Dietary phytoestrogens recalibrate socioemotional behavior in C57Bl/6J mice in a sex- and timing-dependent manner.

Estrogens are potent regulators of socioemotional behavior across species. Ubiquitous in human and animal diets, plant-derived phytoestrogens (PE) bind estrogen receptors. While prior work has examined the impact of PE exposure on socioemotional behavior, findings are inconsistent across studies. To investigate whether the timing of PE diet initiation may govern differential behavioral effects, we compared the impacts of PE-free (<20 mg/kg) versus PE-rich (810 mg/kg) diet exposure across the lifetime versus acutely in adulthood. Reproductive physiology was assessed through age at puberty onset and gonadal size. In adulthood, all mice underwent a behavioral battery consisting of the open field, elevated plus maze, and social interaction tests, followed by assessment of emotional memory dynamics with cued threat conditioning, extinction, recall, and renewal. Lifetime PE exposure delayed puberty onset and increased adult gonadal size selectively in males, whereas both lifetime and adult-only PE exposure decreased adult body weight in both sexes. In males, adult-only exposure increased open-arm avoidance in the elevated plus maze but enhanced threat memory extinction. In females, lifetime PE exposure increased open-arm avoidance, reduced sociability, and impaired threat memory extinction. Interestingly, lifetime PE exposure increased the context-dependent renewal of threat memory in both sexes. These findings demonstrate sex- and timing-dependent effects of PE exposure. Male lifetime PE exposure impacts reproductive measures with limited behavioral effects, whereas female lifetime exposure broadly impairs socioemotional behavior. Conversely, adult-only PE exposure altered behavior in males with limited impact in females. This study highlights the importance of diet composition, exposure period, and sex in rodent behavioral studies.