Detection and Manipulation of the Stress Response Protein Metallothionein

Bhandari, Sadikshya; Melchiorre, Clare; Dostie, Kristen; Laukens, Debby; Devisscher, Lindsey; Louwrier, Ariel; Thees, Amy; Lynes, Michael A.

doi:10.1002/cptx.17

Cited by 15 publications

(11 citation statements)

References 38 publications

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“…The protective effect of Zn on Cd-induced injury has been studied in vitro and in vivo [ 14 , 15 ], however, the underlying mechanisms remain undefined. Since Zn is a potent MT inducer via the metal-response element-binding transcription factor 1 (MTF1, [ 16 – 19 ]), it is possible that Zn-induced MT overexpression plays an important role in protection against Cd toxicity [ 20 – 24 ]. In contrast to Zn-mediated MT induction, Cd also results in MT induction as part of the cellular response to injury.…”

Section: Introductionmentioning

confidence: 99%

Zinc protects against cadmium-induced toxicity in neonatal murine engineered cardiac tissues via metallothionein-dependent and independent mechanisms

Zhen

et al. 2019

Acta Pharmacol Sin

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Cadmium (Cd) is a nonessential heavy metal and a prevalent environmental toxin that has been shown to induce significant cardiomyocyte apoptosis in neonatal murine engineered cardiac tissues (ECTs). In contrast, zinc (Zn) is a potent metallothionein (MT) inducer, which plays an important role in protection against Cd toxicity. In this study, we investigated the protective effects of Zn against Cd toxicity in ECTs and explore the underlying mechanisms. ECTs were constructed from neonatal ventricular cells of wild-type (WT) mice and mice with global MT gene deletion (MT-KO). In WT-ECTs, Cd (5−20 μM) caused a dose-dependent toxicity that was detected within 8 h evidenced by suppressed beating, apoptosis, and LDH release; Zn (50−200 μM) dose-dependently induced MT expression in ECTs without causing ECT toxicity; co-treatment of ECT with Zn (50 µM) prevented Cd-induced toxicity. In MT-KO ECTs, Cd toxicity was enhanced; but unexpectedly, cotreatment with Zn provided partial protection against Cd toxicity. Furthermore, Cd, but not Zn, significantly activated Nrf2 and its downstream targets, including HO-1; inhibition of HO-1 by a specific HO-1 inhibitor, ZnPP (10 µM), significantly increased Cd-induced toxicity, but did not inhibit Zn protection against Cd injury, suggesting that Nrf2-mediated HO-1 activation was not required for Zn protective effect. Finally, the ability of Zn to reduce Cd uptake provided an additional MT-independent mechanism for reducing Cd toxicity. Thus, Zn exerts protective effects against Cd toxicity for murine ECTs that are partially MT-mediated. Further studies are required to translate these findings towards clinical trials.

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Section: Introductionmentioning

confidence: 99%

Zinc protects against cadmium-induced toxicity in neonatal murine engineered cardiac tissues via metallothionein-dependent and independent mechanisms

Zhen

et al. 2019

Acta Pharmacol Sin

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“…Unlike the LNG-IUS, COCs did not cause changes in inflammatory pathways, however both the LNG-IUS and COCs caused significant downregulation of several members of the metallothionein (MT) gene family. MT has well-documented roles in binding of heavy metals including copper for homeostasis and detoxification, and is increasingly being recognized for its role in immunomodulation, apoptosis and the stress response 26,27 . Exposure to LNG-IUS in women with endometrial hyperplasia resulted in decreased immunohistochemical detection of MT protein 28 , consistent with our results showing down-regulation of MT RNA in endometrium in both LNG-exposed groups.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of the Hormonal and Copper Intrauterine Device on the Endometrial Transcriptome

Smith‐McCune

Thomas

Averbach

et al. 2020

Sci Rep

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The contraceptive effectiveness of intrauterine devices (IUDs) has been attributed in part to a foreign body reaction in the endometrium. We performed this study to better understand mechanisms of action of contraceptives of by studying their effects on endometrial and cervical transcriptomes. We collected endometrial and cervical biopsies from women using the levonorgestrel-releasing intrauterine system (LNG-IUS, n = 11), copper intrauterine device (cu-IUD, n = 13) or levonorgestrel-containing combined oral contraceptives (COC, n = 12), and from women not using contraceptives (control group, n = 11). Transcriptional profiling was performed with Affymetrix arrays, Principal Component Analysis and the bioconductor package limma. In endometrial samples from cu-IUD users, there were no genes with statistically significant differential expression compared to controls. In LNG-IUS users, 2509 genes were differentially expressed and mapped predominantly onto immune and inflammatory pathways. The cervical samples showed no statistically significant differential gene expression compared to controls. Hormonal and copper IUDs have significantly different effects on the endometrial transcriptome, with the LNG-IUS transcriptome showing pronounced inflammation and immune activation compared to controls whereas the cu-IUD transcriptome was indistinguishable from luteal phase endometrium. These findings argue against a foreign body reaction as a common mechanism of action of IUDs. The intrauterine device (IUD) is a popular and effective form of contraception used by approximately 14% of women globally 1. Commonly used IUDs include a hormonal IUD that releases levonorgestrel (LNG-IUS), and a non-hormonal copper IUD (cu-IUD) that releases copper ions. The contraceptive efficacy of IUDs has been attributed in part to their effects as foreign bodies that induce local inflammation; in addition, the cu-IUD and LNG-IUS have direct toxic effects on sperm and the LNG-IUS also causes endometrial atrophy and alterations in cervical mucus rendering it unfavorable to sperm penetration 2-5. We recently studied the local immune microenvironment in the upper female reproductive tract of LNG-IUS users compared to mid-luteal samples from women not using hormonal or intrauterine contraceptives 6,7. We found that the endometrial transcriptome from LNG-IUS users was associated with pronounced signals of inflammation consistent with a foreign body reaction 7. These findings could be due to the presence of a foreign body (the IUD), the effect of LNG released by the IUD, or both. The purpose of this study was to compare the independent and combined effects of LNG exposure and IUD exposure on the transcriptome of the upper female reproductive tract, in order to better understand potential mechanisms of contraceptive action by these different methods. Methods Study design. This was a cross-sectional study comparing transcriptomes from the endometrium or cervical transformation zone (TZ) from samples donated by 4 groups of women using: no hormonal or intr...

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“…Of the tested genes, the expression levels of mtl-1 and mtl-2, which encode metallothioneins, changed the most. Metallothionein is a protein with special physiological functions and plays a unique role in reducing the toxicity of heavy metals such as cadmium, nickel, and lead, as well as scavenging excessive free radicals, anti-aging, and tumor (Bhandari et al, 2017). Previous studies have shown that metallothionein can provide a stable redox environment and protect cells from oxidative stress by resisting the stress response of various organelles (Rios et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Silica nanoparticles enhance germ cell apoptosis by inducing reactive oxygen species (ROS) formation in <i>Caenorhabditis elegans</i>

et al. 2020

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Silica nanoparticles (SiO 2 NPs) are widely used in daily life and can enter organisms through several pathways, often causing unpredictable toxicity. Although SiO 2 NPs are known to cause damage to the respiratory system, little is known about their oral toxicity, and their potential harm to the reproductive system is unclear. In this study, we used a Caenorhabditis elegans model to clarify SiO 2 NPs oral toxicity in vivo and explore their effect on the reproductive system. We exposed C. elegans to 0.25, 0.5 and 1 mg /mL SiO 2 NPs for 24 hr. Our results showed that SiO 2 NPs exposure for 24 hr did not affect nematode survival rates, but did affect, to varying degrees, the reproduction, development, and movement of nematodes, with nematode fecundity being the most sensitive to SiO 2 NPs toxicity. The NPs exposed group showed enhanced germ cell apoptosis and increased oxidative stress as seen through an increase in ROS and malondialdehyde (MDA), and decrease in reduced glutathione (GSH). N-acetyl-L-cysteine (NAC), an antioxidant, negated SiO 2 NPs effect on germ cells and restored nematodes reproductive ability. We also found that SiO 2 NPs could affect the expression of genes related to metal detoxification, oxidative stress, and apoptosis. The expression of metallothionein coding genes mtl-1 and mtl-2 changed most significantly among the tested genes. We demonstrated that SiO 2 NPs could enhance germ cell apoptosis by inducing oxidative stress, providing a new area for studies of the mechanism of SiO 2 NP toxicity.

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Detection and Manipulation of the Stress Response Protein Metallothionein

Cited by 15 publications

References 38 publications

Zinc protects against cadmium-induced toxicity in neonatal murine engineered cardiac tissues via metallothionein-dependent and independent mechanisms

Zinc protects against cadmium-induced toxicity in neonatal murine engineered cardiac tissues via metallothionein-dependent and independent mechanisms

Differential Effects of the Hormonal and Copper Intrauterine Device on the Endometrial Transcriptome

Silica nanoparticles enhance germ cell apoptosis by inducing reactive oxygen species (ROS) formation in <i>Caenorhabditis elegans</i>

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