Methoxychlor May Cause Ovarian Follicular Atresia and Proliferation of the Ovarian Epithelium in the Mouse

Borgeest, Christina; Symonds, Daniel A.; Mayer, Loretta P.; Hoyer, Patricia B.; Flaws, Jodi A.

doi:10.1093/toxsci/68.2.473

Cited by 134 publications

(106 citation statements)

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“…Doses of 50 and 100 mg/kg per day MXC stimulated early vaginal opening, inhibited ovarian development, caused irregular reproductive cycles, and reduced fecundity in rats. Exposure to 32 mg/kg MXC for 20 days reduces antral follicle number by atresia in mice (Borgeest et al 2002). However, the effect of brief neonatal (P3-P10) exposure to MXC on pre-pubertal (P20) ovarian folliculogenesis and AMH production in the ovary has not been studied.…”

Section: Introductionmentioning

confidence: 99%

Early postnatal methoxychlor exposure inhibits folliculogenesis and stimulates anti-Mullerian hormone production in the rat ovary

Uzumcu¹,

Kühn²,

Marano³

et al. 2006

Journal of Endocrinology

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Methoxychlor [1,1,1-trichloro-2,2-bis(4-methoxyphenyl) ethane; MXC] is a chlorinated hydrocarbon pesticide commonly used in the United States as a replacement for DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane]. While MXC is a weak estrogenic compound, its more active, major metabolite [2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane; HPTE] shows estrogenic, anti-estrogenic, or anti-androgenic properties depending on the receptor subtype with which it interacts. Anti-Mullerian hormone (AMH) is a paracrine factor that suppresses initial follicle recruitment in the ovary. Studies have shown the effects of exposure to MXC on adult ovarian morphology and function. However, the effect of exposure to MXC at an early postnatal stage on pre-pubertal follicular development and ovarian AMH production has not been studied. Around postnatal day (P) 4, most of the primordial follicular assembly in rats is complete, and a large number of primordial follicles transition into the primary follicle stage, a process that is inhibited by estrogen. The objective of this study was to examine the effect of early postnatal (P3-P10) MXC exposure on ovarian morphology and size, follicle number, and AMH production in the pre-pubertal (P20) rat ovary and to investigate the effect of HPTE on AMH production in immature rat granulosa cells in vitro. Female rats were injected (s.c.) daily with vehicle (control) or 1, 10, 50, 100, or 500 mg MXC/kg per day (referred to here as 1MXC, 10MXC, and so forth.) between P3 and P10. On P20, uterine and ovarian weights were determined, ovarian histology was examined, and follicles were counted and classified into primordial, primary, secondary, pre-antral, or antral stages using the two largest serial sections at the center of the ovary. Ovarian AMH production was examined using immunohistochemistry and western blot analysis. The effect of HPTE (0 . 5-25 mM) on AMH production in cultured immature rat granulosa cells was determined by western blot analysis. Ovarian weight was reduced by 50, 100, and 500MXC (P!0 . 01). MXC treatment inhibited folliculogenesis. Both 100 and 500MXC had a reduced number of antral follicles (P!0 . 05) with a concomitant increase in pre-antral follicles (P!0 . 05). Follicle numbers were not significantly affected by 1, 10, or 50MXC. Total follicle number and the number of primordial, primary, or secondary stage follicles were not significantly different in all treatment groups. Immunohistochemistry showed that MXC-treated ovaries had more AMH-positive follicles with stronger AMH immunostaining.Western blot analysis showed that AMH production was 1 . 6G 0 . 2, 1 . 85G0 . 6, and 2 . 2G0 . 5 times higher in the 50, 100, and 500MXC ovaries as compared with the control ovaries respectively (P!0 . 05). Granulosa cells treated with 1 or 5 mM HPTE had significantly greater AMH production (P!0 . 05).These results demonstrate that MXC inhibits early ovarian development and stimulates AMH production directly in the rat ovary. In addition, HPTE was shown to stimulate AMH producti...

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Section: Introductionmentioning

confidence: 99%

Early postnatal methoxychlor exposure inhibits folliculogenesis and stimulates anti-Mullerian hormone production in the rat ovary

Uzumcu¹,

Kühn²,

Marano³

et al. 2006

Journal of Endocrinology

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“…Further studies demonstrated that adult mice or rats that were exposed to MXC showed persistent vaginal estrus [151], direct inhibition of embryonic growth, implantation failure [152], pregnancy loss [153], and ovarian atrophy due to inhibition of folliculogenesis leading to atretic follicles and reduced ovulation and decreased numbers of CL [151,154,155]. It was shown that exposure to MXC in adult mice selectively affects the antral follicles and induces atresia using the Bcl2/Bax signaling pathway, without affecting the HPG axis [156].…”

Section: Methoxychlor In Vivo Studiesmentioning

confidence: 99%

Effects of Endocrine-disrupting Chemicals on Female Reproductive Health

Zama¹,

Bhurke²,

Uzumcu³

2016

TOBIOTJ

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Endocrine-disrupting chemicals (EDCs) are increasingly prevalent in the environment and the evidence demonstrates that they affect reproductive health, has been accumulating for the last few decades. In this review of recent literature, we present evidence of the effects of estrogen-mimicking EDCs on female reproductive health especially the ovaries and uteri. As representative EDCs, data from studies with a pharmaceutical estrogen, diethylstilbestrol (DES), an organochlorine pesticide methoxychlor (MXC), a phytoestrogen (genistein), and a chemical used in plastics, bisphenol a (BPA) have been presented. We also discuss the effects of a commonly found plasticizer in the environment, a phthalate (DEHP), even though it is not a typical estrogenic EDC. Collectively, these studies show that exposures during fetal and neonatal periods cause developmental reprogramming leading to adult reproductive disease. Puberty, estrous cyclicity, ovarian follicular development, and uterine functions are all affected by exposure to these EDCs. Evidence that epigenetic modifications are involved in the progression to adult disease is also presented.

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“…Early studies reported that MXC induces ovarian atrophy in mice (Eroschenko et al, 1995) and decreases steroidogenesis in rat ovarian cells (Bal et al, 1984). Following MXC exposure in mice, the oocyte in the antral follicles becomes separated from the cumulus granulosa cell layer, which becomes disorganized followed by the appearance of pyknotic bodies (Borgeest et al, 2002). Mechanistic investigations have indicated that MXC accelerates atresia via increased apoptosis involving the BCL-2 proto-oncogene family (Figure 4) (Borgeest et al, 2002, Miller et al, 2005 in isolated mouse antral follicles.…”

Section: Methoxychlormentioning

confidence: 99%

“…Following MXC exposure in mice, the oocyte in the antral follicles becomes separated from the cumulus granulosa cell layer, which becomes disorganized followed by the appearance of pyknotic bodies (Borgeest et al, 2002). Mechanistic investigations have indicated that MXC accelerates atresia via increased apoptosis involving the BCL-2 proto-oncogene family (Figure 4) (Borgeest et al, 2002, Miller et al, 2005 in isolated mouse antral follicles. Immunohistochemical analysis demonstrated increased pro-apoptotic BAX protein staining in MXC-treated antral follicles (Borgeest et al, 2004).…”

Section: Methoxychlormentioning

confidence: 99%