Developmental programming by androgen affects the circadian timing system in female mice

Area of Science:

• Endocrinology and Chronobiology
• Reproductive Biology

Background:

• Circadian clocks regulate the mammalian hypothalamo-pituitary-ovarian (HPO) axis, and their synchrony is crucial for reproductive function.
• The role of circadian clock disruption in fertility disorders like polycystic ovarian syndrome (PCOS) is largely unknown.
• PCOS affects 5-10% of women, characterized by polycystic ovaries, anovulation, elevated androgens, and often metabolic syndrome.

Purpose of the Study:

• To investigate the impact of androgen exposure on circadian clock gene expression within the HPO axis and metabolic tissues.
• To determine if developmental androgen exposure contributes to circadian disruption relevant to PCOS etiology.

Main Methods:

• Female PERIOD2::luciferase (PER2::LUC) mice were exposed to dihydrotestosterone (DHT) during gestation or post-puberty.
• PER2::LUC expression was analyzed in tissue explants from metabolic and HPO axis tissues.
• In vitro DHT treatment was used to assess direct effects on clock gene expression in granulosa cells.

Main Results:

• Androgen-treated mice exhibited disrupted estrous cycles, confirming reproductive dysfunction.
• Excess androgen exposure led to circadian misalignment, with tissue-specific effects on phase distribution.
• In vitro studies demonstrated that DHT directly and differentially impacts PER2::LUC expression in various tissues and granulosa cells.

Conclusions:

• Developmental androgen excess disrupts circadian timing within the reproductive axis.
• Androgen exerts direct, tissue-specific effects on clock gene expression, potentially underlying fertility disorders like PCOS.
• Circadian misalignment may be a key factor in the pathophysiology of PCOS and related endocrine pathologies.