Vitamin D Improves the Maternal Hypothyroidism-induced Cognitive Decline in the Rat Offspring.
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INTRODUCTION: Thyroid hormones (THs) are vital for fetal and neonatal nervous system development. Mild maternal hypothyroidism might render cognitive impairment in offspring during adulthood, by producing oxidative stress, inflammation, and lowering brain-derived neurotrophic factor (BDNF). Vitamin D has anti-oxidant and anti-inflammatory actions. Therefore, we investigated whether vitamin D administration during gestation in hypothyroid dams or after birth would improve cognitive function in offspring. METHODS: For this study, we used propylthiouracil (PTU) to induce hypothyroidism in pregnant rats from the sixth day of gestation until delivery. A group of pregnant rats received vitamin D (5 or 10 mg/kg) along with PTU, while another group received that after delivery until the weaning of offspring and continued for the offspring until they were sacrificed. At the 60th postnatal day, a novel object recognition (NOR) test was performed. Protein assays for lipid peroxidation, superoxide dismutase (SOD), interleukin-6 (1L-6:), tumor necrosis factor alpha (TNF-α), and BDNF were performed in the hippocampus and prefrontal cortex. RESULTS: Results indicated that maternal hypothyroidism reduced cognitive functions in the offspring, and that vitamin D administered during gestation improved memory decline and recognition of the novel object. Vitamin D, either during or after birth, markedly altered oxidative stress, inflammation, and BDNF levels in the brain. CONCLUSION: This study indicates that maternal hypothyroidism-induced oxidation, inflammation, and decreased BDNF are passed and remain with the offspring into their adulthood, as possible causes of cognitive decline. Vitamin D administration, especially during pregnancy, may improve cognitive function by modulating the underlying mechanisms. HIGHLIGHTS: Maternal hypothyroidism reduced cognitive function in the adult offspring, which is possibly related to the oxidative stress, increase in pro-inflammatory cytokines and decrease in the brain derived nerve growth factor.Vitamin D administration to dams during gestation markedly restored cognitive ability in the NOR test.Vitamin D administration either pre- or postnatally, markedly adjusted oxidative stress, inflammatory cytokines, and BDNF levels in the offspring hippocampus and prefrontal cortex. PLAIN LANGUAGE SUMMARY: Hypothyroid mothers usually give birth to children with different levels of nervous system deficiency. This study is based on a model of mild maternal hypothyroidism (MH)-induced cognitive deficiency in male rat offspring. We measured cognitive ability using the novel object recognition (NOR) test, a standard test that evaluates a type of memory used to distinguish between old and new objects in a set, over a 24-hour interval. Our study showed that adult offspring with MH display lower cognitive ability in compare with healthy offspring. In addition, our molecular part of the study showed that in two brain parts that are highly related to learning and memory, the hippocampus and pre-frontal cortex, higher levels of harmful chemicals called oxidants and inflammatory factors and lower brain growth factors were found compared to healthy offspring's brain. Vitamin D is an internal hormone that we use as a food supplement, and it has a strong antioxidant and anti-inflammatory capability. In this study, we injected vitamin D twice a week to mothers during pregnancy (group 1, G1) or after giving birth for 2 weeks (during breastfeeding), following injecting twice to offspring from day 15 to 60 after birth (group 2, G2). G1 offspring responded much closer to normal offspring in NOR in comparison to G2, while vitamin D in both groups lowered the levels of oxidative and inflammatory and improved the level of growth factor in the offspring's brains. This study showed for the first time that mild maternal hypothyroidism can induce cognitive disabilities in offspring even during adulthood and that administering vitamin D (best along with thyroid hormone treatment) during or after birth can help restore cognitive ability.