Protective Role for Ovarian Glutathione S-transferase Isoform Pi During 7,12-dimethylbenz[a]anthracene-induced Ovotoxicity

Overview

Journal Toxicol Appl Pharmacol

Specialties Pharmacology
Toxicology

Date 2012 Mar 13

PMID 22406437

Citations 12

Authors

Poulomi Bhattacharya

Aileen F Keating

Affiliations

Soon will be listed here.

Abstract

7,12-Dimethylbenz[a]anthracene (DMBA) destroys ovarian follicles at all developmental stages. This study investigated a role for the glutathione S-transferase (Gst) isoforms alpha (a), mu (m) and pi (p) and the transcription factors, Ahr and Nrf2, during DMBA-induced ovotoxicity, and their regulation by phosphatidylinositol-3 kinase (PI3K) signaling. Negative regulation of JNK by GSTP during DMBA exposure was also studied. Post-natal day (PND) 4 Fischer 344 rat ovaries were exposed to vehicle control (1% DMSO)±DMBA (1 μM) or vehicle control (1% DMSO)±LY294002 (PI3K inhibitor; 20 μM) for 1, 2, 4, or 6 days. Total RNA or protein was isolated, followed by RT-PCR or Western blotting to determine mRNA or protein level, respectively. Immunoprecipitation using an anti-GSTP antibody was performed to determine interaction between GSTP and JNK, followed by Western blotting to determine JNK and p-c-Jun protein level. DMBA had no impact on Gsta, Gstm or Nrf2 mRNA level, but increased Gstp mRNA and protein after 2 days. Ahr mRNA and protein increased after 2 and 4 days of DMBA exposure, respectively and DMBA increased NRF2 protein level after 4 days. JNK bound to GSTP was increased during DMBA exposure, with a concomitant decrease in unbound JNK and p-c-Jun. Ahr and Gstp mRNA were decreased (2 days) and increased (4 days) by PI3K inhibition, while Gstm mRNA increased (P<0.05) after both time points, and there was no effect on Nrf2 mRNA. PI3K inhibition increased AHR, NRF2 and GSTP protein level. These findings support involvement of ovarian GSTP during DMBA exposure, and indicate a regulatory role for the PI3K signaling pathway on ovarian xenobiotic metabolism gene expression.

Citing Articles

Diet-induced obesity alters the ovarian chemical biotransformation and oxidative stress response proteins both basally and in response to 7,12-dimethylbenz[a]anthracene exposure.

Timme K, Inyang I, White H, Keating A Toxicol Sci. 2025; 204(1):9-19.

PMID: 39910959 PMC: 11879017. DOI: 10.1093/toxsci/kfae150.

High fat diet-induced obesity and gestational DMBA exposure alter folliculogenesis and the proteome of the maternal ovary†.

Novbatova G, Fox I, Timme K, Keating A Biol Reprod. 2024; 111(2):496-511.

PMID: 38813940 PMC: 11327317. DOI: 10.1093/biolre/ioae070.

Zearalenone exposure differentially affects the ovarian proteome in pre-pubertal gilts during thermal neutral and heat stress conditions.

Roach C, Mayorga E, Baumgard L, Ross J, Keating A J Anim Sci. 2024; 102.

PMID: 38666409 PMC: 11217906. DOI: 10.1093/jas/skae115.

Maternal pre-conceptional glyphosate exposure impacts the offspring hepatic and ovarian proteome.

Novbatova G, Timme K, Severin A, Sayadi M, Keating A Toxicol Sci. 2023; 194(1):23-37.

PMID: 37208198 PMC: 10306405. DOI: 10.1093/toxsci/kfad047.

Ovarian mitochondrial and oxidative stress proteins are altered by glyphosate exposure in mice.

Ganesan S, Keating A Toxicol Appl Pharmacol. 2020; 402:115116.

PMID: 32634520 PMC: 8500330. DOI: 10.1016/j.taap.2020.115116.

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