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Article ; Online: Cadmium-Induced Proteinuria

Soisungwan Satarug / David A. Vesey / Glenda C. Gobe

International Journal of Molecular Sciences, Vol 24, Iss 1893, p

Mechanistic Insights from Dose–Effect Analyses

2023 Volume 1893

Abstract: Cadmium (Cd) is a toxic metal that accumulates in kidneys, especially in the proximal tubular epithelial cells, where virtually all proteins in the glomerular ultrafiltrate are reabsorbed. Here, we analyzed archived data on the estimated glomerular ... ...

Abstract	Cadmium (Cd) is a toxic metal that accumulates in kidneys, especially in the proximal tubular epithelial cells, where virtually all proteins in the glomerular ultrafiltrate are reabsorbed. Here, we analyzed archived data on the estimated glomerular filtration rate (eGFR) and excretion rates of Cd (E Cd ), total protein (E Prot ), albumin (E alb ), β 2 -microglobulin (E β2M ), and α1-microglobulin (E α1M ), which were recorded for residents of a Cd contamination area and a low-exposure control area of Thailand. Excretion of Cd and all proteins were normalized to creatinine clearance (C cr ) as E Cd /C cr and E Prot /C cr to correct for differences among subjects in the number of surviving nephrons. Low eGFR was defined as eGFR ≤ 60 mL/min/1.73 m 2 , while proteinuria was indicted by E Pro /C cr ≥ 20 mg/L of filtrate. E Prot /C cr varied directly with E Cd /C cr (β = 0.263, p < 0.001) and age (β = 0.252, p < 0.001). In contrast, eGFR values were inversely associated with E Cd /C cr (β = −0.266, p < 0.001) and age (β = −0.558, p < 0.001). At E Cd /C cr > 8.28 ng/L of filtrate, the prevalence odds ratios for proteinuria and low eGFR were increased 4.6- and 5.1-fold, respectively ( p < 0.001 for both parameters). Thus, the eGFR and tubular protein retrieval were both simultaneously diminished by Cd exposure. Of interest, E Cd /C cr was more closely correlated with E Prot /C cr ( r = 0.507), E β2M ( r = 0.430), and E α1M /C cr ( r = 0.364) than with E Alb /C cr ( r = 0.152). These data suggest that Cd may differentially reduce the ability of tubular epithelial cells to reclaim proteins, resulting in preferential reabsorption of albumin.
Keywords	albumin ; albumin-to-creatinine ratio ; α1-microglobulin ; β 2 -microglobulin ; cadmium ; creatinine clearance ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	290
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Dose–Response Analysis of the Tubular and Glomerular Effects of Chronic Exposure to Environmental Cadmium

Soisungwan Satarug / David A. Vesey / Glenda C. Gobe

International Journal of Environmental Research and Public Health, Vol 19, Iss 10572, p

2022 Volume 10572

Abstract: We retrospectively analyzed data on the excretion of cadmium (E Cd ), β 2 -microglobulin (E β2M ) and N-acetyl-β-D-glucosaminidase (E NAG ), which were recorded for 734 participants in a study conducted in low- and high-exposure areas of Thailand. ... ...

Abstract	We retrospectively analyzed data on the excretion of cadmium (E Cd ), β 2 -microglobulin (E β2M ) and N-acetyl-β-D-glucosaminidase (E NAG ), which were recorded for 734 participants in a study conducted in low- and high-exposure areas of Thailand. Increased E β2M and E NAG were used to assess tubular integrity, while a reduction in the estimated glomerular filtration rate (eGFR) was a criterion for glomerular dysfunction. E Cd , E β2M and E NAG were normalized to creatinine clearance (C cr ) as E Cd /C cr , E β2M /C cr and E NAG /C cr to correct for interindividual variation in the number of surviving nephrons and to eliminate the variation in the excretion of creatinine (E cr ). For a comparison, these parameters were also normalized to E cr as E Cd /E cr , E β2M /E cr and E NAG /E cr . According to the covariance analysis, a Cd-dose-dependent reduction in eGFR was statistically significant only when E cd was normalized to C cr as E Cd /C cr ( F = 11.2, p < 0.001). There was a 23-fold increase in the risk of eGFR ≤ 60 mL/min/1.73 m 2 in those with the highest E Cd /C cr range ( p = 0.002). In addition, doubling of E Cd /C cr was associated with lower eGFR (β = −0.300, p < 0.001), and higher E NAG /C cr (β = 0.455, p < 0.001) and E β2M /C cr (β = 0.540, p < 0.001). In contrast, a covariance analysis showed a non-statistically significant relationship between E Cd /E cr and eGFR ( F = 1.08, p = 0.165), while the risk of low eGFR was increased by 6.9-fold only among those with the highest E Cd /E cr range. Doubling of E Cd /E cr was associated with lower eGFR and higher E NAG /E cr and E β2M /E cr , with the β coefficients being smaller than in the C cr -normalized dataset. Thus, normalization of Cd excretion to C cr unravels the adverse effect of Cd on GFR and provides a more accurate evaluation of the severity of the tubulo-glomerular effect of Cd.
Keywords	β 2- microglobulin ; cadmium ; creatinine clearance ; creatinine excretion ; glomerular filtration rate ; N-acetyl-β-D-glucosaminidase ; Medicine ; R
Subject code	290 ; 669
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Evidence for Ovarian and Testicular Toxicities of Cadmium and Detoxification by Natural Substances

Martin Massányi / Soisungwan Satarug / Roberto Madeddu / Robert Stawarz / Peter Massányi

Stresses, Vol 2, Iss 1, Pp 1-

2022 Volume 16

Abstract: Cadmium (Cd) is an environmental toxicant, capable of reducing mitochondrial ATP production and promoting the formation of reactive oxygen species (ROS) with resultant oxidative stress conditions. The ovary and testis are the primary gonads in which ... ...

Abstract	Cadmium (Cd) is an environmental toxicant, capable of reducing mitochondrial ATP production and promoting the formation of reactive oxygen species (ROS) with resultant oxidative stress conditions. The ovary and testis are the primary gonads in which female gametes (oocytes) and male gametes (spermatozoa), estrogen and testosterone are produced. These organs are particularly susceptible to Cd cytotoxicity due to their high metabolic activities and high energy demands. In this review, epidemiological and experimental studies examining Cd toxicities in gonads are highlighted together with studies using zinc (Zn), selenium (Se), and natural substances to reduce the effects of Cd on follicular genesis and spermatogenesis. Higher blood concentrations of Cd ([Cd] b ) were associated with longer time-to-pregnancy in a prospective cohort study. Cd excretion rate (E Cd ) as low as 0.8 μg/g creatinine was associated with reduced spermatozoa vitality, while Zn and Se may protect against spermatozoa quality decline accompanying Cd exposure. E Cd > 0.68 µg/g creatinine were associated with an increased risk of premature ovarian failure by 2.5-fold, while [Cd] b ≥ 0.34 µg/L were associated with a 2.5-fold increase in the risk of infertility in women. Of concern, urinary excretion of Cd at 0.68 and 0.8 μg/g creatinine found to be associated with fecundity are respectively 13% and 15% of the conventional threshold limit for Cd-induced kidney tubular effects of 5.24 μg/g creatinine. These findings suggest that toxicity of Cd in primary reproductive organs occurs at relatively low body burden, thereby arguing for minimization of exposure and environmental pollution by Cd and its transfer to the food web.
Keywords	cadmium ; ovary ; testis ; oxidative stress ; fecundity ; toxicity mitigation ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Validity of Benchmark Dose Limit Analysis for Estimating Permissible Accumulation of Cadmium

Soisungwan Satarug / David A. Vesey / Glenda C. Gobe / Aleksandra Buha Đorđević

International Journal of Environmental Research and Public Health, Vol 19, Iss 15697, p

2022 Volume 15697

Abstract: Cadmium (Cd) is a toxic metal pollutant that accumulates, especially in the proximal tubular epithelial cells of kidneys, where it causes tubular cell injury, cell death and a reduction in glomerular filtration rate (GFR). Diet is the main Cd exposure ... ...

Abstract	Cadmium (Cd) is a toxic metal pollutant that accumulates, especially in the proximal tubular epithelial cells of kidneys, where it causes tubular cell injury, cell death and a reduction in glomerular filtration rate (GFR). Diet is the main Cd exposure source in non-occupationally exposed and non-smoking populations. The present study aimed to evaluate the reliability of a tolerable Cd intake of 0.83 μg/kg body weight/day, and its corresponding toxicity threshold level of 5.24 μg/g creatinine. The PROAST software was used to calculate the lower 95% confidence bound of the benchmark dose (BMDL) values of Cd excretion (E Cd ) associated with injury to kidney tubular cells, a defective tubular reabsorption of filtered proteins, and a reduction in the estimated GFR (eGFR). Data were from 289 males and 445 females, mean age of 48.1 years of which 42.8% were smokers, while 31.7% had hypertension, and 9% had chronic kidney disease (CKD). The BMDL value of E Cd associated with kidney tubular cell injury was 0.67 ng/L of filtrate in both men and women. Therefore, an environmental Cd exposure producing E Cd of 0.67 ng/L filtrate could be considered as Cd accumulation levels below which renal effects are likely to be negligible. A reduction in eGFR and CKD may follow when E Cd rises from 0.67 to 1 ng/L of filtrate. These adverse health effects occur at the body burdens lower than those associated with E Cd of 5.24 µg/g creatinine, thereby arguing that current health-guiding values do not provide a sufficient health protection.
Keywords	benchmark dose ; BMD lower confidence limit ; BMDL ; BMD upper confidence limit ; BMDU ; cadmium ; Medicine ; R
Subject code	616
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Effects of Environmental Exposure to Cadmium and Lead on the Risks of Diabetes and Kidney Dysfunction

Supabhorn Yimthiang / Phisit Pouyfung / Tanaporn Khamphaya / Saruda Kuraeiad / Paleeratana Wongrith / David A. Vesey / Glenda C. Gobe / Soisungwan Satarug

International Journal of Environmental Research and Public Health, Vol 19, Iss 2259, p

2022 Volume 2259

Abstract: Environmental exposure to cadmium (Cd) or lead (Pb) is independently associated with increased risks of type 2 diabetes, and chronic kidney disease. The aim of this study was to examine the effects of concurrent exposure to these toxic metals on the ... ...

Abstract	Environmental exposure to cadmium (Cd) or lead (Pb) is independently associated with increased risks of type 2 diabetes, and chronic kidney disease. The aim of this study was to examine the effects of concurrent exposure to these toxic metals on the risks of diabetes and kidney functional impairment. The Cd and Pb exposure levels among study subjects were low to moderate, evident from the means for blood concentrations of Cd and Pb ([Cd] b and [Pb] b ) of 0.59 µg/L and 4.67 µg/dL, respectively. Of 176 study subjects (mean age 60), 71 (40.3%) had abnormally high fasting plasma glucose levels. Based on their [Cd] b and [Pb] b , 53, 71, and 52 subjects were assigned to Cd and Pb exposure profiles 1, 2, and 3, respectively. The diagnosis of diabetes was increased by 4.2-fold in those with an exposure profile 3 ( p = 0.002), and by 2.9-fold in those with the estimated glomerular filtration (eGFR) ≤ 60 mL/min/1.73 m 2 ( p = 0.029). The prevalence odds ratio (POR) for albuminuria was increased by 5-fold in those with plasma glucose levels above kidney threshold of 180 mg/dL ( p = 0.014), and by 3.1-fold in those with low eGFR) ( p = 0.050). Collectively, these findings suggest that the Cd and Pb exposure profiles equally impact kidney function and diabetes risk.
Keywords	cadmium ; lead ; albuminuria ; diabetes ; fasting plasma glucose ; glomerular filtration rate ; Medicine ; R
Subject code	333
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Effect of Cadmium on GFR Is Clarified by Normalization of Excretion Rates to Creatinine Clearance

Soisungwan Satarug / David A. Vesey / Muneko Nishijo / Werawan Ruangyuttikarn / Glenda C. Gobe / Kenneth R. Phelps

International Journal of Molecular Sciences, Vol 22, Iss 4, p

2021 Volume 1762

Abstract: Erroneous conclusions may result from normalization of urine cadmium and N-acetyl-β-D-glucosaminidase concentrations ([Cd] u and [NAG] u ) to the urine creatinine concentration ([cr] u ). In theory, the sources of these errors are nullified by ... ...

Abstract	Erroneous conclusions may result from normalization of urine cadmium and N-acetyl-β-D-glucosaminidase concentrations ([Cd] u and [NAG] u ) to the urine creatinine concentration ([cr] u ). In theory, the sources of these errors are nullified by normalization of excretion rates (E Cd and E NAG ) to creatinine clearance (C cr ). We hypothesized that this alternate approach would clarify the contribution of Cd-induced tubular injury to nephron loss. We studied 931 Thai subjects with a wide range of environmental Cd exposure. For x = Cd or NAG, E x /E cr and E x /C cr were calculated as [ x ] u /[cr] u and [ x ] u [cr] p /[cr] u , respectively. Glomerular filtration rate (GFR) was estimated according to the Chronic Kidney Disease (CKD) Epidemiology Collaboration (eGFR), and CKD was defined as eGFR < 60 mL/min/1.73m 2 . In multivariable logistic regression analyses, prevalence odds ratios (PORs) for CKD were higher for log(E Cd /C cr ) and log(E NAG /C cr ) than for log(E Cd /E cr ) and log(E NAG /E cr ). Doubling of E Cd /C cr and E NAG /C cr increased POR by 132% and 168%; doubling of E Cd /E cr and E NAG /E cr increased POR by 64% and 54%. As log(E Cd /C cr ) rose, associations of eGFR with log(E Cd /C cr ) and log(E NAG /C cr ) became stronger, while associations of eGFR with log(E Cd /E cr ) and log(E NAG /E cr ) became insignificant. In univariate regressions of eGFR on each of these logarithmic variables, R 2 was consistently higher with normalization to C cr . Our tabular and graphic analyses uniformly indicate that normalization to C cr clarified relationships of E Cd and E NAG to eGFR.
Keywords	cadmium ; chronic kidney disease ; excretion rate ; GFR ; N-acetyl-β-D-glucosaminidase ; nephrotoxicity ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2021-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Induction of MITF expression in human cholangiocarcinoma cells and hepatocellular carcinoma cells by cyclopamine, an inhibitor of the Hedgehog signaling

Samatiwat, Papavee / Kazuhisa Takeda / Koji Ohba / Shigeki Shibahara / Soisungwan Satarug / Veerapol Kukongviriyapan

Biochemical and biophysical research communications. 2016 Jan. 29, v. 470, no. 1

2016

Abstract: Microphthalmia-associated transcription factor (MITF) is a key regulator of differentiation of melanocytes and retinal pigment epithelial cells, but it also has functions in non-pigment cells. MITF consists of multiple isoforms, including widely ... ...

Abstract	Microphthalmia-associated transcription factor (MITF) is a key regulator of differentiation of melanocytes and retinal pigment epithelial cells, but it also has functions in non-pigment cells. MITF consists of multiple isoforms, including widely expressed MITF-A and MITF-H. In the present study, we explored the potential role played by the Hedgehog signaling on MITF expression in two common types of primary liver cancer, using human cholangiocarcinoma cell lines, the KKU-100 and HuCCT1, along with the HepG2 human hepatocellular carcinoma cell line. Importantly, cholangiocarcinoma is characterized by the activated Hedgehog signaling. Here we show that MITF-A mRNA is predominantly expressed in all three human liver cancer cell lines examined. Moreover, cyclopamine, an inhibitor of the Hedgehog signalling, increased the expression levels of MITF proteins in HuCCT1 and HepG2 cells, but not in KKU-100 cells, suggesting that MITF expression may be down-regulated in some liver cancer cases.
Keywords	cyclopamine ; hepatoma ; human cell lines ; humans ; melanocytes ; messenger RNA ; neoplasm cells ; proteins ; transcription factors
Language	English
Dates of publication	2016-0129
Size	p. 144-149.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2016.01.010
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Cadmium, environmental exposure, and health outcomes O cádmio, a exposição ambiental ao cádmio e as consequências para a saúde

Soisungwan Satarug / Scott H. Garrett / Mary Ann Sens / Donald A. Sens

Ciência & Saúde Coletiva, Vol 16, Iss 5, Pp 2587-

2011 Volume 2602

Abstract: We provide an update of the issues surrounding health risk assessment of exposure to cadmium in food. Bioavailability of ingested cadmium has been confirmed in studies of persons with elevated dietary exposure, and the findings have been strengthened by ... ...

Abstract	We provide an update of the issues surrounding health risk assessment of exposure to cadmium in food. Bioavailability of ingested cadmium has been confirmed in studies of persons with elevated dietary exposure, and the findings have been strengthened by the substantial amounts of cadmium accumulated in kidneys, eyes, and other tissues and organs of environmentally exposed individuals. We hypothesized that such accumulation results from the efficient absorption and systemic transport of cadmium, employing multiple transporters that are used for the body's acquisition of calcium, iron, zinc, and manganese. Adverse effects of cadmium on kidney and bone have been observed in environmentally exposed populations at frequencies higher than those predicted from models of exposure. Population data raise concerns about the validity of the current safe intake level that uses the kidney as the sole target in assessing the health risk from ingested cadmium. The data also question the validity of incorporating the default 5% absorption rate in the threshold-type risk assessment model, known as the provisional tolerable weekly intake (PTWI), to derive a safe intake level for cadmium. Uma atualização sobre as questões relacionadas à avaliação dos riscos de saúde, oriundos da exposição a cádmio nos alimentos, é apresentada. Em um estudo de indivíduos sujeitos a uma elevada exposição dietária ao cádmio, a biodisponibilidade do cádmio ingerido foi confirmada, e os achados foram reforçados, diante da constatação de quantidades substanciais de cádmio acumulado, seja nos rins, nos olhos, assim como em outros tecidos e órgãos de pessoas ambientalmente expostas. Levantamos a hipótese de que essa acumulação seria o resultado de uma absorção eficiente do cádmio e do seu transporte sistêmico na absorção dos elementos cálcio, ferro, zinco e manganês pelo corpo humano. Os dados populacionais encontrados têm gerado uma preocupação quanto à validade do nível, atualmente aceito, de ingestão cádmica isenta de riscos, os rins constituindo o objeto único desses levantamentos de avaliação dos riscos à saúde, provenientes da ingestão de cádmio. Os dados também nos levam, na inferência do nível de ingestão cádmica isenta de riscos, a questionar a validade de se incorporar no modelo de avaliação de riscos para a determinação do limiar a taxa default de 5%, conhecida como nível tolerável de ingestão proporcionada semanalmente (PTWI).
Keywords	Cádmio ; Cálcio ; Câncer ; Dieta ; Carga de doença ; Exposição ambiental ; Cadmium ; Calcium ; Cancer ; Diet ; Disease burden ; Environmental exposure ; Public aspects of medicine ; RA1-1270
Language	English
Publishing date	2011-05-01T00:00:00Z
Publisher	Associação Brasileira de Pós-Graduação em Saúde Coletiva
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Induction of MITF expression in human cholangiocarcinoma cells and hepatocellular carcinoma cells by cyclopamine, an inhibitor of the Hedgehog signaling

Samatiwat, Papavee / Kazuhisa Takeda / Soisungwan Satarug / Koji Ohba / Veerapol Kukongviriyapan / Shigeki Shibahara

Biochemical and biophysical research communications

Volume v. 470

Abstract	Microphthalmia-associated transcription factor (MITF) is a key regulator of differentiation of melanocytes and retinal pigment epithelial cells, but it also has functions in non-pigment cells. MITF consists of multiple isoforms, including widely expressed MITF-A and MITF-H. In the present study, we explored the potential role played by the Hedgehog signaling on MITF expression in two common types of primary liver cancer, using human cholangiocarcinoma cell lines, the KKU-100 and HuCCT1, along with the HepG2 human hepatocellular carcinoma cell line. Importantly, cholangiocarcinoma is characterized by the activated Hedgehog signaling. Here we show that MITF-A mRNA is predominantly expressed in all three human liver cancer cell lines examined. Moreover, cyclopamine, an inhibitor of the Hedgehog signalling, increased the expression levels of MITF proteins in HuCCT1 and HepG2 cells, but not in KKU-100Â cells, suggesting that MITF expression may be down-regulated in some liver cancer cases.
Language	English
Document type	Article
ISSN	0006-291X
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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