Resveratrol pretreatment accompanies fewer DBDPE-associated changes in female mice

A 28-day experiment in female Kunming mice found that resveratrol pretreatment was associated with lower values for several liver, kidney, redox and iron-related endpoints after high-dose exposure to decabromodiphenyl ethane (DBDPE), a brominated flame retardant. The study used 54 female mice assigned to six groups: a control group, a DBDPE-only group, three groups receiving DBDPE with 25, 50 or 100 mg/kg body weight per day of resveratrol, and a resveratrol-alone group. DBDPE was administered orally at 500 mg/kg body weight per day, and resveratrol was given two hours before DBDPE.

The authors describe the design as a high-dose toxicology model, not a representation of typical human dietary exposure. DBDPE exposure was associated with changes in measured organ indices, serum biochemical markers and descriptive liver and kidney morphology. The liver index was 5.06% ± 0.20% in controls and 5.89% ± 0.60% in DBDPE-exposed mice; the kidney index was 1.02% ± 0.10% and 1.16% ± 0.07%, respectively.

Compared with controls, the DBDPE group had higher serum gamma-glutamyltransferase, alkaline phosphatase, creatinine, uric acid, lactate dehydrogenase and total cholesterol values, alongside lower albumin and triglyceride values. Representative liver sections showed hepatocyte vacuolization, cell aggregates, altered tissue arrangement and areas with a necrosis-like appearance, while Oil Red O staining showed more prominent lipid droplets in the DBDPE group. Representative kidney sections showed tubular epithelial degeneration and desquamation, periglomerular cell aggregation, vasodilation and congestion.

Because no histopathological scoring or morphometry was applied, these images describe morphology without quantifying lesion severity or establishing functional organ damage. Its liver index was 5.17% ± 0.41% and its kidney index was 1.06% ± 0.03%, both lower than in the DBDPE-only group. The liver-index mean difference was −0.72 percentage points, with a two-sided 97.5% confidence interval of −1.32 to −0.12 and a Bonferroni-adjusted p value of 0.018.

The kidney-index difference was −0.10 percentage points, with a confidence interval of −0.16 to −0.04 and an adjusted p value of 0.002. The multiplicity adjustment covered these two primary outcomes. In the wider serum panel, gamma-glutamyltransferase, creatinine and uric acid were lower and triglycerides and albumin were higher in one or more resveratrol pretreatment groups than in DBDPE-only animals, although responses varied among endpoints and doses.

Redox-related measurements also differed after DBDPE exposure. Serum malondialdehyde, a readout compatible with increased lipid peroxidation, rose from 8.05 to 10.61 nmol/mL, while total nitric oxide synthase activity increased from 12.23 to 14.81 U/mL. Serum glutathione S-transferase, glutathione peroxidase and superoxide dismutase activities fell from 20.53 to 18.50 U/mL, 428.19 to 368.99 U/mL and 272.02 to 185.50 U/mL, respectively.

In liver tissue, malondialdehyde increased from 2.00 to 7.91 nmol/mg, while glutathione peroxidase, catalase, reduced glutathione and superoxide dismutase values were lower than in controls. The kidney followed a similar measured pattern: malondialdehyde rose from 2.26 to 4.44 nmol/mg, with lower glutathione peroxidase, catalase, glutathione and superoxide dismutase values. Dihydroethidium-derived liver fluorescence was also higher in the DBDPE group.

This fluorescence is an indirect, semiquantitative redox-associated measure rather than a species-specific measurement of reactive oxygen species or superoxide. Several resveratrol groups had values closer to the control pattern in these redox endpoints. Hepatic malondialdehyde was 3.98 nmol/mg in the medium-dose pretreatment group.

In the high-dose group, hepatic glutathione peroxidase, catalase, glutathione and superoxide dismutase were 60.11 U/mg, 853.90 U/g, 1.55 μmol/g and 327.48 U/mg, compared with 37.26 U/mg, 721.83 U/g, 1.07 μmol/g and 236.55 U/mg in the DBDPE-only group. Renal malondialdehyde was lower in all three pretreatment groups, at 3.81, 3.06 and 3.98 nmol/mg for the 25, 50 and 100 mg/kg groups. Glutathione peroxidase and glutathione were higher in the medium- and high-dose groups, while high-dose catalase activity was 115.99 U/g.

Dihydroethidium fluorescence was also lower in the resveratrol groups. These are group associations; the experiment did not show that resveratrol directly scavenged reactive molecules or that any redox change mediated the organ-index or morphological differences. RT-qPCR measurements identified further differences in selected antioxidant-related transcripts.

The researchers quantified Pik3r1, Nfe2l2, Sod2, Cat and Gpx1 in liver and kidney tissue, using three biological samples per group. DBDPE exposure was associated with lower expression of these selected transcripts than in controls. In liver, Sod2 and Cat expression fell from 1.00 ± 0.08 and 1.00 ± 0.22 in controls to 0.29 ± 0.04 and 0.24 ± 0.06 after DBDPE exposure, while the medium-dose resveratrol group measured 11.11 ± 0.38 and 9.58 ± 0.19.

In kidney, Nfe2l2 and Cat expression declined from 1.00 ± 0.03 and 1.00 ± 0.10 to 0.47 ± 0.01 and 0.33 ± 0.07 after DBDPE alone; the high-dose resveratrol group measured 3.55 ± 0.09 and 1.90 ± 0.56. These transcript measurements do not demonstrate PI3K activity, Nrf2 protein abundance or nuclear translocation, and the response was not monotonic across the three resveratrol doses. DBDPE exposure was also accompanied by higher assay-accessible iron readouts in serum, liver and kidney.

The commercial assay output was labelled Fe2+, but its selectivity for the ferrous iron pool over total assay-accessible iron was not established, so the results are interpreted as assay-accessible iron rather than a specific measurement of that pool. Serum values increased from 57.41 ± 0.79 to 91.76 ± 1.37 μmol/L, liver readings from 2.01 ± 0.03 to 3.44 ± 0.02 μmol/g protein, and kidney readings from 2.33 ± 0.05 to 4.61 ± 0.04 μmol/g protein. Values were lower in the resveratrol pretreatment groups than in the DBDPE-only group across all three sample types.

Western blots showed lower GPX4 and higher TFR1 abundance in DBDPE-exposed liver, with higher GPX4 in the high-dose resveratrol group and lower TFR1 in the low- and medium-dose groups. The kidney protein pattern was less consistent, and hepatic ACSL4 did not show the canonical increase associated with the DBDPE group. Changes in ferroptosis-associated transcripts accompanied these measurements but did not establish ferroptotic cell death.

In DBDPE-exposed liver, Tfrc expression increased from 1.01 ± 0.12 to 2.15 ± 0.02 and Acsl4 rose from 1.00 ± 0.02 to 1.54 ± 0.04, while Slc7a11 fell from 1.00 ± 0.07 to 0.12 ± 0.01 and Gpx4 declined from 1.01 ± 0.13 to 0.45 ± 0.06. In the high-dose resveratrol group, Tfrc and Acsl4 measured 0.88 ± 0.06 and 0.96 ± 0.14. In kidney, DBDPE-associated Tfrc and Acsl4 expression was higher than in controls, whereas the high-dose resveratrol group had Slc7a11 and Gpx4 expression of 3.30 ± 0.18 and 5.09 ± 0.05 and Acsl4 expression of 1.04 ± 0.01.

Representative transmission electron micrographs from DBDPE-exposed tissues showed irregular or shrunken mitochondria, blurred or discontinuous membranes, fragmented cristae and increased matrix electron density; some pretreatment fields appeared more regular. No ferroptosis-specific inhibitor, genetic perturbation, rescue experiment or quantitative ultrastructural analysis was performed. Several limitations restrict how far the results can be interpreted.

Only female Kunming mice were studied, estrous-cycle stage was not monitored or controlled, and no prospective power calculation was performed. Several terminal assays used three randomly selected animals from each nine-animal group, limiting sensitivity and making those findings exploratory. Cage was not included as a random or fixed effect in the analysis, so possible dependence among cage mates was not fully accounted for.

Histology and mitochondrial observations relied on representative fields without quantitative scoring. The delivered DBDPE concentration, homogeneity and stability were not analytically verified, and resveratrol storage stability was not separately assessed. The apparent non-monotonic response across 25, 50 and 100 mg/kg cannot establish hormesis, a formal dose-response relationship or an optimal dose because no prespecified trend analysis, dose-response model or pharmacokinetic assessment was performed.

Resveratrol alone also changed several transcripts, including lower hepatic Slc7a11, showing that its effects were marker- and tissue-dependent. The findings support a narrower conclusion than a demonstration of protection against human disease. Under this high-dose, 28-day mouse model, DBDPE exposure was accompanied by selected serum biochemical changes, descriptive liver and kidney morphology, redox differences, higher assay-accessible iron values, mitochondrial changes and tissue-dependent ferroptosis-associated markers.

Resveratrol pretreatment accompanied lower values across several of those endpoints, with the clearest primary results involving the two relative organ indices. The experiment does not establish ferroptosis, inhibition of ferroptosis, activation of PI3K/Nrf2 signaling or a causal sequence from oxidative stress to tissue changes. It also cannot define a DBDPE dose-response relationship, a no-observed-adverse-effect level or a dietary risk estimate.

The purified resveratrol doses were experimental gavage regimens and are not proposed as achievable through ordinary intake of resveratrol-containing foods, so the results do not support a dietary recommendation or direct extrapolation to typical human exposure.

Subject of Research: Resveratrol pretreatment and DBDPE-associated liver, kidney, redox and ferroptosis-associated markers in female mice

Article Title: Resveratrol Pretreatment and Decabromodiphenyl Ethane‐Associated Hepatorenal Changes in a High‐Dose Female Mouse Model: Redox Changes and Ferroptosis‐Associated Markers

Article References: Ji, Y., Liu, C., Wu, X., Shi, M., Hu, T., He, J., Wei, Y., Wang, L., & Yu, M. (2026). Resveratrol Pretreatment and Decabromodiphenyl Ethane‐Associated Hepatorenal Changes in a High‐Dose Female Mouse Model: Redox Changes and Ferroptosis‐Associated Markers. Food Science & Nutrition, 14(10), Article e72495. https://doi.org/10.1002/fsn3.72495

Image Credits: AI Generated

DOI: 10.1002/fsn3.72495

Keywords: DBDPE, resveratrol, female mice, hepatotoxicity, renal toxicity, oxidative stress, iron homeostasis, ferroptosis markers, brominated flame retardants, food safety, Pretreatment, Decabromodiphenyl