CYP11A1
Cholesterol side-chain cleavage enzyme, mitochondrial precursor (EC 1.14.15.6) (CYPXIA1) (Cholesterol desmolase) (Cytochrome P450 11A1) (Cytochrome P450(scc)) [CYP11A]
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Perfluoroalkyl acids (PFAAs) are widely used in industrial and commercial products and possess endocrine disrupting properties. Perfluorononanoic acid (PFNA), one of PFAAs, has been mainly reported to produce testicular toxicity in adult animals. The objective of the present study was to examine the effect of acute exposure of PFNA to prepubertal male Parkes (P) mice on spermatogenesis and testicular steroidogenesis, and to study the possible mechanism(s) of its action. PFNA (2 and 5 mg/kg) was orally administered to male P mice for 14 days from postnatal day 25-38. Histologically, testis in PFNA-treated mice showed non-uniform diverse degenerative changes in the seminiferous tubules; both normal and affected tubules were seen in the same testicular sections. The treatment caused a reduction in intra-testicular and serum testosterone levels accompanied by a decrease in testicular expression of SF1, StAR, CYP11A1, and 3β- and17β-HSD. Further, the activity of antioxidant enzymes and expression of Nrf2 and HO-1 in the testis were markedly decreased, while the level of lipid peroxidation and expression of IKKβ, NF-κB and caspase-3 were significantly increased in testis of PFNA-treated mice. There was also a decrease in PCNA expression and in PCNA-index and an increase in TUNEL-positive germ cells in testes of PFNA-treated mice. In conclusion, the results suggest that PFNA exposure to prepubertal male mice altered antioxidant enzymes activity and Nrf2-HO-1 signaling, leading to oxidative stress and a decrease in testosterone biosynthesis in the testis; these changes, in turn, caused increased apoptosis and decreased proliferation of germ cells, thereby suppression of spermatogenesis.
MeSH Terms
- Aging
- Animals
- Antioxidants
- Endocrine Disruptors
- Fluorocarbons
- Male
- Mice
- Oxidative Stress
- Signal Transduction
- Spermatogenesis
- Testis
- Testosterone
Keywords
- Oxidative stress
- Perfluorononanoic acid
- Prepuberty
- Spermatogenesis
- Steroidogenesis
The ovary is a structurally dynamic organ that alters with age. Modifications in the paracrine status influence the capacity of aging oocytes to develop normal embryos. Despite the importance of understanding the cellular and molecular mechanism involved in the process of ovarian aging, histological changes remain poorly understood. Correlating the process of folliculogenesis and somatic cell function during ovarian aging is essential to explain the reproductive decline of aged mammalian species, including humans. Here, we performed a morphological and immunohistological study on the ovaries of chinchilla rabbits that varied in age from one to 34-months. The spatiotemporal expression of the cholesterol side-chain cleavage cytochrome P450scc (CYP11A) and the smooth muscle actin (SMA) were analyzed. A significant histological rearrangement of immunodetected cells in theca interna, theca externa and the interstitial tissue around the follicles occurred. The expression of CYP11A1 decreased considerably in antral follicles of aging ovaries. Moreover, we found that the secondary interstitial gland developed extensively, and a remarkable rearrangement of the surface epithelium occurred in aging ovaries. In contrast to ovaries during the reproductive period, the immunohistological changes demonstrate that the interstitial gland became the most abundant tissue during the aging of ovaries. Thus, the current study provides new data for understanding the alteration of somatic cell function in elderly ovaries and how this affects their declined fertility.
MeSH Terms
- Actins
- Aging
- Animals
- Cholesterol Side-Chain Cleavage Enzyme
- Epithelium
- Female
- Oocytes
- Ovarian Follicle
- Ovary
- Rabbits
- Theca Cells
Reactive oxygen species (ROS) produced in biological reactions have been shown to contribute to ovarian aging. Peroxiredoxin 2 (Prx2) is an antioxidant enzyme that protects cells by scavenging ROS; however, its effect on age-related, oxidative stress-associated ovarian failure has not been reported. Here, we investigated its role in age-related ovarian dysfunction and 4-vinylcyclohexene diepoxide (VCD)-induced premature ovarian failure using Prx2-deficient mice. Compared to those in wildtype (WT) mice, serum levels of anti-Müllerian hormone, 17β-estradiol, and progesterone and numbers of follicles and corpora lutea were significantly lower in 18-month-old Prx2 mice. Moreover, levels of Bax, cytochrome c, cleaved caspase-3, and phosphorylated JNK proteins were higher and numbers of apoptotic (terminal deoxynucleotidyl transferase dUTP nick end labeling-positive) cells were considerably greater in 18-month-old Prx2 ovaries than WT ovaries. Furthermore, the effects of the ovarian toxicant VCD in significantly enhancing ROS levels and apoptosis through activation of JNK-mediated apoptotic signaling were more pronounced in Prx2 than WT mouse embryonic fibroblasts. Expression of the steroidogenic proteins StAR, CYP11A1, and 3β-HSD and serum levels of 17β-estradiol and progesterone were also reduced to a greater extent in Prx2 mice than WT mice after VCD injection. This reduced steroidogenesis was rescued by addition of the Prx mimic ebselen or JNK inhibitor SP600125. This constitutes the first report that Prx2 deficiency leads to acceleration of age-related or VCD-induced ovarian failure by activation of the ROS-induced JNK pathway. These findings suggest that Prx2 plays an important role in preventing accelerated ovarian failure by inhibiting ROS-induced JNK activation.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Carcinogens
- Corpus Luteum
- Cyclohexenes
- Female
- MAP Kinase Signaling System
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Ovarian Diseases
- Ovarian Follicle
- Oxidative Stress
- Peroxiredoxins
- Reactive Oxygen Species
- Signal Transduction
- Vinyl Compounds
Keywords
- 4-vinylcyclohexene diepoxide
- Aging
- Ovarian failure
- Oxidative stress
- Peroxiredoxin 2
Current studies have revealed that aging is a negative factor that suppresses granulosa cell functions and causes low fertility in women. However, the difference in gene expression between normal and aging granulosa cells remains undefined. Therefore, the aim of this study was to investigate the gene expression profiles of granulosa cells during aging. Granulosa cells from young healthy porcine ovaries were aged [i]in vitro[/i] by prolonging the culture time (for 48h). First, the extracellular ultrastructure was observed by scanning electron microscopy followed by RNA-seq and KEGG pathway analysis. The results showed that the extracellular ultrastructure was significantly altered by aging; cell membranes were rough, and cavitations were found. Moreover, the formations of filopodia were greatly reduced. RNA-seq data revealed that 3411 genes were differentially expressed during aging, of which 2193 genes were up-regulated and 1218 genes were down-regulated. KEGG pathway analysis revealed that 25 pathways including pathway in cancer, PI3K-Akt signaling pathway, focal adhesion, proteoglycans in cancer, and cAMP signaling pathway were the most changed. Moreover, several high differentially expressed genes (CEBPB, CXCL12, ANGPT2, IGFBP3, and BBOX1) were identified in aging granulosa cells, The expressions of these genes and genes associated with extracellular matrix remodeling associated genes (TIMP3, MMP2, MMP3, and CTGF), energy metabolism associated genes (SLC2A1, PPARγ) and steroidogenesis associated genes (StAR, CYP11A1 and LHCGR) were confirmed by quantitative PCR. This study identifies the differently changed pathways and their related genes, contributes to the understanding of aging in granulosa cells, and provides an important foundation for further studies.
Keywords
- Gerotarget
- RNA-seq
- aging
- gene expression
- granulosa cell
- porcine
Individual and combined toxicities of endosulfan (ENDO) with phenanthrene (PHE) were evaluated using zebrafish (Danio rerio) adults. The 96-h LC values for ENDO and PHE were 4.6 μg L and 920 μg L , respectively. To evaluate the mixture toxicity, LC and LC concentrations were grouped into four combinations as ENDO-LC PHE-LC , ENDO-LC PHE-LC , ENDO-LC PHE-LC , and ENDO-LC PHE-LC , and their acute toxicities were determined. The combination of LC -ENDO and LC -PHE exhibited a synergistic effect. In addition, acetylcholinesterase activity decreased in zebrafish bodies exposed to ENDO with or without PHE. Combined treatments induced higher glutathione S-transferase activity compared to individual treatments. Carboxylesterase activity increased in both heads and bodies of ENDO-treated fishes compared with PHE-treated fishes. Using RT-qPCR technique, CYP1A gene expression significantly up-regulated in all combinations, whereas CYP3A was unchanged, suggesting that enzymes involved in defense may play different roles in the detoxification. CYP7A1 gene responsible for bile acid biosynthesis is dramatically down-regulated after exposure to the synergistic combination exposure, referring that the synergistic effect may be resulted from the reduction of bile production in zebrafishes. Among gender-related genes, CYP11A1 and CYP17A1 genes in female zebrafish decreased after treatment with ENDO alone and combination of LC -ENDO and LC -PHE. This might be related to a reduction in cortisol production. The overall results indicated that ENDO and PHE were toxic to zebrafish adults both individually and in combination, and that their co-presence induced changes in the expression of genes responsible for metabolic processes and defense mechanisms.
MeSH Terms
- Acetylcholinesterase
- Aging
- Animals
- Carboxylesterase
- Cytochrome P-450 Enzyme System
- Drug Synergism
- Endosulfan
- Female
- Glutathione Transferase
- Insecticides
- Male
- Phenanthrenes
- Water Pollutants, Chemical
- Zebrafish
Keywords
- Endosulfan
- Enzyme activity
- Gene expression
- Mixture toxicity
- Phenanthrene
- Zebrafish
Developmental and aging changes in testicular factors related to steroidogenesis are unknown in dogs. Using reverse transcription quantitative real-time PCR, this study examined testicular mRNA levels of CYP11A1 (P450 cholesterol side-chain cleavage enzyme, P450scc), CYP17A1 (P450 17α-hydroxylase/C17-20 lyase, P450c17), HSD3B2 (3β-hydroxysteroid dehydrogenase, 3β-HSD), CYP19A (P450 aromatase, P450arom), STAR (steroidogenic acute regulatory protein, StAR), cyclooxygenase (COX) -1 and COX-2 in prepubertal (4-6 months of age), postpubertal (1 year of age), and aging (2-18 years of age) dogs. Testicular mRNA levels for P450scc, 3β-HSD, StAR, COX-1, and COX-2 did not change from prepubertal to postpubertal stages, whereas that for P450arom markedly and abruptly increased and that for P450c17 gradually decreased. In postpubertal and aging dogs, a negative correlation was found between aging and testicular P450arom mRNA levels. Based on the rapid testicular growth observed during puberty, these results suggested that total testis gene expression for steroidogenesis-related factors, in particular for P450arom, increases during puberty in dogs. In addition, the decline in P450arom gene expression during aging may affect the ability to synthesize steroids in canine testes.
MeSH Terms
- 3-Hydroxysteroid Dehydrogenases
- Aging
- Animals
- Aromatase
- Cholesterol Side-Chain Cleavage Enzyme
- Cyclooxygenase 1
- Cyclooxygenase 2
- Dogs
- Gene Expression Regulation, Developmental
- Male
- Phosphoproteins
- RNA, Messenger
- Steroid 17-alpha-Hydroxylase
- Testis
Keywords
- Aging
- Dog
- Puberty
- Steroidogenesis
- Testis