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Developmental Vitamin D Deficiency Produces Behavioral Phenotypes of Relevance to Autism in an Animal Model.

ABSTRACT: Emerging evidence suggests that gestational or developmental vitamin D (DVD) deficiency is associated with an increased risk of autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder characterized by impairments in social interaction, lack of verbal and non-verbal communications, stereotyped repetitive behaviors and hyper-activities. There are several other clinical features that are commonly comorbid with ASD, including olfactory impairments, anxiety and delays in motor development. Here we investigate these features in an animal model related to ASD-the DVD-deficient rat. Compared to controls, both DVD-deficient male and female pups show altered ultrasonic vocalizations and stereotyped repetitive behavior. Further, the DVD-deficient animals had delayed motor development and impaired motor control. Adolescent DVD-deficient animals had impaired reciprocal social interaction, while as adults, these animals were hyperactive. The DVD-deficient model is associated with a range of behavioral features of interest to ASD.

SUBMITTER: Ali A

PROVIDER: S-EPMC6566814 | biostudies-other | 2019 May

REPOSITORIES: biostudies-other

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Developmental Vitamin D Deficiency Produces Behavioral Phenotypes of Relevance to Autism in an Animal Model.

Ali Asad A Vasileva Svetlina S Langguth Mia M Alexander Suzanne S Cui Xiaoying X Whitehouse Andrew A McGrath John J JJ Eyles Darryl D

Nutrients 20190527 5

Emerging evidence suggests that gestational or developmental vitamin D (DVD) deficiency is associated with an increased risk of autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder characterized by impairments in social interaction, lack of verbal and non-verbal communications, stereotyped repetitive behaviors and hyper-activities. There are several other clinical features that are commonly comorbid with ASD, including olfactory impairments, anxiety and delays in motor developmen ...[more]

PMID: 31137843

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Project description:We investigated the combined effect of fluoride exposure and Vitamin D deficiency in causing bone damage as a precursor to development of Fluorotoxic Metabolic Bone Disease. Thirty-six male Sprague-Dawley rats were divided into 6 groups of six; 3 groups received a Vitamin D deficient diet whereas the other 3 received a Vitamin D adequate diet. Serum total 25-hydroxyvitamin D (25OHD), calcium, phosphorus, creatinine, Alkaline phosphatase (ALP), albumin, Parathyroid hormone (PTH), Osteocalcin and C terminal telopeptide (CTx) were measured following exposure to varying levels of fluoride in drinking water (< 1.0, 15 and 50 ppm). Full body Dual-energy X-ray Absorptiometry (DXA) scans were used to examine changes in bone morphology pre and post exposure to fluoride. Renal tubular function was assessed using serum creatinine and urine Cystatin C. Histopathological examination of sections of bone and kidney tissues were also performed. Prior to fluoride exposure, DXA scans revealed a significant decrease in Bone Mineral Density (BMD) and Bone Mineral content (BMC) (p < 0.05) but a significant increase in fat mass (p < 0.05) and fat percentage (p < 0.01) among Vitamin D deficient rats, with no significant change in biochemical parameters. Following exposure to fluoride, BMD was significantly increased (p < 0.05) in both groups with a corresponding increase in serum ALP, bone fluoride content, Osteocalcin, CTx and urine fluoride with increasing levels of fluoride exposure. Serum creatinine calcium and phosphate and urinary cystatin C levels showed no significant changes. Light microscopy examination revealed mild thickening and increased osteoid in 80% of the Vitamin D deficient rats exposed to high levels of fluoride but renal tubular changes were found only in one experimental and one control animal. Fluoride deposited in rat bone affects both osteoblastic and osteoclastic activity. Also, these effects are accentuated in the presence of Vitamin D deficiency.

Project description:IntroductionAutism Spectrum Disorder (ASD) has been associated with a wide variety of genetic and environmental risk factors in both human and preclinical studies. Together, findings support a gene-environment interaction hypothesis whereby different risk factors independently and synergistically impair neurodevelopment and lead to the core symptoms of ASD. To date, this hypothesis has not been commonly investigated in preclinical ASD models. Mutations in the Contactin-associated protein-like 2 (Cntnap2) gene and exposure to maternal immune activation (MIA) during pregnancy have both been linked to ASD in humans, and preclinical rodent models have shown that both MIA and Cntnap2 deficiency lead to similar behavioral deficits.MethodsIn this study, we tested the interaction between these two risk factors by exposing Wildtype, Cntnap2+/- , and Cntnap2 -/- rats to Polyinosinic: Polycytidylic acid (Poly I:C) MIA at gestation day 9.5.ResultsOur findings showed that Cntnap2 deficiency and Poly I:C MIA independently and synergistically altered ASD-related behaviors like open field exploration, social behavior, and sensory processing as measured through reactivity, sensitization, and pre-pulse inhibition (PPI) of the acoustic startle response. In support of the double-hit hypothesis, Poly I:C MIA acted synergistically with the Cntnap2 -/- genotype to decrease PPI in adolescent offspring. In addition, Poly I:C MIA also interacted with the Cntnap2+/- genotype to produce subtle changes in locomotor hyperactivity and social behavior. On the other hand, Cntnap2 knockout and Poly I:C MIA showed independent effects on acoustic startle reactivity and sensitization.DiscussionTogether, our findings support the gene-environment interaction hypothesis of ASD by showing that different genetic and environmental risk factors could act synergistically to exacerbate behavioral changes. In addition, by showing the independent effects of each risk factor, our findings suggest that ASD phenotypes could be caused by different underlying mechanisms.

Dataset Information

Developmental Vitamin D Deficiency Produces Behavioral Phenotypes of Relevance to Autism in an Animal Model.

Publications

Developmental Vitamin D Deficiency Produces Behavioral Phenotypes of Relevance to Autism in an Animal Model.

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