Stressor: 664

Title

To create a new stressor, from the Listing Stressors page at https://aopwiki.org/stressors click ‘New stressor.’ This will bring you to a page entitled “New Stressor” where a stressor title can be entered. Click ‘Create stressor’ to create a new Stressor page listing the stressor title at the top. More help

Uranium

Stressor Overview

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. More help

AOPs Including This Stressor

This table is automatically generated and lists the AOPs associated with this Stressor. More help

Events Including This Stressor

This table is automatically generated and lists the Key Events associated with this Stressor. More help

Chemical Table

The Chemical Table lists chemicals associated with a stressor. This table contains information about the User’s term for a chemical, the DTXID, Preferred name, CAS number, JChem InChIKey, and Indigo InChIKey.To add a chemical associated with a particular stressor, next to the Chemical Table click ‘Add chemical.’ This will redirect you to a page entitled “New Stressor Chemical.’ The dialog box can be used to search for chemical by name, CAS number, JChem InChIKey, and Indigo InChIKey. Searching by these fields will bring forward a drop down list of existing stressor chemicals formatted as  Preferred name, “CAS- preferred name,” “JChem InChIKey – preferred name,” or “Indigo InChIKey- preferred name,” depending on by which field you perform the search. It may take several moments for the drop down list to display. Select an entity from the drop down list and click ‘Add chemical.’ This will return you to the Stressor Page, where the new record should be in the ‘Chemical Table’ on the page.To remove a chemical associated with a particular stressor, in the Chemical Table next to the chemical you wish to delete, click ‘Remove’ and then click 'OK.' The chemical should no longer be visible in the Chemical table. More help
User term DTXID Preferred name Casrn jchem_inchi_key indigo_inchi_key
Uranium DTXSID1042522 Uranium 7440-61-1 JFALSRSLKYAFGM-UHFFFAOYSA-N JFALSRSLKYAFGM-UHFFFAOYSA-N

AOP Evidence

This table is automatically generated and includes the AOPs with this associated stressor as well as the evidence term and evidence text from this AOP Stressor. More help

Event Evidence

This table is automatically generated and includes the Events with this associated stressor as well as the evidence text from this Event Stressor. More help
Inhibition, Mitochondrial Electron Transport Chain Complexes

Yu et al. (2021) found that uranyl nitrate solution was capable of inhibiting electron transport chain complexes within a HK-2 cell line. This article shows inhibition of complex IV and ATP synthase at very low concentrations (>1 µM and <0.1 µM) (Yu et al., 2021). The IC50 values of complex IV and V were determined to be 3.8 mM (0.9 mg/L) and 4.8 (1.1 mg/L), respectively (Yu et al., 2021), from which it can be inferred that uranium exposure is more toxic to CIV than CV. However, within this experiment none of the other complexes were inhibited, despite the much higher concentrations being used for the treatment (50, 100, 250, and 500 µM) (Yu et al., 2021).

Increase, Mitochondrial Dysfunction

Shaki et al. (2012) found that uranyl acetate (UA) exposure in isolated rat kidney mitochondria decreased the ATP production levels and ATP/ADP ratio in a concentration-dependent manner, through inhibition of complexes II and III of the ETC. Both of these levels were significantly changed at UA concentrations of 100 µM and 200 µM. In addition, a concentration-dependent decrease in activity of complex II with exposure to U was observed (Shaki et al., 2012). They also found that mitochondrial membrane potential damage and mitochondrial swelling both increased significantly time- and dose-dependently in the treated rat kidneys (Shaki et al., 2012). ATP/ADP ratios were also decreased significantly by treatment with 100 µM or more uranium (Shaki et al., 2012). Mitochondrial outer membrane damage was significantly decreased by treatment with 200 µM of uranium (Shaki et al., 2012).

Shaki et al. (2013) also investigated the effects of uranium on rat kidneys. They found that mitochondrial permeability transition was also impacted by uranium treatment, causing increased mitochondrial swelling and increased disruption of energy homeostasis (Shaki et al., 2013).

Hao et al. (2014) assessed the changes in mitochondrial potential in human kidney proximal tubular cells treated with uranium and found that the group treated with 500 µM of depleted uranium for 24 hours showed a significant decreased mitochondrial membrane potential.

In their study of the effects of depleted uranium treatment on human embryonic kidney cells, Hao et al. (2016) found that ETHE1, a mitochondrial protein involved in mitochondrial homeostasis and mitochondrial diseases, had significant dose- and time-dependant decreases in gene expression when treated with 125 µM or more depleted uranium (DU) for 2 hours or more.

Increase, Oxidative Stress

In Shaki et al.’s article (2012), they found rat kidney mitochondria treated with uranyl acetate caused increased formation of ROS, increased lipid peroxidation, and decreased GSH content when exposed to 100 μM or more for an hour.

Hao et al. (2014), found that human kidney proximal tubular cells (HK-2 cells) treated with uranyl nitrate for 24 hours with 500 μM showed a 3.5 times increase in ROS production compared to the control. They also found that GSH content was decreased by 50% of the control when the cells were treated with uranyl nitrate (Hao et al., 2014).

Occurrence, Kidney toxicity

Arzuaga et al. (2010) conducted an occupational exposure study investigating renal function in uranium mill workers compared with a group of workers from a cement plant. They found that the workers exposed to the uranium mill showed higher β2-microglobulin excretion in their urine, which is indicative of proximal tubular dysfunction (Arzuaga et al., 2010).

Oxidative Stress

In Shaki et al.’s article (2012), they found rat kidney mitochondria treated with uranyl acetate caused increased formation of ROS, increased lipid peroxidation, and decreased GSH content when exposed to 100 μM or more for an hour.

Hao et al. (2014), found that human kidney proximal tubular cells (HK-2 cells) treated with uranyl nitrate for 24 hours with 500 μM showed a 3.5 times increase in ROS production compared to the control. They also found that GSH content was decreased by 50% of the control when the cells were treated with uranyl nitrate (Hao et al., 2014).

N/A, Mitochondrial dysfunction 1

Shaki et al. (2012) found that uranyl acetate (UA) exposure in isolated rat kidney mitochondria decreased the ATP production levels and ATP/ADP ratio in a concentration-dependent manner, through inhibition of complexes II and III of the ETC. Both of these levels were significantly changed at UA concentrations of 100 µM and 200 µM. In addition, a concentration-dependent decrease in activity of complex II with exposure to uranium (U) was observed (Shaki et al., 2012). They also found that mitochondrial membrane potential damage and mitochondrial swelling significantly increased both time- and dose-dependently in the treated rat kidneys (Shaki et al., 2012). ATP/ADP ratios were also decreased significantly by treatment with 100 µM or more of uranium (Shaki et al., 2012). Mitochondrial outer membrane damage was significantly decreased by treatment with 200 µM of uranium (Shaki et al., 2012).

Shaki et al. (2013) also investigated the effects of uranium on rat kidneys. They found that mitochondrial permeability transition was also impacted by uranium treatment, causing increased mitochondrial swelling and increased disruption of energy homeostasis (Shaki et al., 2013).

Hao et al. (2014) assessed the changes in mitochondrial potential in human kidney proximal tubular cells treated with uranium and found that the group treated with 500 µM of depleted uranium for 24 hours showed a significant decrease in mitochondrial membrane potential.

In their study of the effects of depleted uranium treatment on human embryonic kidney cells, Hao et al. (2016) found that ETHE1, a mitochondrial protein involved in mitochondrial homeostasis and mitochondrial diseases, had significant dose- and time-dependant decreases in gene expression when treated with 125 µM or more depleted uranium (DU) for 2 hours or more.

Increase, Cytotoxicity (renal tubular cell)

Rouas et al. (2010) treated human embryonic kidney cells (HEK-293) with depleted uranium of varying concentrations for 24 or 48 hours to assess the effect on cell viability. They found that the cells showed a time- and dose-dependant increase in cytotoxicity, as the 24 hour treatment was not significant below 700 μM but increased up to 1000 μM. The 48 hour treatment was significant at as low as 100 μM and showed dose-dependant increase up to 1000 μM (Rouas et al., 2010).

Shaki et al. (2012) investigated the effects of uranium on rat kidney cell viability, finding that cytochrome c increases were significant in cells treated with 100 μM for 24 hours.

In their investigation of the effects of uranium treatment on human kidney cells, Hao et al. (2014) learned that cells treated with depleted uranium had significantly increased levels of caspase-3, caspase-8, and caspase-9. They also found that the treated cells released more mitochondrial cytochrome c and lactate dehydrogenase (LDH) and had increased levels of Bax, while Bcl-2 levels were decreased (Hao et al., 2014). These results indicate an increase in apoptosis in cells treated with depleted uranium (Hao et al., 2014). Hao et al. (2014) also directly observed cytotoxicity in the treated cells and found dose- and time-dependant decreases in cell viability when cells were treated with 0 to 700 μM of depleted uranium for 0 to 48 hours.

In a study conducted by Hao et al. (2016) they assessed the effects of depleted uranium on kidney mitochondria in human embryonic kidney cells. They found that the treated cells showed significant increases in mitochondrial damage and subsequent apoptosis (Hao et al., 2016).

Guéguen et al. (2015) treated human hepatocyte carcinoma cells with uranium to determine cytotoxicity. Their results showed that caspase 3/7 activity was significantly increased in a dose-dependant manner when cells were treated with 300 to 1000 μM for 4, 6, 12, to 24 hours (Guéguen et al., 2015).

Yu et al. (2021) investigated the effects of uranium on human kidney cells and found that the treated cells showed time- and dose-dependant decreases in cell viability when treated with concentrations from 1 to 10000 μM and when treated for 5 to 40 hours. The IC50 value of uranium was determined to be 520 μM for uranium in this study (Yu et al., 2021).

Muller et al. (2006) treated pig kidney cells with uranium and found both time- and dose-dependant increases in cytotoxicity when treated with 0 to 1.4 mM of uranium for 0 to 35 hours.

Stressor Info

Text sections under this subheading include the Chemical/Category Description and Characterization of Exposure. More help
Chemical/Category Description
To edit the Chemical/Category Description” section, on a KER page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Stressor.”  Scroll down to the “Chemical/Category Description” section, where a text entry box allows you to submit text. Click ‘Update’ to save your changes and return to the Stressor page.  The new text should appear under the “Chemical/Category Description”  section on the page. More help
Characterization of Exposure
To edit the “Characterization of Exposure” section, on a Stressor page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Stressor.”  Scroll down to the “Characterization of Exposure”  section, where a text entry box allows you to submit text. Click ‘Update’ to save your changes and return to the Stressor page.  The new text should appear under the “Characterization of Exposure” section on the page. More help

References

List of the literature that was cited for this Stressor description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015).To edit the “References” section, on a Stressor page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Stressor.”  Scroll down to the “References” section, where a text entry box allows you to submit text. Click ‘Update’ to save your changes and return to the Stressor page.  The new text should appear under the “References” section on the page. More help