Gene expression profiling of the hippocampal dentate gyrus in an adult toxicity study captures a variety of neurodevelopmental dysfunctions in rat models of hypothyroidism

Abstract

We previously found that developmental hypothyroidism changed the expression of genes in the rat hippocampal dentate gyrus, a brain region where adult neurogenesis is known to occur. In the present study, we performed brain region-specific global gene expression profiling in an adult rat hypothyroidism model to see if it reflected the developmental neurotoxicity we saw in the developmental hypothyroidism model. Starting when male rats were 5 weeks old, we administered 6-propyl-2-thiouracil at a doses of 0, 0.1 and 10 mg kg(-1) body weight by gavage for 28 days. We selected four brain regions to represent both cerebral and cerebellar tissues: hippocampal dentate gyrus, cerebral cortex, corpus callosum and cerebellar vermis. We observed significant alterations in the expression of genes related to neural development (Eph family genes and Robo3) in the cerebral cortex and hippocampal dentate gyrus and in the expression of genes related to myelination (Plp1 and Mbp) in the hippocampal dentate gyrus. We observed only minor changes in the expression of these genes in the corpus callosum and cerebellar vermis. We used real-time reverse-transcription polymerase chain reaction to confirm Chrdl1, Hes5, Mbp, Plp1, Slit1, Robo3 and the Eph family transcript expression changes. The most significant changes in gene expression were found in the dentate gyrus. Considering that the gene expression profile of the adult dentate gyrus closely related to neurogenesis, 28-day toxicity studies looking at gene expression changes in adult hippocampal dentate gyrus may also detect possible developmental neurotoxic effects.

Influence of hypothyroidism on testicular mitochondrial oxidative stress by activating the p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase signaling pathways in rats

“…Then, rats were randomly divided into three groups ( n = 10 per group), the control (C), low dose (L), and high dose (H) groups, and received normal saline, 0.001%, and 0.1% PTU by intragastric gavage for 60 days, respectively. 15,28 Their body weights (BWs) were measured once every 3 days.…”

Roles of ERK1/2 and PI3K/AKT signaling pathways in mitochondria-mediated apoptosis in testes of hypothyroid rats

“…Then, the experimental rats were randomly divided into control (C), low dose (L) and high dose (H) groups, and were administered with 1 mL per 100 g BW per day normal saline, 0.001% and 0.1% PTU, respectively, by intragastrical gavage for 60 days. 7,36 The body weights of the rats were measured every three days.…”

Gene expression profiles of multiple brain regions in rats differ between developmental and postpubertal exposure to valproic acid

“…In agreement with this hypothesis, we demonstrated earlier that different patterns of disruption of hippocampal neurogenesis occur between developmental and postpubertal exposure of VPA (Watanabe et al, 2019; Watanabe, Murakami, et al, 2017). We also previously reported that the pattern of disruption of hippocampal neurogenesis by developmental neurotoxicants such as PTU and MNU may be different between developmental and postpubertal exposure; this is in contrast to the similar patterns of disruption that occur after developmental and postpubertal exposure to adult‐type neurotoxicants, such as cuprizone and glycidol (Abe et al, 2015, 2016; Akane, Shiraki, et al, 2013, 2014; Shiraki et al, 2016; Watanabe, Nakajima, et al, 2017). In the present study, the finding of no or very low similarity in the gene expression profiles of the four brain regions between developmental and postpubertal exposure to VPA supported our hypothesis.…”

“…These results suggest that it is possible to predict adult‐type neurotoxicity by examining cellular responses in hippocampal adult neurogenesis and its regulatory system in a 28‐day repeated toxicity test using rats. In contrast, developmental neurotoxicants, such as 6‐propyl‐2‐thiouracil (PTU) and N ‐methyl‐ N ‐nitrosourea (MNU), have been reported to affect the granule cell lineage and γ‐aminobutyric acid (GABA)‐ergic interneuron subpopulations differently between developmental and postpubertal exposure (Shiraki et al, 2016; Watanabe, Nakajima, et al, 2017). Of note, the effects of developmental neurotoxicants may also be detected after postpubertal exposure if disruption of hippocampal neurogenesis is confirmed.…”