title: Identifying a novel role for X-prolyl aminopeptidase (Xpnpep) 2 in CrVI-induced adverse effects on germ cell nest breakdown and follicle development in rats.
abstract: Environmental exposure to endocrine-disrupting chemicals (EDCs) is one cause of premature ovarian failure (POF). Hexavalent chromium (CrVI) is a heavy metal EDC widely used in more than 50 industries, including chrome plating, welding, wood processing, and tanneries. Recent data from U.S. Environmental Protection Agency indicate increased levels of Cr in drinking water from several American cities, which potentially predispose residents to various health problems. Recently, we demonstrated that gestational exposure to CrVI caused POF in F1 offspring. The current study was performed to identify the molecular mechanism behind CrVI-induced POF. Pregnant rats were treated with 25 ppm of potassium dichromate from Gestational Day (GD) 9.5 to GD 14.5 through drinking water, and the fetuses were exposed to CrVI through transplacental transfer. Ovaries were removed from the fetuses or pups on Embryonic Day (ED) 15.5, ED 17.5, Postnatal Day (PND) 1, PND 4, or PND 25, and various analyses were performed. Results showed that gestational exposure to CrVI: 1) increased germ cell/oocyte apoptosis and advanced germ cell nest (GCN) breakdown; 2) increased X-prolyl aminopeptidase (Xpnpep) 2, a POF marker in humans, during GCN breakdown; 3) decreased Xpnpep2 during postnatal follicle development; and 4) increased colocalization of Xpnpep2 with Col3 and Col4. We also found that Xpnpep2 inversely regulated the expression of Col1, Col3, and Col4 in all the developmental stages studied. Thus, CrVI advanced GCN breakdown and increased follicle atresia in F1 female progeny by targeting Xpnpep2.
authors.affiliation: Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas skbanu@cvm.tamu.edu.
authors.forename: Sakhila K
authors.initials: SK
authors.lastname: Banu
authors.affiliation: Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas.
authors.forename: Jone A
authors.initials: JA
authors.lastname: Stanley
authors.affiliation: Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas.
authors.forename: Kirthiram K
authors.initials: KK
authors.lastname: Sivakumar
authors.affiliation: Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas.
authors.forename: Joe A
authors.initials: JA
authors.lastname: Arosh
authors.affiliation: Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas.
authors.forename: Rola
authors.initials: R
authors.lastname: Barhoumi
authors.affiliation: Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Burghardt
mesh_terms: D000626:Aminopeptidases / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002274:Carcinogens, Environmental / Q000009:adverse effects / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002857:Chromium / Q000009:adverse effects* / Q000494:pharmacology*; D024042:Collagen Type I / Q000502:physiology; D024061:Collagen Type III / Q000502:physiology; D024141:Collagen Type IV / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005496:Follicular Atresia / Q000187:drug effects / Q000502:physiology; D005498:Follicular Phase / Q000187:drug effects* / Q000502:physiology; D010053:Ovary / Q000187:drug effects / Q000502:physiology; D010063:Ovum / Q000187:drug effects* / Q000502:physiology; D011247:Pregnancy; D016649:Primary Ovarian Insufficiency / Q000139:chemically induced* / Q000503:physiopathology*; D051381:Rats
chemical_list: D002274:Carcinogens, Environmental; D024042:Collagen Type I; D024061:Collagen Type III; D024141:Collagen Type IV; D002857:Chromium; C074702:chromium hexavalent ion; D000626:Aminopeptidases; C022750:X-Pro aminopeptidase
keywords: Xpnpep2; chromium; collagen; follicle atresia; follicle maturation; germ cell nest breakdown; oocyte; ovary; premature ovarian failure; primordial follicle