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Ovotoxic Environmental Chemicals: Indirect Endocrine Disruptors
Published in Rajesh K. Naz, Endocrine Disruptors, 2004
Patrick J. Devine, Patricia B. Hoyer
Such increases in circulating FSH levels have been observed in long-term studies in both female mice and rats treated with the occupational chemicals, 4-vinylcyclohexene (VCH) and its ovotoxic metabolite, 4-vinylcyclohexene diepoxide, respectively, for 30 days (age 28 to 58 days) and then observed for up to 1 year.[27,29] In spite of a selective loss of the majority of primordial and primary follicles measured by 30 days, FSH levels were only increased above control animals at 240 days in mice and 120 days in rats. This corresponded with a time point at which numbers of antral follicles were significantly decreased in the rat.[29] Therefore, ovarian changes preceded the rise in circulating FSH levels. In spite of such ovarian damage, vaginal cytology still displayed evidence of ovarian cyclicity in VCH-treated mice at 240 days. By 360 days (from the onset of 30 days of dosing), unlike control animals, treated animals of both species displayed complete ovarian failure, as determined by increased circulating levels of FSH, loss of estrous cyclicity, the complete absence of ovarian follicular or luteal structures, and marked ovarian atrophy. Furthermore, at 360 days there was histological evidence of pre-neoplastic changes in ovaries of treated mice. From these studies, it was concluded that the ovarian failure and pre-neoplastic changes that occur long after cessation of chemical exposure are indirect consequences resulting from the depletion of small, pre-antral follicles.
Bu-Shen-Ning-Xin decoction alleviates premature ovarian insufficiency (POI) by regulating autophagy of granule cells through activating PI3K/AKT/mTOR pathway
Published in Gynecological Endocrinology, 2022
Xiaoqing Dou, Xin Jin, Xingbei Chen, Qun Zhou, Hanyu Chen, Mingxiao Wen, Wenjun Chen
Seventy-two female 21-day SD rats were divided into 6 groups randomly: control, POI, Low BSNXD + POI, Mid BSNXD + POI, High BSNXD + POI, and Progynova + POI (n = 12/group). Rats in the control group were dosed with 2.5 mL/kg sesame oil (i.p) per day for 15 days, followed by orally administered with normal saline for a consecutive 45 days. The animals in the POI group were dosed with 80 mg/kg 4-vinylcyclohexene diepoxide (VCD, i.p) per day for 15 days, followed by orally administered with normal saline for a consecutive 45 days. In the Low BSNXD + POI group, Mid BSNXD + POI, and High BSNXD + POI groups, animals were dosed with 80 mg/kg VCD (i.p) per day for 15 days, followed by administered intragastrically with 3.74 g/(kg·d), 7.47 g/(kg·d), and 14.5 g/(kg·d) BSNXD for a consecutive 45 days, respectively. In the Progynova + POI group, animals were dosed with 80 mg/kg VCD per day for 15 days, followed by dosed intragastrically with 0.13 mg/(kg·d) Progynova for a consecutive 45 days, which was taken as the positive control. VCD was dissolved in 2.5 mL/kg sesame oil. Serum was achieved from each animal after anesthesia using 3 mL/kg chloral hydras, followed by oophorectomy. Part of the ovarian tissues was fixed in 10% formaldehyde for HE staining and 2.5% glutaraldehyde for the transmission electron microscope, while the rest was stored for molecular experiments. Animals were sacrificed by CO2 inhalation at the end of the experiments.
Timing of hormone therapy and its association with cardiovascular risk and metabolic parameters in 4-vinylcyclohexene diepoxide-induced primary ovarian insufficiency mouse model
Published in Gynecological Endocrinology, 2023
Hyun Joo Lee, Min Jung Park, Jeong-Doo Heo, Bo Sun Joo, Jong Kil Joo
The summarized study design and group classification are demonstrated in Table 1 and Figure 1(A). First, in order to induce ovarian failure, mice were weighed and administered via intra-peritoneal (IP) injections of 4-vinylcyclohexene diepoxide (VCD) (V3630; Sigma Aldrich, St Louis, MO, USA), in sesame oil as solvent, at a dose of 160 mg/kg/day using a dosing standard of 2.5 ml/kg/day for the first 15 consecutive days, as previously established [14]. After the establishment of POI mouse model with the 15-day injection period of VCD, serum anti-Müllerian hormone (AMH), and FSH levels were measured, and the results confirmed POI status of the VCD-treated mice, as shown in Figure 1(B). Afterward, 10 mice were randomly selected as controls with continuing normal diet and no intervention such as E2 treatment, and the remaining 40 mice were switched from the normal diet to high-fat diet (HFD) as the intervention group in order to exacerbate metabolic and cardiovascular risks along with the estrogen deprivation. Mice in the intervention group were further randomized into four groups: no estradiol treatment group (NT); treatment group 1 with delayed estradiol treatment for 3 weeks (T1); treatment group 2 with on-time estradiol treatment for 6 weeks (T2); treatment group 3 with on-time estradiol treatment lasted for 3 weeks and paused (T3). As the repletion of estradiol, 17β-estradiol (E2; Sigma Aldrich, St. Louis, MO, USA) was dissolved in sesame oil and was administered orally at a dose of 0.2 mg/kg/day according to the study protocol described in Table 1 and Figure 1. For NT, 0.1 ml of sesame oil was treated as vehicle control.
Effects of dehydroepiandrosterone supplementation on mice with diminished ovarian reserve
Published in Gynecological Endocrinology, 2018
Xiufeng Lin, Jing Du, Yan Du, Riran Wu, Xiaowu Fang, Yuechan Liao, Song Quan
Dehydroepiandrosterone (DHEA), one of the important steroid substances, is mainly secreted by adrenal cortex and identified as a precursor of testosterone and estradiol in the peripheral circulation[3]. The accumulated evidences have shown DHEA supplement during IVF cycle can improve the outcome of pregnancy, especially in patients with DOR. Comparing the parameters of patients with DOR before and after IVF, the researchers found that the embryo numbers and grades were significantly elevated after DHEA treatment [4]. As a result, DHEA could increase the pregnancy rate and decrease the miscarriage rate [5–7]. However, the conclusions on DHEA treatment to the patients with DOR were still controversial because large-scale, well-designed studies were still lacking. To further evaluate the effect of DHEA on DOR, ovarian reserve markers such as anti-Mullerian hormone (AMH), inhibin-B and antral follicle count were detected and significant changes were observed [8]. However, some trials also reported no significant changes in serum AMH and FSH levels. In order to identify the function and mechanism of DHEA supplement, several vivo models have been induced to DOR for further investigations. Rats with 4-vinylcyclohexene diepoxide application could induce DOR and DHEA administration resulted in a larger follicular pool. The analysis on ovary tissue sections showed that decreased atresia might be one of the possible effects of DHEA in DOR rats [9]. However, the hormone parameters have not been well detected in vivo. Similar study was also carried in the in vivo ovine models and the findings suggested that the effects of DHEA on follicle development may be mediated in part by regulating AMH expression [10].