Mei Tan1, Ting Yang1, Huan Liu1, Lu Xiao1, Cheng Li1, Jiang Zhu1, Jie Chen2, Tingyu Li3. 1. Children's Nutrition Research Center, Children's Hospital of Chongqing Medical University, Chongqing Key Laboratory of Child Nutrition and Health, China; Ministry of Education Key Laboratory of Child Development and Disorders, China; National Clinical Research Center for Child Health and Disorder, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, China. 2. Children's Nutrition Research Center, Children's Hospital of Chongqing Medical University, Chongqing Key Laboratory of Child Nutrition and Health, China; Ministry of Education Key Laboratory of Child Development and Disorders, China; National Clinical Research Center for Child Health and Disorder, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, China. Electronic address: jchen010@hospital.cqmu.edu.cn. 3. Children's Nutrition Research Center, Children's Hospital of Chongqing Medical University, Chongqing Key Laboratory of Child Nutrition and Health, China; Ministry of Education Key Laboratory of Child Development and Disorders, China; National Clinical Research Center for Child Health and Disorder, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, China. Electronic address: tyli@vip.sina.com.
Abstract
AIMS: Many gastrointestinal (GI) disorders are developmental in origin and are caused by abnormal enteric nervous system (ENS) formation. Maternal vitamin A deficiency (VAD) during pregnancy affects multiple central nervous system developmental processes during embryogenesis and fetal life. Here, we evaluated whether maternal diet-induced VAD during pregnancy alone can cause changes in the ENS that lead to GI dysfunction in rat offspring. MAIN METHODS: Rats were selected to construct animal models of normal VA, VA deficiency and VA supplementation. The fecal water content, total gastrointestinal transmission time and colonic motility were measured to evaluate gastrointestinal function of eight-week-old offspring rats. The expression levels of RARβ, SOX10, cholinergic (ChAT) and nitrergic (nNOS) enteric neurons in colon tissues were detected through western blot and immunofluorescence. Primary enteric neurospheres were treated with retinoic acid (RA), infection with Ad-RARβ and siRARβ adenovirus, respectively. KEY FINDINGS: Our data revealed marked reductions in the mean densities of cholinergic and nitrergic enteric neurons in the colon and GI dysfunction evidenced by mild intestinal flatulence, increased fecal water content, prolonged total GI transit time and reduced colon motility in adult offspring of the VAD group. Interestingly, maternal VA supplementation (VAS) during pregnancy rescued these changes. In addition, in vitro experiments demonstrated that exposure to appropriate doses of RA promoted enteric neurosphere differentiation into cholinergic and nitrergic neurons, possibly by upregulating RARβ expression, leading to enhanced SOX10 expression. SIGNIFICANCE: Maternal VAD during pregnancy is an environmental risk factor for GI dysfunction in rat offspring.
AIMS: Many gastrointestinal (GI) disorders are developmental in origin and are caused by abnormal enteric nervous system (ENS) formation. Maternal vitamin A deficiency (VAD) during pregnancy affects multiple central nervous system developmental processes during embryogenesis and fetal life. Here, we evaluated whether maternal diet-induced VAD during pregnancy alone can cause changes in the ENS that lead to GI dysfunction in rat offspring. MAIN METHODS:Rats were selected to construct animal models of normal VA, VA deficiency and VA supplementation. The fecal water content, total gastrointestinal transmission time and colonic motility were measured to evaluate gastrointestinal function of eight-week-old offspring rats. The expression levels of RARβ, SOX10, cholinergic (ChAT) and nitrergic (nNOS) enteric neurons in colon tissues were detected through western blot and immunofluorescence. Primary enteric neurospheres were treated with retinoic acid (RA), infection with Ad-RARβ and siRARβ adenovirus, respectively. KEY FINDINGS: Our data revealed marked reductions in the mean densities of cholinergic and nitrergic enteric neurons in the colon and GI dysfunction evidenced by mild intestinal flatulence, increased fecal water content, prolonged total GI transit time and reduced colon motility in adult offspring of the VAD group. Interestingly, maternal VA supplementation (VAS) during pregnancy rescued these changes. In addition, in vitro experiments demonstrated that exposure to appropriate doses of RA promoted enteric neurosphere differentiation into cholinergic and nitrergic neurons, possibly by upregulating RARβ expression, leading to enhanced SOX10 expression. SIGNIFICANCE: Maternal VAD during pregnancy is an environmental risk factor for GI dysfunction in rat offspring.