title: Postnatal exposure to chromium through mother's milk accelerates follicular atresia in F1 offspring through increased oxidative stress and depletion of antioxidant enzymes.
abstract: Hexavalent chromium, CrVI, is a heavy metal endocrine disruptor, known as a mutagen, teratogen, and a group A carcinogen. Environmental contamination with CrVI, including drinking water, has been increasing in more than 30 cities in the United States. CrVI is rapidly converted to CrIII intracellularly, and CrIII can cause DNA strand breaks and cancer or apoptosis through different mechanisms. Our previous study demonstrated that lactational exposure to chromium results in a delay or arrest in follicle development and a decrease in steroid hormone levels in F1 female rats, both of which are mitigated (partial inhibition) by vitamin C. The current study tested the hypothesis that lactational exposure to CrIII accelerates follicle atresia in F1 offspring by increasing reactive oxygen species (ROS) and decreasing cellular antioxidants. Results showed that lactational exposure to CrIII dose-dependently increased follicular atresia and decreased steroidogenesis in postnatal day 25, 45, and 65 rats. Vitamin C mitigated or inhibited the effects of CrIII at all doses. CrIII increased hydrogen peroxide and lipid hydroperoxide in plasma and ovary; decreased the antioxidant enzymes (AOXs) GPx1, GR, SOD, and catalase; and increased glutathione S-transferase in plasma and ovary. To understand the effects of CrVI on ROS and AOXs in granulosa (GC) and theca (TC) cell compartments in the ovary, ROS levels and mRNA expression of cytosolic and mitochondrial AOXs, such as SOD1, SOD2, catalase, GLRX1, GSTM1, GSTM2, GSTA4, GR, TXN1, TXN2, TXNRD2, and PRDX3, were studied in GCs and TCs and in a spontaneously immortalized granulosa cell line (SIGC). Overall, CrVI downregulated each of the AOXs; and vitamin C mitigated the effects of CrVI on these enzymes in GCs and SIGCs, but failed to mitigate CrVI effects on GSTM1, GSTM2, TXN1, and TXN2 in TCs. Thus, these data for the first time reveal that lactational exposure to CrIII accelerated follicular atresia and decreased steroidogenesis in F1 female offspring by altering the ratio of ROS and AOXs in the ovary. Vitamin C is able to protect the ovary from CrIII-induced oxidative stress and follicle atresia through protective effects on GCs rather than TCs.
authors.affiliation: Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Jone A
authors.initials: JA
authors.lastname: Stanley
authors.affiliation: Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Kirthiram K
authors.initials: KK
authors.lastname: Sivakumar
authors.affiliation: Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Thamizh K
authors.initials: TK
authors.lastname: Nithy
authors.affiliation: Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Joe A
authors.initials: JA
authors.lastname: Arosh
authors.affiliation: Department of Physiology, University of Arizona, Tucson, AZ 85724-5051, USA.
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Hoyer
authors.affiliation: Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Burghardt
authors.affiliation: Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA. Electronic address: skbanu@cvm.tamu.edu.
authors.forename: Sakhila K
authors.initials: SK
authors.lastname: Banu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D002857:Chromium / Q000633:toxicity*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D005496:Follicular Atresia / Q000187:drug effects*; D008892:Milk / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011962:Receptors, FSH / Q000235:genetics
chemical_list: D000975:Antioxidants; D011962:Receptors, FSH; D002857:Chromium; C074702:chromium hexavalent ion; D005640:Follicle Stimulating Hormone
keywords: Antioxidants; Atresia; Chromium; Free radicals; Ovary; Reactive oxygen species; Vitamin C