Effects of 4-vinylcyclohexene diepoxide on peripubertal and adult Sprague-Dawley rats: ovarian, clinical, and pathologic outcomes.

Young rats treated daily with intraperitoneal 4-vinylcyclohexene diepoxide (VCD) undergo selective destruction of primordial follicles, resulting in gradual ovarian failure resembling the menopausal transition in women. To determine whether VCD has similar effects on ovaries of older rats, adult and peripubertal Sprague-Dawley rats were injected intraperitoneally daily for 30 d with vehicle or VCD at 40 or 80 mg/kg. Body weight, food intake, complete blood counts, and markers of liver injury and renal function were measured during VCD treatment.

Serum antimüllerian hormone predicts ovarian reserve in a monkey model.

Objective: A monkey model of the menopausal transition (perimenopause) would facilitate efforts to understand better the effect of hormonal fluctuations during this life phase on the initiation of chronic diseases associated with the postmenopausal years. Antimüllerian hormone (AMH) is a promising marker of ovarian reserve (primordial follicle number) in women. Here, we describe the relationship between AMH and ovarian reserve in cynomolgus monkeys (Macaca fascicularis) estimated to be 12 to 15 years of age (approximately 36-45 y in women).

Steroidogenic capacity of residual ovarian tissue in 4-vinylcyclohexene diepoxide-treated mice.

Menopause is an important public health issue because of its association with a number of disorders. Androgens produced by residual ovarian tissue after menopause could impact the development of these disorders. It has been unclear, however, whether the postmenopausal ovary retains steroidogenic capacity.

Involvement of the KIT/KITL signaling pathway in 4-vinylcyclohexene diepoxide-induced ovarian follicle loss in rats.

Repeated daily dosing of rats with the occupational chemical 4-vinylcyclohexene diepoxide (VCD) depletes the ovary of primordial and primary follicles through an increase in the natural process of atresia. Additionally, in vitro exposure of Postnatal Day 4 (PND 4) rat ovaries to VCD causes similar follicular depletion. This study was designed to investigate survival signaling pathways that may be associated with VCD-induced ovotoxicity in small preantral follicles.

Comparison of skeletal effects of ovariectomy versus chemically induced ovarian failure in mice.

Bone loss associated with menopause leads to an increase in skeletal fragility and fracture risk. Relevant animal models can be useful for evaluating the impact of ovarian failure on bone loss. A chemically induced model of menopause in which mice gradually undergo ovarian failure yet retain residual ovarian tissue has been developed using the chemical 4-vinylcyclohexene diepoxide (VCD).

Drinking water with uranium below the U.S. EPA water standard causes estrogen receptor-dependent responses in female mice.

Background: The deleterious impact of uranium on human health has been linked to its radioactive and heavy metal-chemical properties. Decades of research has defined the causal relationship between uranium mining/milling and onset of kidney and respiratory diseases 25 years later.

Objective: We investigated the hypothesis that uranium, similar to other heavy metals such as cadmium, acts like estrogen.

Effects of impending ovarian failure induced by 4-vinylcyclohexene diepoxide on fertility in C57BL/6 female mice.

Repeated daily dosing of mice with 4-vinylcyclohexene diepoxide (VCD) causes a gradual onset of ovarian failure, providing a model for perimenopause. Because increasing numbers of women are delaying starting a family, infertility in aging women is of concern. This study was designed to determine the effects of impending ovarian failure on fertility in VCD-treated mice.

Destruction of primordial ovarian follicles in adult cynomolgus macaques after exposure to 4-vinylcyclohexene diepoxide: a nonhuman primate model of the menopausal transition.

Objective: To determine whether the 4-vinylcyclohexene diepoxide (VCD)-treated mouse menopause model, which involves accelerated atresia of primordial follicles and induces gradual ovarian failure (while sparing the ovarian stroma), can be adapted to nonhuman primates.

Design: Controlled periclinical trial (nonhuman primates).

Setting: Comparative Medicine Clinical Research Center.

Effect of duration of dosing on onset of ovarian failure in a chemical-induced mouse model of perimenopause.

Objective: Repeated daily dosing with 4-vinylcyclohexene diepoxide (VCD) causes gradual ovarian failure in mice. As a result, the animal undergoes ovarian failure, but retains residual ovarian tissue. The purpose of this study was to use a mouse model to regulate the induction of a period analogous to perimenopause in women.

Effect of bcl-2 overexpression in mice on ovotoxicity caused by 4-vinylcyclohexene.

The occupational chemical 4-vinylcyclohexene (VCH) destroys small preantral ovarian follicles in mice following repeated daily dosing. The cell survival gene bcl-2 is thought to protect against follicular death during embryogenesis because primordial follicle numbers in newborn bcl-2 overexpressing (OE) mice are greater than in wild-type (WT) controls. Thus, this study was designed to determine if overexpression of bcl-2 protects against VCH-induced follicle loss during embryonic development.

Characterization of cyclicity and hormonal profile with impending ovarian failure in a novel chemical-induced mouse model of perimenopause.

4-Vinylcyclohexene diepoxide (VCD) causes early, gradual ovarian failure in mice because it specifically targets small pre-antral ovarian follicles. The period between loss of these follicles and ovarian failure is analogous to perimenopause in women. We sought to characterize the period of onset of ovarian failure in VCD-treated mice in regard to estrous cycle length and hormonal changes.

Differences between rats and mice in the involvement of the aryl hydrocarbon receptor in 4-vinylcyclohexene diepoxide-induced ovarian follicle loss.

Repeated dosing with the occupational chemical 4-vinylcyclohexene diepoxide (VCD) selectively depletes small pre-antral follicles in the ovaries of rats and mice via apoptosis. The aryl hydrocarbon receptor (AhR) plays a role in mediating the effects of several xenobiotics. Therefore, this study was designed to investigate a potential role of the AhR in VCD-induced ovotoxicity.

Expression and activity of cytochromes P450 2E1, 2A, and 2B in the mouse ovary: the effect of 4-vinylcyclohexene and its diepoxide metabolite.

4-Vinylcyclohexene (VCH), an occupational chemical, causes destruction of small preantral follicles (F1) in mice. Previous studies suggested that VCH is bioactivated via cytochromes P450 (CYP450) to the ovotoxic, diepoxide metabolite, VCD. Whereas hepatic CYP450 isoforms 2E1, 2A, and 2B can metabolize VCH, the role of ovarian metabolism is unknown.

Long-term effects of ovarian follicular depletion in rats by 4-vinylcyclohexene diepoxide.

4-Vinylcyclohexene diepoxide (VCD) destroys preantral ovarian follicles in rats. Female 28-day Fisher 344 (F344) rats were dosed (30 days) with VCD (80 mg/kg per day, i.p.

Expression and activity of microsomal epoxide hydrolase in follicles isolated from mouse ovaries.

Microsomal epoxide hydrolase (mEH) is involved in the detoxification of xenobiotics that are or can form epoxide metabolites, including the ovotoxicant, 4-vinylcyclohexene (VCH). This industrial chemical is bioactivated by hepatic CYP450 to the diepoxide metabolite, VCD, which destroys mouse small preantral follicles (F1). Since ovarian mEH may play a role in VCD detoxification, these studies investigated the expression and activity of mEH in isolated ovarian fractions.