Developmental methoxychlor exposure affects multiple reproductive parameters and ovarian folliculogenesis and gene expression in adult rats.
Methoxychlor (MXC) is an organochlorine pesticide with estrogenic, anti-estrogenic, and anti-androgenic properties. To investigate whether transient developmental exposure to MXC could cause adult ovarian dysfunction, we exposed Fischer rats to 20 microg/kg/day (low dose; environmentally relevant dose) or 100 mg/kg/day (high dose) MXC between 19 days post coitum and postnatal day 7. Multiple reproductive parameters, serum hormone levels, and ovarian morphology and molecular markers were examined from prepubertal through adult stages. High dose MXC accelerated pubertal onset and first estrus, reduced litter size, and increased irregular cyclicity (P<0.05). MXC reduced superovulatory response to exogenous gonadotropins in prepubertal females (P<0.05). Rats exposed to high dose MXC had increasing irregular estrous cyclicity beginning at 4 months of age, with all animals showing abnormal cycles by 6 months. High dose MXC reduced serum progesterone, but increased luteinizing hormone (LH). Follicular composition analysis revealed an increase in the percentage of preantral and early antral follicles and a reduction in the percentage of corpora lutea in high dose MXC-treated ovaries (P<0.05). Immunohistochemical staining and quantification of the staining intensity showed that estrogen receptor beta was reduced by high dose MXC while anti-Mullerian hormone was upregulated by both low- and high dose MXC in preantral and early antral follicles (P<0.05). High dose MXC significantly reduced LH receptor expression in large antral follicles (P<0.01), and down-regulated cytochrome P450 side-chain cleavage. These results demonstrated that developmental MXC exposure results in reduced ovulation and fertility and premature aging, possibly by altering ovarian gene expression and folliculogenesis.
Department of Animal Sciences School of Environmental and Biological Sciences Rutgers, The State 84 Lipman Drive University of New Jersey New Brunswick, NJ 08901-8525, USA.
AnnMarie E
AE
Armenti
Aparna Mahakali
AM
Zama
Lisa
L
Passantino
Mehmet
M
Uzumcu
D000818:Animals; D054304:Anti-Mullerian Hormone / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000378:metabolism; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D007150:Immunohistochemistry; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity*; D008098:Litter Size / Q000187:drug effects; D007986:Luteinizing Hormone / Q000187:drug effects / Q000378:metabolism; D008731:Methoxychlor / Q000008:administration & dosage / Q000633:toxicity*; D006080:Ovarian Follicle / Q000187:drug effects* / Q000473:pathology; D010060:Ovulation / Q000187:drug effects*; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012741:Sexual Maturation / Q000187:drug effects
D047629:Estrogen Receptor beta; D007306:Insecticides; D011374:Progesterone; D054304:Anti-Mullerian Hormone; D007986:Luteinizing Hormone; D002786:Cholesterol Side-Chain Cleavage Enzyme; D008731:Methoxychlor