Effects of dietary quercetin on female fertility in mice: implication of transglutaminase 2 Original paper

What was studied?

This original research investigated the long-term effects of dietary quercetin supplementation on female fertility and ovarian physiology in mice, with a specific focus on the role of the enzyme transglutaminase 2 (TG2). Quercetin, a widely consumed flavonoid supplement, is known for its antioxidant properties, but its effects on female reproductive health remain poorly characterized. The study evaluated birth outcomes (number and size of litters, birth spacing) and detailed ovarian histology (folliculogenesis) in mice administered quercetin (5 mg/kg/day) for nine months. Two breeding periods were analyzed: one during prime reproductive age (2–6 months) and another during later reproductive age (8–11 months). The researchers also compared wild-type mice with TG2-null mice to determine whether the observed effects were mediated through TG2 inhibition.

Who was studied?

The subjects were C57BL/6 female mice, either wild-type or genetically modified to lack TG2 (TG2-null), and their offspring. Each experimental group consisted of four females and two males, with both wild-type and TG2-null genotypes represented. Mice were randomly assigned to receive either quercetin or vehicle via drinking water, and breeding outcomes were monitored during two distinct reproductive periods. The offspring of these dams were also analyzed for ovarian morphology and follicle counts at four weeks of age. Additionally, male fertility was assessed by mating quercetin-exposed males with untreated females to exclude male-mediated effects.

Most important findings

Dietary quercetin supplementation produced complex, age-dependent effects on female fertility and ovarian physiology in mice. In young wild-type females, quercetin reduced the total number of litters by approximately 60% and increased the interval between births (birth spacing), indicating a reduction in overall reproductive potential. Paradoxically, these same young females exhibited a nearly 70% increase in average litter size, a change associated with significantly enhanced ovarian folliculogenesis—specifically, an increase in mature antral follicles and a corresponding depletion of primordial and primary follicles. In older females, quercetin reversed its effect, reducing litter size. Importantly, TG2-null mice displayed similar changes in follicle development and litter size as quercetin-treated wild-type mice, and were unresponsive to additional quercetin, indicating that quercetin’s effects are predominantly mediated via TG2 inhibition.

Key implications

This study demonstrates that chronic dietary quercetin, at doses relevant to human supplementation, can adversely affect female reproductive potential by accelerating follicle maturation and depleting ovarian reserves, likely through inhibition of TG2. The findings suggest a risk of premature ovarian aging and reduced fertility with long-term quercetin use in females of reproductive age. The data also highlight TG2 as a novel regulator of ovarian aging and folliculogenesis. These insights are clinically relevant for counseling women considering quercetin supplementation and inform potential mechanisms underlying reproductive disorders, such as those observed in TG2-targeting autoimmune diseases like celiac disease. For microbiome signatures databases, the study underscores the importance of tracking host-microbe interactions influenced by dietary polyphenols and their systemic enzymatic targets.