODUCTION: Acrylamide is widely present in heat-processed food, cigarette smoke and environment. Reproductive toxicity was reported in animals treated with acrylamide, particularly in males. The reproductive toxicity of acrylamide and its active metabolite, glycidamide, was reported to be mainly mediated through DNA damage in spermatocytes. However, the effect of acrylamide on sex hormones in men is unknown. METHODS: There were 468 male subjects (age ≧ 12 years) enrolled to determine the relationships between hemoglobin adducts of acrylamide (HbAA) and hemoglobin adducts of glycidamide (HbGA) with several sex hormones using the National Health and Nutrition Examination Survey (NHANES), 2003 to 2004. All potential confounding variables in the data set were properly adjusted. RESULTS: We found that one unit increase in the natural log-transformed HbAA level was associated with an increase in natural log transformed serum inhibin B level by 0.10 (SE = 0.05; P = 0.046), and natural log transformed serum sex hormone binding globulin (SHBG) by 0.15 (SE = 0.15; P = 0.036). With respect to HbGA, one unit increase in the natural log-transformed HbGA level was associated with an increase in natural log transformed serum anti-Müllerian Hormone (AMH) level by 0.31 (SE = 0.00; P = 0.003). CONCLUSION: In this representative cohort, we identified positive associations between acrylamide exposure and several sex hormones in men. The HbAA is positively associated with inhibin B and SHBG, and HbGA is positively associated with AMH. Other than genotoxicity, our findings suggested that altered sex hormones might also play a role in acrylamide-related reproductive toxicity in males.


Subject(s)
Acrylamide/toxicity , Environmental Exposure/adverse effects , Epoxy Compounds/toxicity , Gonadal Steroid Hormones/blood , Sex Hormone-Binding Globulin/metabolism , Acrylamide/blood , Adolescent , Adult , Child , Cohort Studies , Epoxy Compounds/blood , Hemoglobins/analysis , Humans , Male , Middle Aged , Nutrition Surveys , United States , Young Adult
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