Effects on neurodevelopment in the animal offspring.

The 14 animal studies listed below report on the offspring born from mothers that were exposed to different levels of fluoride. They were published from 2017-2019 and mirror in large part the human Mother-Offspring studies. These fluoride studies report that the animal offspring were adversely affected compared to the controls (not exposed to fluoride) in tests to discern memory and learning and other indices for neurodevelopment. Examination of their brains also revealed adverse effects.

Only one animal study that used offspring during this period did not find a significant adverse effect (McPherson et al. 2018). The study noted that the “low-level F^– diet did not show a significant effect on the behavioral endpoints examined.” The study used male rats only, with no discussion for the exclusion of the female.

THE STUDIES

2019: Bartos et al. “Exposure to fluoride (F) during the development affects central nervous system of the offspring rats which results in the impairment of cognitive functions… results showed that the memory ability declined in 45-day-old offspring, together with a decrease of catalase and glutamate transaminases activity in specific brain areas. The present study reveals that exposure to F in early stages of rat development leads to impairment of memory in young offspring..”
Effects of Perinatal Fluoride Exposure on Short- and Long-Term Memory, Brain Antioxidant Status, and Glutamate Metabolism of Young Rat Pups. International Journal of Toxicology, June 20.

2019: Dec et al. “Exposure to fluoride in the prenatal and neonatal period result in the increase in COX2 activity and increase in PGE2 concentration in rats brain, which may lead to disturbances in central nervous system homeostasis… this study showed statistically significant changes in the concentration of fluoride in brain structures between study group and control animals…”
Long-term exposure to fluoride as a factor promoting changes in the expression and activity of cyclooxygenases (COX1 and COX2) in various rat brain structures. Neurotoxicology 74:81-90. June 5.

2019: Zhou et al. “Using Sprague-Dawley rats exposed to sodium fluoride from 60 days before pregnancy until 6 months post-delivery as in vivo model, we showed that fluoride impaired the learning and memory abilities of offspring rats, with decreased neuronal number, suppressed autophagy and enhanced apoptosis in hippocampus.”
Effects of long-term fluoride exposure on cognitive ability and the underlying mechanisms: Role of autophagy and its association with apoptosis. Toxicology and Applied Pharmacology 378:114608.

2019: Zhao et al. “… Sprague-Dawley rats developmentally exposed to NaF (10, 50, and 100 mg/L) from pre-pregnancy until 2 months of delivery to mimic human exposure, we showed that perinatal exposure to environmentally relevant levels of fluoride caused learning and memory impairments, accompanied by hippocampal mitochondrial morphological alterations manifested as fission suppression and fusion acceleration, along with defective autophagy, excessive apoptosis and neuronal loss… Collectively, our results suggest that mitochondrial fission inhibition induces mitochondrial abnormalities, triggering abnormal autophagy and apoptosis, thus contributing to neuronal death, and that the mitochondrial dynamics molecules may act as promising indicators for developmental fluoride neurotoxicity.”
Roles of mitochondrial fission inhibition in developmental fluoride neurotoxicity: mechanisms of action in vitro and associations with cognition in rats and children. Archives of Toxicology [Epub ahead of print]

2019: Kinawy. “…sodium fluoride (NaF, 0.15 g/L) and aluminum chloride (AlCl₃, 500 mg/L) added, individually or in combination, to the deionized drinking water starting from day 6 of gestation until just after weaning, or until the age of 70 days postnatal life… administration of Al and NaF, alone or in combination abated the quenching effects of the antioxidant system and induced oxidative stress in most brain regions under investigation. In conclusion, aluminum and fluoride are very noxious environmental pollutants that interfere with the proper functions of the brain neurons and their combination together aggravates their hazard.”
Synergistic oxidative impact of aluminum chloride and sodium fluoride exposure during early stages of brain development in the rat. Environmental Science and Pollution Research International. Feb 20. [Epub ahead of print]

2018:  Ge et al. “… an animal model of fluoride exposure was created by providing ICR mice were treated with vehicle F at a dose of 0 (control group), 50 (low-fluoride group) or 100 mg/L (high-fluoride group) in water for one month. After the mice mated, parents and offspring were treated and maintained under these conditions. The cognitive abilities of the mice were examined using a Morris water maze test. Results indicated that fluoride exposure significantly prolonged the escape latency period and decreased the number of crossings in a particular zone. Histopathologic analysis revealed the shrinkage and fragmentation of glial cells in the fluoride-treated groups. Pyramidal cells in the cerebral cortices of fluoride-treated groups were fewer than those of the control group... fluoride-mediated reduction in cognitive dysfunction is likely caused by the disruption of the expression of these synapse-associated proteins [MAP2, SYP, Dbn, and  NMDAR] resulting in attenuated neuronal functioning.”
Fluoride-induced alterations of synapse-related proteins in the cerebral cortex of ICR offspring mouse brain. Chemosphere 201:874-883.

2018:  Chen et al. “Using Sprague-Dawley rats developmentally exposed to sodium fluoride (NaF) from pregnancy until 6 months of delivery as in vivo model, we showed that fluoride impaired the cognitive abilities of offspring rats, decreased the density of dendritic spines and the expression of synapse proteins synaptophysin (SYN) and postsynaptic density protein-95 (PSD-95) in hippocampus, suggesting fluoride-induced cognitive deficit associates with synaptic impairment…”
ERK1/2-mediated disruption of BDNF–TrkB signaling causes synaptic impairment contributing to fluoride–induced developmental neurotoxicity. Toxicology [Epub ahead of print].

2018: Sun et al. “F exposure during embryonic to suckling stages impaired the learning and memory ability of the mouse pups.”
Maternal fluoride exposure during gestation and lactation decreased learning and memory ability, and glutamate receptor mRNA expressions of mouse pups. Human and Experimental Toxicology 37(1):87-93.

2018: Wang et al. “… In the eight-arm maze test, the number of working memory errors, reference memory errors, and the total arm entries were significantly increased in fluoride treatment groups, compared to the control group… These findings suggested that the impairment of learning and memory in mouse offspring induced by perinatal fluoride exposure may partly result from the enhanced miR-124 and miR-132 and the alterations of their target genes.
Effects of perinatal fluoride exposure on the expressions of miR-124 and miR-132 in hippocampus of mouse pups. Chemosphere 197:117-122.

2018: Bartos et al. “Our data indicates that low F concentrations administrated during gestation and lactation decrease the memory of 90-day-old female offspring. This suggests that the mechanism might be connected with an a7 nAChR deficit in the hippocampus, induced by oxidative stress.”
Alterations in the memory of rat offspring exposed to low levels of fluoride during gestation and lactation: Involvement of the a7 nicotinic receptor and oxidative stress. Reproductive Toxicology July.

2018: Wei et al. “Sprague-Dawley rats were divided randomly into a fluorosis group (50 ppm fluoride in the drinking water for 6 months) and controls (<0.5ppm fluoride) and the offspring from these rats sacrificed on postnatal days 1, 7, 14, 21 and 28… The results indicate that such modifications may involve brain damage induced by chronic fluorosis. … the numbers of Nissl bodies in neurons in the hippocampus and cortex of brains from both adult rats and their pups with fluorosis were lowered. Such reduction in Nissl bodies, showing large granular bodies consisting of rough endoplasmic reticulum with rosettes of free ribosomes carrying out protein synthesis, indicates injury of neurons.
Changed expressions of N-methyl-D-aspartate receptors in the brains of rats and primary neurons exposed to high level of fluoride. Journal of Trace Elements in Medicine and Biology 45:31-40.

2017:  Zhu et al. “Control rats drank tap water, while rats in the three exposure groups drank water with sodium fluoride (100 mg/L), sodium arsenite (75 mg/L), and a sodium fluoride (100 mg/L) and sodium arsenite (75 mg/L) combination during gestation and lactation. After weaning, rat pups drank the same solution as their mothers… These data indicate that exposure to fluoride and arsenic in early life stage changes ERK, p-ERK, CREB and p-CREB protein expression in the hippocampus and cerebral cortex of rat offspring at PND21 and PND 42, which may contribute to impaired neurodevelopment following exposure.” Fluoride and arsenic exposure affects spatial memory and activates the ERK/CREB signaling pathway in offspring rats. Neurotoxicology 59:56-64.

2017: Zigu et al.  “The results suggested that dietary calcium significantly affected hippocampal synaptic plasticity of offspring of mothers exposed to water fluorosis… The findings also demonstrate the important effects of maternal exposure to water fluorosis on offspring brain functions before water improvement. Effects of Calcium on Drinking Fluorosis-induced Hippocampal Synaptic Plasticity Impairment in the Offspring of Rats. Translational Neuroscience 8:191-200.

2017: Cui et al. From the English translation of this study: “…Results of testing spatial learning and memory abilities of offspring rats: In the position navigation test, the time taken by offspring rats of the medium- and high-fluoride groups was clearly longer than that of the control group, and it was longer for the high fluoride group than the low-fluoride group, with all differences having statistical significance (P < 0.05). The lengths of routes taken by the high-fluoride group were longer than those of the control group and the low-fluoride group, with all differences having statistical significance (P < 0.05). In the spatial exploration test, the ratios of time (and route length) in the target quadrant to the total time (and route length) by the low, medium, and high fluoride groups were clearly smaller than that of the control group, with all differences having statistical significance (P < 0.05) … To sum up, high fluorine content can induce a disorder of thyroid hormone levels, which could be a reason that causes intelligence impairment in offspring rats. The abnormality of mitochondrial dynamics in peripheral lymphocytes may represent a clue or a possibility for finding a biomarker for fluorine-induced intelligence impairment.”
Effects of fluoride exposure on thyroid hormone level and intelligence in rats. Chinese Journal of Industrial Hygiene and Occupational Diseases. December.

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