RESUMEN
Chromosomal abnormalities are a common cause of human miscarriage but rarely reported in any other species. As a result, there are currently inadequate animal models available to study this condition. Horses present one potential model since mares receive intense gynecological care. This allowed us to investigate the prevalence of chromosomal copy number aberrations in 256 products of conception (POC) in a naturally occurring model of pregnancy loss (PL). Triploidy (three haploid sets of chromosomes) was the most common aberration, found in 42% of POCs following PL over the embryonic period. Over the same period, trisomies and monosomies were identified in 11.6% of POCs and subchromosomal aberrations in 4.2%. Whole and subchromosomal aberrations involved 17 autosomes, with chromosomes 3, 4, and 20 having the highest number of aberrations. Triploid fetuses had clear gross developmental anomalies of the brain. Collectively, data demonstrate that alterations in chromosome number contribute to PL similarly in women and mares, with triploidy the dominant ploidy type over the key period of organogenesis. These findings, along with highly conserved synteny between human and horse chromosomes, similar gestation lengths, and the shared single greatest risk for PL being advancing maternal age, provide strong evidence for the first animal model to truly recapitulate many key features of human miscarriage arising due to chromosomal aberrations, with shared benefits for humans and equids.
Asunto(s)
Aborto Espontáneo , Aberraciones Cromosómicas , Animales , Caballos , Femenino , Aborto Espontáneo/genética , Embarazo , Modelos Animales de Enfermedad , Humanos , TriploidíaRESUMEN
The aim of this double-blinded placebo-controlled study was to investigate the effect of acetylsalicylic acid (ASA) on uterine blood flow, gestation length, placental and foal weights in pregnant mares. Sixteen Thoroughbred mares of different age (13.3 ± 4.1) and parity (7.4 ± 3.1) were randomly assigned to three treatment groups. Mares in group C (n = 4) served as controls and received 5,000 mg lactose orally once daily from D 120 (D 0 = day of ovulation) until parturition. Mares in group ASA1 (n = 7) received 5,000 mg ASA orally once daily from D 120 until parturition. Mares in group ASA2 (n = 5) received the same dose ASA as group ASA1 from D 120 to D 285, but twice daily from D 285 until parturition. Mares were examined by ultrasonography on D 14, 28, and 60, and in 21-days intervals from D 120 until parturition. The cross-sectional area, time average maximum velocity (TAMV), and pulsatility index were measured in both uterine arteries and the blood flow volume was calculated for each uterine artery and then summarized. All 16 mares carried a normal pregnancy and delivered live foals. In group ASA2 TAMV in the ipsilateral artery was significantly higher (P = .03) and these mares showed a tendency of increased total blood flow volume (P = .07) during late pregnancy (D 305-346). Results indicate that oral administration of 5,000 mg of ASA twice daily in pregnant mares causes a rise in uterine blood flow during late pregnancy.
Asunto(s)
Circulación Placentaria , Útero , Caballos , Embarazo , Animales , Femenino , Peso al Nacer , Útero/diagnóstico por imagen , Proyectos Piloto , Aspirina/farmacología , Placenta , Arteria Uterina/diagnóstico por imagen , PartoRESUMEN
Embryonic and foetal loss remain one of the greatest challenges in equine reproductive health with 5-10% of established day 15 pregnancies and a further 5-10% of day 70 pregnancies failing to produce a viable foal. The underlying reason for these losses is variable but ultimately most cases will be attributed to pathologies of the environment of the developing embryo and later foetus, or a defect intrinsic to the embryo itself that leads to lethality at any stage of gestation right up to birth. Historically, much research has focused on the maternal endometrium, endocrine and immune responses in pregnancy and pregnancy loss, as well as infectious agents such as pathogens, and until recently very little was known about the both small and large genetic variants associated with reduced foetal viability in the horse. In this review, we first introduce key aspects of equine placental and foetal development. We then discuss incidence, risk factors and causes of pregnancy loss, with the latter focusing on genetic variants described to date that can impact equine foetal viability.
Asunto(s)
Aborto Inducido , Aborto Espontáneo , Humanos , Animales , Embarazo , Caballos , Femenino , Placenta/patología , Feto , Embrión de MamíferosRESUMEN
BACKGROUND: Early pregnancy loss (EPL) occurs in approximately 8% of equine pregnancies, although the aetiology is mostly unknown and embryonic/fetal morphological abnormalities associated with EPL are not defined. OBJECTIVES: To compare the morphology of EPL to clinically normal embryos/fetuses and previously described embryonic/fetal developmental milestones. To identify morphological abnormalities associated with equine EPL. STUDY DESIGN: Observational case-control study. METHODS: Embryos/fetuses were obtained from clinically normal Thoroughbred and pony pregnancies (n = 11) and following EPL from Thoroughbred mares (n = 27). The crown-rump length (CRL) of embryos/fetuses was measured and macroscopic morphology and developmental age were determined independently by three blinded examiners. Sagittal sections of EPL (n = 13) and control (n = 6) embryos/fetuses were assessed microscopically. Fisher's exact test was used to determine significance (P < .05) and correlations were expressed by Pearson coefficient. RESULTS: Age and CRL were strongly positively correlated in clinically normal Thoroughbred and reference (n = 15, R = .9 (95% CI: 0.8-1.0), R2 = .9, P < .0001) but not EPL embryos/fetuses (n = 19, R = .1 (95% CI: -0.4 to 0.5), R2 = .01, P = .75). Relative to controls, the CRL of EPL embryos/fetuses was smaller, with evidence of intrauterine growth retardation (IUGR) in 3/8 fetuses assessed. In 9/13 EPL embryos/fetuses, nonspecific neural tissue alterations were identified including disruption of developing pros-, mes- and rhombencephalon and the presence of haemosiderin, indicating premortem haemorrhage. Failed neural tube closure was identified in 1/13 EPL embryos/fetuses. Subcutaneous haemorrhage was present in 14/27 EPL embryos/fetuses. MAIN LIMITATIONS: Autolysis significantly affected 15/27 EPL embryos/fetuses, excluding them from complete assessment. The IUGR reference cut-off values were based on a small number of controls. CONCLUSIONS: Morphological features associated with equine EPL were a mismatch between embryonic/fetal size and age, and alterations of the developing neural tissue and localised subcutaneous haemorrhage. Failed neural tube closure was confirmed as a rare specific abnormality.
Asunto(s)
Aborto Veterinario , Enfermedades de los Caballos , Animales , Estudios de Casos y Controles , Largo Cráneo-Cadera , Femenino , Retardo del Crecimiento Fetal/veterinaria , Feto , Edad Gestacional , Enfermedades de los Caballos/etiología , Caballos , EmbarazoRESUMEN
The first 8 weeks of pregnancy is a critical time, with the majority of pregnancy losses occurring during this period. Abnormal chromosome number (aneuploidy) is a common finding in human miscarriage, yet is rarely reported in domestic animals. Equine early pregnancy loss (EPL) has no diagnosis in over 80% of cases. The aim of this study was to characterise aneuploidies associated with equine EPL. Genomic DNA from clinical cases of spontaneous miscarriage (EPLs; 14-65 days of gestation) and healthy control placentae (various gestational ages) were assessed using a high density genotyping array. Aneuploidy was detected in 12/55 EPLs (21.8%), and 0/15 healthy control placentae. Whole genome sequencing (30X) and digital droplet PCR (ddPCR) validated results. The majority of these aneuploidies have never been reported in live born equines, supporting their embryonic/fetal lethality. Aneuploidies were detected in both placental and fetal compartments. Rodents are currently used to study how maternal ageing impacts aneuploidy risk, however the differences in reproductive biology is a limitation of this model. We present the first evidence of aneuploidy in naturally occurring equine EPLs at a similar rate to human miscarriage. We therefore suggest the horse as an alternative to rodent models to study mechanisms resulting in aneuploid pregnancies.