Pre-Conceptional Maternal Circadian Disruption Impairs Reproductive and Metabolic Health in Male Offspring

Maternal circadian disruption prior to conception is increasingly recognized as a potential environmental risk factor. Yet, its specific impact on the reproductive health of male offspring remains poorly understood.

To determine whether maternal circadian disruption prior to conception exerts intergenerational effects on male offspring fertility and metabolic function, using a mouse model of pre-conceptional maternal circadian disruption.

A mouse model of pre-conceptional maternal circadian disruption was established by housing female mice under constant conditions for 4 weeks prior to mating. Male offspring were assessed at 8 weeks of age for reproductive and metabolic phenotypes, including serum hormone profiles, sperm quality, systemic lipid parameters, and adipokine levels. Mechanistic investigations focused on hypothalamic leptin signaling, hypothalamic-pituitary-testicular axis function, testicular spermatogenesis, and testicular immune cell composition. Testicular expression of core circadian clock genes was also examined.

Pre-conceptional maternal circadian disruption significantly impaired fertility and disrupted systemic lipid metabolism in male offspring. These animals exhibited reduced serum testosterone and androstenedione concentrations, increased sperm apoptosis, overt dyslipidemia, and altered adipokine secretion. Mechanistically, pre-conceptional maternal circadian disruption induced hypothalamic upregulation of TCPTP, a critical negative regulator of leptin signaling, resulting in central leptin resistance and subsequent dysregulation of the hypothalamic-pituitary-testicular axis. Despite these endocrine perturbations, testicular spermatogenesis remained grossly intact. Instead, the testes displayed a compensatory immunoregulatory response characterized by an increase in M2 macrophages, which likely mitigated more severe inflammatory injury. In contrast to findings in females, testicular clock gene expression was unaltered in males.

This study provides evidence that maternal circadian disruption prior to conception constitutes a critical window for developmental programming, resulting in persistent reproductive and metabolic dysfunction in male offspring. These findings establish a conceptual framework for further studies investigating the intergenerational consequences of circadian misalignment.