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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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE289561 | GEO | 2026/02/14

REPOSITORIES: GEO

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	GSE289561_Picard_Livers_raw_count.tsv.gz	Tabular

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Project description:Current human reproductive risk assessment methods rely on semen and serum hormone analyses, which are not easily comparable to the histopathological endpoints and mating studies used in animal testing. Because of these limitations, there is a need to develop universal evaluations that reliably reflect male reproductive function. We hypothesized that toxicant-induced testicular injury can be detected in sperm using mRNA transcripts as indicators of insult. To test this, we exposed adult male Fischer 344 rats to low doses of model testicular toxicants and classically characterized the testicular injury while simultaneously evaluating sperm mRNA transcripts from the same animals. Overall, this study aimed to: 1) identify sperm transcripts altered after exposure to the model testicular toxicant, 2,5-hexanedione (HD) using microarrays; 2) expand on the HD-induced transcript changes in a comprehensive time course experiment using qRT-PCR arrays; and 3) test these injury indicators after exposure to another model testicular toxicant, carbendazim (CBZ). Microarray analysis of HD-treated adult Fischer 344 rats identified 128 altered sperm mRNA transcripts when compared to control using linear models of microarray analysis (q < 0.05). All transcript alterations disappeared after 3 months of post-exposure recovery. In the time course experiment, time-dependent alterations were observed for 12 candidate transcripts selected from the microarray data based upon fold change and biological relevance, and 8 of these transcripts remained significantly altered after the 3-month recovery period (p < 0.05). In the last experiment, 8 candidate transcripts changed after exposure to CBZ (p < 0.05). The two testicular toxicants produced distinct molecular signatures with only 4 overlapping transcripts between them, each occurring in opposite directions. Overall, these results suggest that sperm mRNA transcripts are indicators of low dose toxicant-induced testicular injury in the rat. Rats were exposed to sub-chronic low doses of the Sertoli cell toxicant 2,5-hexanedione (HD) or water (control for HD) for 3 months. Some rats in each group underwent 3 months of post-exposure recovery.

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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

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