Tag Archives: toxicology

Methoxychlor-Induced Atresia: DISCUSSION(5)

The doses and duration of dosing in these previous studies were greater than those used in this study. Furthermore, the authors of the previous studies suggested that the effects of MXC on gonadotropins might be a secondary effect due to ovarian atrophy. In other studies of female CD-1 mice, the effects of MXC on female reproduction were speculated to be due to estrogen mimicry and/ or damage to the hypothalamic-pituitary-ovarian axis. These studies, however, did not include measurements of estradiol, FSH, or LH. It appears from the results of our study that the increase in atresia and the decline in healthy antral follicles observed after MXC treatment are not due to a decrease in estradiol, FSH, or LH.

Methoxychlor-Induced Atresia: DISCUSSION(4)

 DISCUSSION(4)

Regarding the effect of MXC on hormonal parameters, MXC-induced atresia did not result in changes in estradiol, FSH, or LH, hormones known to be important antiapoptotic factors in follicles. In spite of the decline in antral follicles that we observed in mice treated with MXC, we did not see a difference in estradiol levels between the sesame oil- and MXC-treated mice. This was initially surprising because antral follicles are a major producer of estradiol, but there may be several explanations for this finding. canadian neighbor pharmacy

Methoxychlor-Induced Atresia: DISCUSSION(3)

There has been little work in vivo investigating the effects of pesticides on Bcl-2 family members and none, to our knowledge, investigating the effects of MXC on Bcl-2 family members in the ovary. Still, some studies have looked at other chemicals, and previous studies conducted in Bax-deficient mouse models found some protection from toxicant-induced apoptosis in primordial follicles and oocytes. For example, Takai et al. found that Bax-deficient mice were partially protected by the effects of the industrial chemical and primordial follicle toxicant, 4-vinylcyclo-hexene diepoxide.

Methoxychlor-Induced Atresia: DISCUSSION(2)

DISCUSSION(2)

That is, we may have captured the follicles in the process of dying but prior to their complete death and removal. It is likely, however, that the increased atresia in MXC-treated wild-type mice will eventually lead to complete death/removal of antral follicles and thus a reduced number of antral follicles because previous work indicates that it is not possible to rescue atretic follicles in vivo or in vitro.

Methoxychlor-Induced Atresia: DISCUSSION(1)

We have previously shown that MXC increases the percentage of atretic antral follicles and reduces the number of antral follicles in the mouse ovary; however, to our knowledge, these are the first experiments to show that the mechanism through which MXC induces atresia involves the Bcl-2 pathway. Specifically, the results of our study suggest Bax protein plays an important role in MXC-in-duced atresia, for we saw increased expression of Bax in the ovaries of MXC-treated CD-1 mice compared with the sesame oil-treated mice.

Methoxychlor-Induced Atresia: RESULTS(5)

RESULTS(5)Effect of MXC on Estradiol, FSH, and LH Levels

After 20 days of dosing, there were no differences in estradiol levels between sesame oil-treated mice and mice dosed with 8, 16, 32, or 64 mg kg-1 day-1 MXC (Fig. 6A; n = 6-9, P = 0.74). FSH levels also did not differ between sesame oil-treated mice and mice treated with 8, 16, 32, or 64 mg kg-1 day-1 MXC (Fig. 6B; n = 6-9; P = 0.39). Finally, LH levels were unchanged between sesame oil-treated mice and those treated with 32 mg kg-1 day-1 MXC (Fig. 6C; n = 3; P = 0.2). my canadian neighbor pharmacy

Methoxychlor-Induced Atresia: RESULTS(4)

Effect of MXC on the Ovaries of Mice Deficient in Bax Protein

In wild-type mice treated with MXC (64 mg kg-1 day-1 for 20 days), there was a significant increase in the percentage of atretic follicles compared with sesame oil-treated counterparts (73% atretic follicles in the MXC-treated wild-type mice vs. 49% in the sesame oil-treated wild-type mice; Fig. 5; n = 3-5; P < 0.0001). In BaxKO mice, however, MXC was unable to increase the percentage of atretic follicles (31% atretic follicles in the MXC-treated BaxKO vs. 27% in the sesame oil-treated BaxKO mice; Fig. 5; n = 35; P = 0.5).

Methoxychlor-Induced Atresia: RESULTS(3)

RESULTS(3)

Effect of MXC on the Ovaries of Mice That Overexpress Bcl-2 Protein

In wild-type mice, MXC (64 mg kg-1 day-1 for 20 days) significantly increased the percentage of atretic follicles compared with controls (Fig. 4). Wild-type mice treated with MXC had 59% atretic follicles, whereas wild-type mice treated with sesame oil had 43% atretic follicles (Fig. 4A; n = 8; P < 0.03). In Bcl-2 overexpressing mice, MXC was unable to significantly increase the percentage of atretic follicles compared with the sesame oil-treated Bcl-2 overexpressing mice. MXC-treated Bcl-2 overexpressing mice had 48% atretic follicles and sesame oil-treated Bcl-2 overexpressing mice had 50% atretic follicles (Fig. 4A; n = 7; P = 0.7).

Methoxychlor-Induced Atresia: RESULTS(2)

Effect of MXC on Bcl-2 and Bax Levels

Using immunohistochemical analysis, Bcl-2 staining was found in the oocyte, granulosa, and thecal cells of the follicles in sesame oil- and MXC-treated ovaries. MXC (64 mg kg—1 day1 for 20 days) did not affect the expression of Bcl-2 in the antral follicles of the ovary. There was no difference with regard to follicle staining whether the follicles were healthy or atretic. Small (primordial and primary) follicles were unstained, although staining was present in some larger preantral follicles (Fig. 2, A-D). Image analysis confirmed there was no difference in staining in either the granulosa or thecal cell layers between the sesame oil- and MXC-treated ovaries (n = 3, P = 0.5).

Methoxychlor-Induced Atresia: RESULTS(1)

RESULTS(1)

Effect of MXC on Atresia in CD-1 Mice

MXC caused a dose-dependent increase in the percentage of atretic antral follicles compared with controls at the 32 mg/kg dose (72% atretic follicles with MXC treatment compared with 57% atretic follicles with sesame oil treatment) and 64 mg/kg dose (87% atretic follicles with MXC treatment compared with 57% atretic follicles with sesame oil treatment) after 20 days of dosing (Fig. 1; n = 3-9, P s 0.001). In addition, mice treated with 64 mg/kg MXC had fewer antral follicles than those treated with sesame oil. The sesame oil-treated animals had a total of 1632 ± 192 antral follicles, whereas animals treated with 64 mg/kg MXC had a total number of 936 ± 136 antral follicles (n = 3-9, P s 0.01).

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