The role of epoxidation in 4-vinylcyclohexene-induced ovarian toxicity

Smith, Bill J.; Mattison, Donald R.; Sipes, I. G.

doi:10.1016/0041-008x(90)90141-g

Cited by 113 publications

(84 citation statements)

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“…A metabolite of VCH, 4-vinylcyclohexene diepoxide (VCD) is used as an industrial diluent for epoxides (IARC, 1976). VCD is ovotoxic and specifically destroys small pre-antral follicles (primordial and primary) in ovaries of rats and mice (Doerr et al, 1995;Smith et al, 1990) by enhancing the natural process of atresia (apoptosis; Springer et al, 1996a,b;Hu et al, 2001a,b). VCH is metabolized in the liver by cytochrome P450 enzyme isoforms, CYP2A and CYP2B (Fontaine et al, 2001a,b).…”

Section: Introductionmentioning

confidence: 99%

Expression of ovarian microsomal epoxide hydrolase and glutathione S-transferase during onset of VCD-induced ovotoxicity in B6C3F1 mice

Keating

Sipes

Hoyer

2008

Toxicology and Applied Pharmacology

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Abstract4-vinylcyclohexene diepoxide (VCD) specifically destroys small pre-antral follicles in the rodent ovary. VCD can be detoxified to an inactive tetrol by microsomal epoxide hydrolase (mEH), or by conjugation to glutathione (GSH) by glutathione S-transferase (GST). Formation of VCD-GSH adducts in the mouse ovary 4 h after VCD exposure (0.57mmol/kg/day) has been demonstrated. Because the mouse ovary expresses both mEH and GST, expression of mEH and GST pi and mu during a time-course of VCD-induced ovotoxicity was evaluated in a neonatal mouse ovarian culture system. Ovaries from postnatal day 4 (PND4) B6C3F 1 mice were incubated with VCD (15μM) for 2, 4, 6, 8, 10, 12, or 15 days. Following incubation, ovaries were histologically evaluated, or assessed for mRNA or protein expression. VCD did not cause follicle loss (P>0.05) on days 2, 4, or 6 of culture. At days 8, 10, 12, and 15, VCD reduced (P<0.05) both primordial and primary follicle numbers. Increased (P<0.05) expression of mEH, GST pi and GST mu mRNA was detected after 4 days of VCD exposure. This expression was reduced on days 6 and 8, when follicle loss was underway, but increased (P<0.05) after 10 days of exposure. mEH and GST pi proteins were elevated (P<0.05) following 8 days of VCD-exposure however there was no increase in GST mu protein.These findings suggest that with continuous exposure to VCD, increased expression of detoxification enzymes may participate in retarding the onset of follicle loss, but that this loss cannot ultimately be prevented.

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Section: Introductionmentioning

confidence: 99%

Expression of ovarian microsomal epoxide hydrolase and glutathione S-transferase during onset of VCD-induced ovotoxicity in B6C3F1 mice

Keating

Sipes

Hoyer

2008

Toxicology and Applied Pharmacology

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“…The results of our early studies demonstrated a greater susceptibility of m ice than rats to these compounds. Although 30 days of intraperitoneal dosing with VCH produced ovarian follicle loss in mice but not in rats, dosing with the diepoxide m etabolite 4-vinylcyclohexene diepoxide (VCD) caused this loss in both species (40). In a number of m etabolic and structure-function studies, it was determ ined that VCD is the ovotoxic form of the parent com pound VCH and that m ice have a signi cantly greater ability to bioactivate VCH than do rats (8, 14, 39 -41).…”

Section: -Vinylcyclohexene and Ovotoxicitymentioning

confidence: 99%

Ovarian Toxicity of 4-Vinylcyclohexene Diepoxide: A Mechanistic Model

Hoyer

Devine

et al. 2001

Toxicol Pathol

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Fem ale m ammals are born with a nite number of ovarian primordial follicles that cannot be regenerated; thus, chemicals that destroy oocytes contained in these follicles can produce prem ature ovarian failure (early menopuas e in women). Exposure of women to know n ovotoxican ts, such as contaminants in cigarette smoke, is associated with early menopause . Thus, the potential risks posed by ovotoxic chemicals is of concern. Our studies have focused on the environmental chemical 4-vinylcyclohexene (VCH), which is produced during the manufacture of rubber tires, ame retardants, insecticides, plasticizers, and antioxidants. Dosing of female rats and mice with the ovotoxic diepoxide metabolite of VCH, 4-vinylcyclohexene diepoxide (VCD), for 30 days destroye d the majority of ovarian primordial follicles. Using VCD in rats as a generalized mode l for ovotoxicity, we determined that 1) repeated daily dosing is required, 2) cell death is via apoptosis, and 3) altered expression of speci c genes is involved. An integrated approach at the morphologic, biochemical, and molecular level was used to support these conclusions. Studies in isolated rat small preantral follicles (targeted for VCD-induced ovotoxicit y) focused on the role of cell death genes, mitochondrion-associated events, and VCD metabolism. We also evaluated how this information relates to human risk for early menopause . These animal research results provide a better understand ing of the potential risk of human exposure to environmental ovarian toxicants and greater insight as to the impact of these toxicants on reproductive health in wom en.

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“…In a previous study, while the administration of neither VCH (800 mg/kg, ip) nor VCM (200 mg/kg, ip) caused testicular deformities in mice, it was ascertained that VCD, which is yet another metabolite of VCH, caused damage to the spermatogonia and spermatocytes (Hooser et al 1995). While VCD administration has been reported to cause ovarian intoxication in female mice and rats as a result of the lysis of germ cells, in the same study, testicular damage was observed in only male mice and not in male rats (Smith et al 1990). The present study was aimed at determining whether intra-testicular CaCl 2 and VCM injections could be used as chemical agents, for the control of reproduction in guinea pigs without any side effects.…”

Section: Introductionmentioning

confidence: 87%

“…In the present study, microscopic examination revealed marked de-generation and necrosis associated with significant hypospermatogenesis in the testicular tissue of the animals included in Group V. On the other hand, different from the results of the present study, Hooser et al (1995) determined that the intraperitoneal administration of VCM to male mice at a dose of 200 mg/kg did not cause testicular deformities. Furthermore, Smith et al (1990) suggested that the observation of different effects in male mice and rats may be due to differences in epoxide formation in the liver. The level of germ cell degeneration caused by CaCl 2 and VCM may be related to the decreased serum concentration of testosterone, which is the prime regulator for the maintenance of the normal physiology and structural morphology of the seminiferous tubules (Tilbrook and Clarke 2001).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of intra-testicular injections of calcium chloride and 4-vinylcyclohexene 1,2 monoepoxide for chemical sterilization in guinea pigs

Şen

Yumuşak

Faúndez³

et al. 2017

Polish Journal of Veterinary Sciences

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This study was aimed at investigating the use of intra-testicular calcium chloride (CaCl 2 ) and 4-vinylcyclohexene 1,2-monoepoxide (VCM) injections as a side effect-free alternative method for the control of reproduction in guinea pigs. Fifty male guinea pigs were randomly assigned to five groups. In all groups, the chemical agents were injected into both testes in 1% lidocaine hydrochloride. While Groups I, II and III were administered with a single dose (0.25 mL) of sterile physiological saline, 15 mg/100 g CaCl 2 , and 240 mg/kg VCM, respectively, Group IV and V received a daily dose of 15 mg/100 g CaCl 2 , and 240 mg/kg VCM for 3 days, respectively. On day 90 post-administration, all animals were weighed and later decapitated under ether anaesthesia. Blood and tissue (testis, liver, hypophysis and adrenal gland) samples were taken. Sperm samples from the cauda epididymis were examined for spermatological parameters. Blood was used for hormone analyses and tissue samples were examined histopathologically (haematoxylin-eosin) and immunohistochemically (Tunel staining). The epididymal sperm count decreased in all treatment groups. Excluding 2 animals, Group V displayed azoospermia. When compared to the control group, Group V displayed the highest prolactin and lowest testosterone levels, and Group III showed the highest testosterone level. Histopathological examination revealed no intoxication finding. Chemical castration with VCM may be a good alternative to surgical castration as it enables mass sterilization without postoperative risks in guinea pig.

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The role of epoxidation in 4-vinylcyclohexene-induced ovarian toxicity

Cited by 113 publications

References 50 publications

Expression of ovarian microsomal epoxide hydrolase and glutathione S-transferase during onset of VCD-induced ovotoxicity in B6C3F1 mice

Expression of ovarian microsomal epoxide hydrolase and glutathione S-transferase during onset of VCD-induced ovotoxicity in B6C3F1 mice

Ovarian Toxicity of 4-Vinylcyclohexene Diepoxide: A Mechanistic Model

Evaluation of intra-testicular injections of calcium chloride and 4-vinylcyclohexene 1,2 monoepoxide for chemical sterilization in guinea pigs

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