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Fetal malformations and early embryonic gene expression response in Cynomolgus monkeys maternally exposed to thalidomide

ABSTRACT: EXPERIMENT: The animal experiments were performed at Shin Nippon Biomedical Laboratories (SNBL), Ltd. (Kagoshima, Japan) in compliance with the Guideline for Animal Experimentation (1987), and in accordance with the Law Concerning the Protection and Control of Animals (1973) and the Standards Relating to the Care and Management of Experimental Animals (1980). This study was approved by the Institutional Animal Care and Use Committee of SNBL and performed in accordance with the ethics criteria contained in the bylaws of the SNBL committee. Each female monkey was paired with a male of proven fertility for one day between day 11 and day 15 of the menstrual cycle. Pregnant females, aged 5-8 years and weighing 2.84-3.76 kg on day 22 of gestation, were allocated randomly to two groups, each with three monkeys, and housed individually. The monkeys were orally dosed with (Â±)-thalidomide (Lot no. SDH7273/SDJ3347, Wako Pure Chemical Industries, Ltd., Osaka, Japan) at 0 or 20 mg/kg by oral intubation on day 26 of gestation, which was during the critical period for thalidomide-induced teratogenesis [Delahunt and Lassen, 1964; Hendrickx, 1973]. Dosage was adjusted to the body weight on day 22 of gestation and the drug was packed in a gelatin capsule. Control monkeys received the capsule only. ANIMAL MODEL: Macaca fascicularis INTERVAL: NON. PLATFORM: Proprietary Affymetrix NHP GeneChipÂ® Array for Cynomolgus genome derived from Biogen Idec Keywords = Developmental Keywords = Monkeys Keywords = Thalidomide TFetal malformations and early embryonic gene expression response in cynomolgus monkeys maternally exposed to thalidomidechannel oligonucleotide (Affymetrix) platform.

ORGANISM(S): Macaca fascicularis

SUBMITTER: Ryota Ise

PROVIDER: E-GEOD-15542 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:We used the rhesus monkey (Macaca mulatta) as our animal model for the current study with two goals: to characterize the changes in histology and gene expression from early to late gestation (prenatal uterine organogenesis) and to determine if there are effects of prenatal exposure to bisphenol A (BPA) on the developing female uterus. Pregnant rhesus monkeys carrying a female fetus (N=22) were divided into two experimental groups, based on gestational timing: 'early' (N=10) and 'late' (N=12). These groups were then equally sub-divided into control (unexposed) and BPA (exposed) groups (5 Early Control, 5 Early BPA-exposed, 6 Late Control and 6 Late BPA-exposed.) The BPA-exposed monkeys received a deuterated BPA (dBPA, CDN Isotopes, Quebec, Canada) fruit treat on a daily basis, at a dose of 400ug/kg/day). The dosing was aimed at achieving serum levels of BPA detected in adult human biomonitoring studies. The control animals received a vehicle control on a daily basis. The 'early' time period (mid-gestation) referred to gestational days 50-100, approximating the second trimester of human gestation. The fetal monkeys in the 'early' group were delivered via cesarean section on gestation day 100 and euthanized. Samples of maternal and fetal blood and amniotic fluid were obtained. Maternal and fetal weights were also recorded. The 'late' time period referred to gestational days 100-165, approximating the third trimester of human gestation. The fetal monkeys in the 'late' group were delivered vaginally and euthanized. There were five idiopathic stillbirths (2 Control, 3 BPA-exposed) in the late group. Samples of maternal and fetal blood and amniotic fluid were obtained. Maternal and fetal weights were also recorded. After delivery, the fetal uterus was excised and cut sagitally from fundus to cervix; one side was fixed for histological evaluation and the other half was frozen for analysis of gene expression by microarray. The stillbirths were excluded from the microarray.

Project description:The long-tailed macaque, also referred to as cynomolgus monkey (Macaca fascicularis), is one of the most important non-human primate animal models in basic and applied biomedical research. To improve the predictive power of primate experiments for humans, we determined the genome sequence of a Macaca fascicularis female of Mauritian origin using a whole-genome shotgun sequencing approach. We applied a template switch strategy which employs either the rhesus or the human genome to assemble sequence reads. The 6-fold sequence coverage of the draft genome sequence enabled discovery of about 2.1 million potential single-nucleotide polymorphisms based on occurrence of a dimorphic nucleotide at a given position in the genome sequence. Homology-based annotation allowed us to identify 17,387 orthologs of human protein-coding genes in the M. fascicularis draft genome and the predicted transcripts enabled the design of a M. fascicularis-specific gene expression microarray. Using liver samples from 36 individuals of different geographic origin, we identified 718 genes with highly variable expression in liver, whereas the majority of the transcriptome shows relatively stable and comparable expression. Knowledge of the M. fascicularis draft genome is an important contribution to both the use of this animal in disease models and the safety assessment of drugs and their metabolites. In particular, this information allows high-resolution genotyping and microarray-based gene expression profiling for animal stratification, thereby allowing the use of well-characterized animals for safety testing. Finally, the genome sequence presented here is a significant contribution to the global "3R" animal welfare initiative, which has the goal to reduce, refine and replace animal experiments. A 36-microarray study using total RNA recovered from liver samples of untreated Cynomolgus monkeys of good laboratory practice (GLP) drug safety studies. The monkeys were from the Philippines, a Chinese colony, and Mauritius. Each microarray measures the expression level of 16,896 genes using 20,047 probe sets with six 60-mer probes (PM) per probe set. Each probe set is represented once on the array. The Cynomolgus monkey gene expression results analyzed in this study are further described in Ebeling et al. (2011) (PMID 21862625).

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Fetal malformations and early embryonic gene expression response in Cynomolgus monkeys maternally exposed to thalidomide

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