Hydroxyurea Treatment and Development of the Rat Cerebellum: Effects on the Neurogenetic Profiles and Settled Patterns of Purkinje Cells and Deep Cerebellar Nuclei Neurons

Abstract

The current paper analyzes the development of the male and female rat cerebellum exposed to hydroxyurea (HU) (300 or 600 mg/kg) as embryo and collected at postnatal day 90. Our study reveals that the administration of this drug compromises neither the cytoarchitecture of the cerebellar cortex nor deep nuclei (DCN). However, in comparison with the saline group, we observed that several cerebellar parameters were lower in the HU injected groups. These parameters included area of the cerebellum, cerebellar cortex length, molecular layer area, Purkinje cell number, granule cell counts, internal granular layer, white matter and cerebellar nuclei areas, and number of deep cerebellar nuclei neurons. These features were larger in the rats injected with saline, smaller in those exposed to 300 mg/kg of HU and smallest in the group receiving 600 mg/kg of this agent. No sex differences in the effect of the HU were observed. In addition, we infer the neurogenetic timetables and the neurogenetic gradients of PCs and DCN neurons in rats exposed to either saline or HU as embryos. For this purpose, 5-bromo-2'-deoxyuridine was injected into pregnant rats previously administered with saline or HU. This thymidine analog was administered following a progressively delayed cumulative labeling method. The data presented here show that systematic differences exist in the pattern of neurogenesis and in the spatial location of cerebellar neurons between rats injected with saline or HU. No sex differences in the effect of the HU were observed. These findings have implications for the administration of this compound to women in gestation as the effects of HU on the development of the cerebellum might persist throughout their offsprings' life.

An Animal Model for Assessing the Effects of Hydroxyurea Exposure Suggests That the Administration of This Agent to Pregnant Women and Young Infants May Not Be as Safe as We Thought

“…(2) The cerebellum is highly vulnerable to insults, the expression of mutant genes and intoxication [43,44,45]. In this context, it has been reported that several spontaneous murine mutations, including lurcher, staggerer, reeler and weaver cause a marked reduction in the volume and shape of the cerebellum due to the severe depletion of neurons [46,47,48]. In addition, it has also been indicated that the selective elimination of neuron precursors with X-irradiation [36], platinum compounds [49,50], impairment of the thyroid status [51], ethanol [52] and virus infection [53] produce an important reduction in size of the cerebellar cortex.…”

“…Here, we show that a single administration of HU during embryonic life modifies the regular cytoarchitecture of the cerebellum and alters the neurogenetic profiles and settled patterns of PCs and DNC neurons. The results of this section are taken from a previous published paper [48].…”

An Animal Model to Assess the Effects of Hydroxyurea Exposure Suggests That the Administration of This Agent to Pregnant Women and Young Infants May Not Be as Safe as We Thought<strong> </strong>

“…(II) The cerebellum is highly vulnerable to insults, expression of mutant genes and intoxication [44][45][46]. In this context, it has been reported that several spontaneous murine mutations, including lurcher, staggerer, reeler and weaver cause a marked reduction in the volume and shape of the cerebellum due to the severe depletion of neurons [47][48][49]. In addition, it has also been indicated that the selective elimination of neuron precursors with X-irradiation [37], platinum compounds [50][51], impairment of the thyroid status [52], ethanol [53] and virus infection [54] produce an important reduction in size of the cerebellar cortex.…”

“…neurogenetic profiles and settled patterns of PCs and DNC neurons. The results of this section are taken from a previous published paper [49].…”

Administration of 5‐bromo‐2′‐deoxyuridine interferes with neuroblast proliferation and promotes apoptotic cell death in the rat cerebellar neuroepithelium

“…The major goal of this study is to analyze whether a single injection of BrdU, doses ranging from 25 to 300 μg/g b.w., alters the development of the cerebellar neuroepithelium. Dams were injected on embryonic day (E) 13, as it corresponds to the onset of Purkinje cells and deep cerebellar nuclei neurons neurogenesis in wild type rats (Altman & Bayer, 1997; Martí et al, 2015, 2016). The selection of the cerebellum was supported by the evidence that this region is highly vulnerable to poisoning (Samson & Claassen, 2017).…”