Determination of Iron Toxicity in Mice

Eickholt, Theodore H.; White, Wallace F.

doi:10.1002/jps.2600540829

Cited by 8 publications

(6 citation statements)

References 1 publication

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“…This new concept of iron-induced ferroptosis has recently been shown by others by using FeCl 2 in organotypic hippocampal slice cultures, BAY 11-7085 in breast cancer cell lines and glioblastoma and FINO2 in HT1080 fibrosarcoma cells . Both in humans as well as in rodents, − an acute overdose of iron in vivo typically results in multiple organ failure and often death. , First, we have tested the potency of our inhibitors for (NH 4 ) 2 Fe(SO 4 ) 2 -induced ferroptosis in vitro. Similar to erastin-induced ferroptosis, we found that our most potent inhibitors show similar or lower IC 50 values than Fer-1 when inhibiting ferrous ammonium sulfate-induced ferroptosis (see Supporting Information).…”

Section: Resultsmentioning

confidence: 86%

“…26 This new concept of iron-induced ferroptosis has recently been shown by others by using FeCl2 in organotypic hippocampal slice cultures 27 , BAY 11-7085 in breast cancer cell lines and glioblastoma 28 and FINO2 in HT1080 fibrosarcoma cells. 29 Both in humans 30 as well as in rodents [31][32][33] , an acute overdose of iron in vivo typically results in multiple organ failure and often death. 34,35 First, we have tested the potency of our inhibitors for…”

Section: In Vivo Evaluation Of Efficacy Of Novel Fer-1 Analoguesmentioning

confidence: 99%

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Discovery of Novel, Drug-Like Ferroptosis Inhibitors with in Vivo Efficacy

et al. 2018

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Ferroptosis is an iron-catalysed, non-apoptotic form of regulated necrosis that results in oxidative lipid damage in cell membranes that can be inhibited by the radical-trapping antioxidant Ferrostatin-1 (Fer-1).Novel inhibitors derived from the Fer-1 scaffold inhibited ferroptosis potently but suffered from solubility issues. In this paper, we report the synthesis of a more stable and readily soluble series of Fer-1 analogues that potently inhibit ferroptosis. The most promising compounds (37, 38 and 39) showed an improved protection compared to Fer-1 against multi-organ injury in mice. No toxicity was observed in mice after daily injection of 39 (UAMC-3203) for 4 weeks. UAMC-3203 inserts rapidly in a phospholipid bilayer in silico, which aligns with the current understanding of the mechanism of action of these compounds. Concludingly, these analogues have superior properties compared to Fer-1, show in vivo efficacy and represent novel lead compounds with therapeutic potential in relevant ferroptosis-driven disease models.

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Section: Resultsmentioning

confidence: 86%

Section: In Vivo Evaluation Of Efficacy Of Novel Fer-1 Analoguesmentioning

confidence: 99%

Discovery of Novel, Drug-Like Ferroptosis Inhibitors with in Vivo Efficacy

et al. 2018

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“…The results showed that these metal impurities are present at very low concentrations; most elements were present at less than 1 ppm in SAS (Table S1). Although levels of individual elements such as iron (Fe) were slightly higher in S200 powder than A200F, they were far from the toxic dose reported in rodents and humans; − thus, these elements do not have a major impact on the safety of SAS even during exposure to high-dose SAS.…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide DNA Methylation Alterations and Potential Risk Induced by Subacute and Subchronic Exposure to Food-Grade Nanosilica in Mice

Lou

et al. 2021

ACS Nano

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The intensive application of nanomaterials in the food industry has raised concerns about their potential risks to human health. However, limited data are available on the biological safety of nanomaterials in food, especially at the epigenetic level. This study examined the implications of two types of synthetic amorphous silica (SAS), food-grade precipitated silica (S200) and fumed silica Aerosil 200F (A200F), which are nanorange food additives. After 28-day continuous and intermittent subacute exposure to these SAS via diet, whole-genome methylation levels in mouse peripheral leukocytes and liver were significantly altered in a dose- and SAS type-dependent manner, with minimal toxicity detected by conventional toxicological assessments, especially at a human-relevant dose (HRD). The 84-day continuous subchronic exposure to all doses of S200 and A200F induced liver steatosis where S200 accumulated in the liver even at HRD. Genome-wide DNA methylation sequencing revealed that the differentially methylated regions induced by both SAS were mainly located in the intron, intergenic, and promoter regions after 84-day high-dose continuous exposure. Bioinformatics analysis of differentially methylated genes indicated that exposure to S200 or A200F may lead to lipid metabolism disorders and cancer development. Pathway validation experiments indicated both SAS types as potentially carcinogenic. While S200 inhibited the p53-mediated apoptotic pathway in mouse liver, A200F activated the HRAS-mediated MAPK signaling pathway, which is a key driver of hepatocarcinogenesis. Thus, caution must be paid to the risk of long-term exposure to food-grade SAS, and epigenetic parameters should be included as end points during the risk assessment of food-grade nanomaterials.

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“…30 mg Fe/kg body weight (bw)) administered via gavage to female Fairfield Webster mice has been reported (Eickholt & White, 1965 Table IV.2). For ferrous lactate an LD50 of 147 mg/kg bw (ca.…”

Section: Acute Toxicitymentioning

confidence: 99%

“…For ferrous lactate an LD50 of 147 mg/kg bw (ca. 30 mg Fe/kg body weight (bw)) administered via gavage to female Fairfield Webster mice has been reported (Eickholt & White, 1965).…”

Section: Acute Toxicitymentioning

confidence: 99%

Flavouring Group Evaluation 42: Iron containing organic substances from chemical group 30

Flavourings¹

2009

EFSA Journal

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The Scientific Panel on Materials in Contact with Food, Enzymes, Flavourings and Processing Aids (the Panel) was asked to provide scientific advice to the Commission on the implications for human health of chemically defined flavouring substances used in or on foodstuffs in the Member States. In particular, the Scientific Panel was asked to evaluate two flavouring substances in the Flavouring Group Evaluation 42 (FGE.42), using the Procedure as referred to in the Commission Regulation (EC) No 1565/2000. These two flavouring substances belong to chemical group 30, Annex I of the Commission Regulation (EC) No 1565/2000. The two candidate substances (ferric ammonium citrate .089] and ferrous lactate .096]) are organic non-haem iron complexes. The Panel considered it inappropriate to evaluate these two substances using the Procedure for the evaluation of flavouring substances, because in their Opinion, the Procedure is not sufficiently underpinned for the evaluation of metal containing compounds. Instead, the Panel decided to evaluate the safety of these flavouring substances on the basis of data on iron toxicity in general and on toxicity data for several iron salts and complexes, including the candidate substances. Candidate substance .096] possesses a chiral centre and may occur as optical isomers. This substance has been presented without specifying the stereoisomeric composition. The substances have not been reported to occur naturally. However, the substances are complexes or salts which are composed of naturally occurring substances (iron with ammonium and citrate or iron and lactate). these levels are additional to a background exposure that would suffice to cover the daily iron requirement. However, for people suffering from hereditary haemochromatosis (inadequate down-regulation of iron absorption) a safety concern is concluded. In order to improve the safety assessment for ferrous lactate [FLno: 16.096] based on the mTAMDI exposure estimates, more detailed information on use levels and the foods in which these substances are used are required. For ferric ammonium citrate .089], the conservative exposure estimate for the Scottish subpopulation corresponds to a consumption of the particular drink of about 1 L per adult per day. That may be a large amount, but in comparison with other non-alcoholic drinks it is not an extreme amount. In order to determine whether the conclusion for the candidate substances can be applied to the materials of commerce, it is necessary to consider the available specifications. Incomplete specifications have been provided for the two flavouring substances. For .089] no assay minimum and identification test have been provided. For ] no identification test is available and no information on stereochemical composition has been submitted. Thus, the final evaluation of the materials of commerce cannot be performed for both candidate substances, pending further information. KEY WORDS

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Determination of Iron Toxicity in Mice

Cited by 8 publications

References 1 publication

Discovery of Novel, Drug-Like Ferroptosis Inhibitors with in Vivo Efficacy

Discovery of Novel, Drug-Like Ferroptosis Inhibitors with in Vivo Efficacy

Genome-Wide DNA Methylation Alterations and Potential Risk Induced by Subacute and Subchronic Exposure to Food-Grade Nanosilica in Mice

Flavouring Group Evaluation 42: Iron containing organic substances from chemical group 30

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