TY - JOUR
T1 - Pregnenolone co-treatment partially restores steroidogenesis, but does not prevent growth inhibition and increased atresia in mouse ovarian antral follicles treated with mono-hydroxy methoxychlor
AU - Craig, Zelieann R.
AU - Hannon, Patrick R.
AU - Flaws, Jodi A.
N1 - Funding Information:
The authors thank Ayelet Ziv-Gal and Timothy DelValle for technical help, Lalji Gedia (Dr. Vincent Njar laboratory) for the synthesis of mono-OH MXC, and grant support provided by the National Institute of Environmental Health Sciences (NIEHS) grants R01ES019178 (JAF), K99ES021467 (ZRC), the University of Illinois Billie A. Field Fellowship in Reproductive Biology program (ZRC) , and an Environmental Toxicology Scholarship (PRH).
PY - 2013/11/1
Y1 - 2013/11/1
N2 - Mono-hydroxy methoxychlor (mono-OH MXC) is a metabolite of the pesticide, methoxychlor (MXC). Although MXC is known to decrease antral follicle numbers, and increase follicle death in rodents, not much is known about the ovarian effects of mono-OH MXC. Previous studies indicate that mono-OH MXC inhibits mouse antral follicle growth, increases follicle death, and inhibits steroidogenesis in vitro. Further, previous studies indicate that CYP11A1 expression and production of progesterone (P4) may be the early targets of mono-OH MXC in the steroidogenic pathway. Thus, this study tested whether supplementing pregnenolone, the precursor of progesterone and the substrate for HSD3B, would prevent decreased steroidogenesis, inhibited follicle growth, and increased follicle atresia in mono-OH MXC-treated follicles. Mouse antral follicles were exposed to vehicle (dimethylsulfoxide), mono-OH MXC (10μg/mL), pregnenolone (1μg/mL), or mono-OH MXC and pregnenolone together for 96h. Levels of P4, androstenedione (A), testosterone (T), estrone (E1), and 17β-estradiol (E2) in media were determined, and follicles were processed for histological evaluation of atresia. Pregnenolone treatment alone stimulated production of all steroid hormones except E2. Mono-OH MXC-treated follicles had decreased sex steroids, but when given pregnenolone, produced levels of P4, A, T, and E1 that were comparable to those in vehicle-treated follicles. Pregnenolone treatment did not prevent growth inhibition and increased atresia in mono-OH MXC-treated follicles. Collectively, these data support the idea that the most upstream effect of mono-OH MXC on steroidogenesis is by reducing the availability of pregnenolone, and that adding pregnenolone may not be sufficient to prevent inhibited follicle growth and survival.
AB - Mono-hydroxy methoxychlor (mono-OH MXC) is a metabolite of the pesticide, methoxychlor (MXC). Although MXC is known to decrease antral follicle numbers, and increase follicle death in rodents, not much is known about the ovarian effects of mono-OH MXC. Previous studies indicate that mono-OH MXC inhibits mouse antral follicle growth, increases follicle death, and inhibits steroidogenesis in vitro. Further, previous studies indicate that CYP11A1 expression and production of progesterone (P4) may be the early targets of mono-OH MXC in the steroidogenic pathway. Thus, this study tested whether supplementing pregnenolone, the precursor of progesterone and the substrate for HSD3B, would prevent decreased steroidogenesis, inhibited follicle growth, and increased follicle atresia in mono-OH MXC-treated follicles. Mouse antral follicles were exposed to vehicle (dimethylsulfoxide), mono-OH MXC (10μg/mL), pregnenolone (1μg/mL), or mono-OH MXC and pregnenolone together for 96h. Levels of P4, androstenedione (A), testosterone (T), estrone (E1), and 17β-estradiol (E2) in media were determined, and follicles were processed for histological evaluation of atresia. Pregnenolone treatment alone stimulated production of all steroid hormones except E2. Mono-OH MXC-treated follicles had decreased sex steroids, but when given pregnenolone, produced levels of P4, A, T, and E1 that were comparable to those in vehicle-treated follicles. Pregnenolone treatment did not prevent growth inhibition and increased atresia in mono-OH MXC-treated follicles. Collectively, these data support the idea that the most upstream effect of mono-OH MXC on steroidogenesis is by reducing the availability of pregnenolone, and that adding pregnenolone may not be sufficient to prevent inhibited follicle growth and survival.
KW - Antral follicles
KW - Metabolites
KW - Methoxychlor
KW - Ovary
KW - Pregnenolone
KW - Steroidogenesis
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U2 - 10.1016/j.taap.2013.08.002
DO - 10.1016/j.taap.2013.08.002
M3 - Article
C2 - 23948739
AN - SCOPUS:84884718749
SN - 0041-008X
VL - 272
SP - 780
EP - 786
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
IS - 3
ER -