Gestational cadmium exposure triggers POI-Like ovarian dysfunction and accelerated ovarian aging through epigenetic repression of Kl in mice

Abstract

Cadmium (Cd), a bioaccumulative toxic heavy metal, poses a growing concern for offspring reproductive health following gestational exposure. Premature ovarian insufficiency (POI), a major cause of female infertility, remained poorly understood in terms of environmental etiology. This study investigated whether gestational Cd exposure induced ovarian functional decline via epigenetic mechanisms in mice. Using a mouse model of maternal Cd exposure via drinking water, we found that gestational Cd exposure led to POI-like ovarian dysfunction in adult offspring, characterized by diminished ovarian reserve, disrupted estrous cycles, altered serum hormone profiles, and accelerated ovarian aging with fibrosis and DNA damage. Mechanistically, Cd exposure upregulated DNMT1 and DNMT3A expression in offspring ovaries, promoting hypermethylation of the Klotho (Kl) promoter and suppressing its expression. Kl downregulation subsequently attenuated its inhibition of the p53/p21 pathway, triggering granulosa cell senescence and premature follicular depletion. Importantly, administration of the DNA methylation inhibitor 5-aza-2′-deoxycytidine (5-Aza) during gestation partially reversed these Cd-induced epigenetic modifications and ameliorated the ovarian phenotypes in offspring. Our findings revealed a complete pathway through which gestational Cd exposure promoted ovarian aging via DNMT-mediated Kl silencing and p53/p21 activation. This work provided novel mechanistic insights into environmental reproductive toxicity and identified potential targets for intervention.

Environmental implication

Cd is a pervasive environmental toxicant threatening female reproductive health, yet its long-term developmental impacts on offspring ovarian aging remain unclear. This study reveals that gestational Cd exposure epigenetically silences the anti-aging gene Kl via promoter hypermethylation, activating the p53/p21/p16-Rb senescence pathway and triggering POI-like ovarian dysfunction in offspring. Importantly, this epigenetic damage is partially reversible with 5-Aza, offering a potential intervention strategy. These findings provide mechanistic insights into how Cd pollution contributes to rising POI incidence, informing developmental origins of reproductive dysfunction and guiding preventive policies for hazardous material regulation.