Long-term exposure of mice to sodium fluoride and to a mixture of endocrine disruptors causes tooth enamel and retina abnormalities associated with changes in hepatic metabolism

Exposure to environmental pollutants may contribute to various health disorders, often manifesting after a prolonged period of latency. The identification of early markers is, therefore, of paramount importance. To achieve this objective, realistic models of environmental exposure were set up. Whereas most studies consider one substance or mixture with one target organ, here, in addition to the liver, two easily accessible sensitive organs, the eyes and teeth, were analyzed as good potential candidates to be original markers of environmental exposures. C57BL/6J mice were exposed to either sodium fluoride or a mixture of 15 endocrine-disrupting substances, or both, in their drinking water from the time of conception until 1 or 10 months after birth. The doses of these substances were chosen to be close to the tolerable daily intake. All mice in test groups presented lower weight gain than controls with the most significant differences observed in females 30 days after birth. Alterations in the eye retina were detected as early as 1 month of age and considerably worsened by 10 months. Dental defects were observed in all test groups at the last time point. At that age, metabolic disruptions were identified through molecular metabolomic and RNAseq analyses, while histological analyses showed no significant defects in liver. This study shows that chronic exposure to widespread toxicants resulted in hepatic metabolic disorders. However, the most evident histological and clinical signs were observed in eyes and teeth. These easily accessible stigmata may be used as early markers of low-dose exposure to environmental toxicants.