Long-term chronic exposure of mice to sodium fluoride and a mixture of endocrine disruptors lead to easily observable tooth enamel and retina abnormalities underlying changes in hepatic metabolism

Background: Long-term exposure to environmental pollutants contributes to multiple health disorders diagnosed after years when pathologies are established. Early markers are urgently needed. Objectives: To identify early new markers of exposure to low-dose toxicants widely present in daily environment. To achieve this objective, we set up realistic models of environmental exposure and analyzed, in addition to the liver, the most studied xenobiotic target organ, two easily accessible sensitive organs, eyes and teeth, as good potential candidates to be original markers of environmental exposures. Methods: C57BL/6 mice were chronically exposed in drinking water to either 1 mM sodium fluoride (NaF), or a mixture of 15 widely present substances with endocrine-disrupting activities, or both, from the conception to 1 or 10 months after birth. Most doses of the components in the mixture were below the tolerated dose intakes. Eyes, livers and teeth were analyzed at the histological, biochemical and functional levels.Results: All mice in test groups presented lower weight gain than controls with the most significant differences observed in females 30 days after birth (PND 30). Whereas histological analyses showed no significant defects in liver despite metabolic disruptions highlighted by molecular metabolomic and RNAseq analyses, eye retina and tooth enamel presented disorders detected as soon as 3 months of age that considerably worsened in all 10-months old animals. Discussion: Despite clear molecular hepatic metabolic disorders occurring in all test groups, the most evident histological and clinical signs were reported in eyes and teeth. These easily accessible defects may be used as early markers of low-dose exposure to environmental toxicants.