Public Health Implications of Foodborne Testosterone, Estrogen, and Progesterone in Triggering Sex-Specific Hepatic, Cardiovascular, andMetabolic Dysfunction

Introduction: Growing evidence suggests foodborne hormonal contaminants like testosterone, estrogen, and progesterone may disrupt endocrine function, yet their sex-specific physiological impacts remain poorly understood. This study investigated the chronic effects of these hormones on metabolic and organ function in both sexes to characterize sex-divergent toxicity patterns and identify underlying mechanisms. Methods: Male and female mice received 16-week subcutaneous doses of testosterone (20 μg/kg/day), estrogen (20 μg/kg/day), progesterone (0.71 mg/kg/day), or vehicle. Assessments included body weight monitoring, serum biochemical analyses, oxidative stress and inflammatory markers, hormonal assays, qRT-PCR analysis of AMPK and AKT expression, and histopathological evaluation of liver and heart tissues. Results: Our results revealed striking sexual dimorphism in physiological responses. Testosterone exposure induced weight gain in males but transient weight loss in females, while estrogen caused significant weight reduction in males. Estrogen demonstrated the most pronounced hepatotoxicity, markedly elevating ALT levels compared to more moderate effects from testosterone and progesterone. Histopathological analysis showed male-predominant hepatic necrosis rather than female-specific steatosis. Cardiovascular impacts were particularly notable, with estrogen inducing severe cardiac inflammation in females and testosterone causing interstitial edema. Metabolic disruptions included significant reductions in HDL-C and elevations in oxidative stress markers. Molecular analyses revealed profound disruptions in the AMPK/AKT signaling pathway, especially in estrogen-exposed animals. Discussion: The findings highlight hormone-specific and sex-divergent toxicity mechanisms, implicating receptor-mediated pathways and altered metabolic signaling. Estrogen emerged as the most disruptive contaminant, exerting widespread biochemical and histological damage. Limitations include extrapolation to humans and focus on subcutaneous rather than dietary exposure. Conclusion: These findings demonstrate that chronic exposure to foodborne testosterone, estrogen, and progesterone induces distinct, sex-specific multiorgan toxicity through receptormediated pathways. The results highlight the urgent need for sex-stratified risk assessments of endocrine-disrupting compounds in food products and suggest particular concern for estrogenic contaminants. Our work provides a foundation for developing more nuanced food safety guidelines that account for fundamental biological differences between sexes.