Calorie restriction and pravastatin administration during pregnancy in obese rhesus macaques modulates maternal and infant metabolism and infant brain and behavioral development.

Background: Maternal obesity has been associated with a higher risk of pregnancy-related complications in mothers and offspring; however, effective interventions have not yet been developed. We tested two interventions, calorie restriction and pravastatin administration, during pregnancy in a rhesus macaque model with the hypothesis that these interventions would normalize metabolic dysregulation in pregnant mothers leading to an improvement in infant metabolic and cognitive/social development.

Methods: A total of 19 obese mothers were assigned to either one of the two intervention groups ( = 5 for calorie restriction;  = 7 for pravastatin) or an obese control group ( = 7) with no intervention, and maternal gestational samples and postnatal infant samples were compared with lean control mothers ( = 6) using metabolomics methods.

Multi-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models.

Maternal obesity during pregnancy is associated with neurodevelopmental disorder (NDD) risk. We utilized integrative multi-omics to examine maternal obesity effects on offspring neurodevelopment in rhesus macaques by comparison to lean controls and two interventions. Differentially methylated regions (DMRs) from longitudinal maternal blood-derived cell-free fetal DNA (cffDNA) significantly overlapped with DMRs from infant brain.

Chimpanzee and pig-tailed macaque iPSCs: Improved culture and generation of primate cross-species embryos.

As our closest living relatives, non-human primates uniquely enable explorations of human health, disease, development, and evolution. Considerable effort has thus been devoted to generating induced pluripotent stem cells (iPSCs) from multiple non-human primate species. Here, we establish improved culture methods for chimpanzee (Pan troglodytes) and pig-tailed macaque (Macaca nemestrina) iPSCs.

Impact of Maternal Obesity on the Gestational Metabolome and Infant Metabolome, Brain, and Behavioral Development in Rhesus Macaques.

Maternal gestational obesity is associated with elevated risks for neurodevelopmental disorder, including autism spectrum disorder. However, the mechanisms by which maternal adiposity influences fetal developmental programming remain to be elucidated. We aimed to understand the impact of maternal obesity on the metabolism of both pregnant mothers and their offspring, as well as on metabolic, brain, and behavioral development of offspring by utilizing metabolomics, protein, and behavioral assays in a non-human primate model.

Shared aspects of mRNA expression associated with oocyte maturation failure in humans and rhesus monkeys indicating compromised oocyte quality.

Oocyte maturation failure observed in assisted reproduction technology (ART) cycles can limit the number of quality oocytes obtained and present a pronounced barrier for some patients. The potential exists to use unmatured oocytes for ART through in vitro maturation. Understanding the molecular basis of oocyte maturation failure is pertinent to minimizing this loss of oocytes and considerations of whether such oocytes can be used safely for ART.

Temporal patterns of gene regulation and upstream regulators contributing to major developmental transitions during Rhesus macaque preimplantation development.

The preimplantation period of life in mammals encompasses a tremendous amount of restructuring and remodeling of the embryonic genome and reprogramming of gene expression. These vast changes support metabolic activation and cellular processes that drive early cleavage divisions and enable the creation of the earliest primitive cell lineages. A major question in mammalian embryology is how such vast, sweeping changes in gene expression are orchestrated, so that changes in gene expression are exactly appropriate to meet the developmental needs of the embryo over time.

Prenatal Bisphenol A Exposure Alters Epithelial Cell Composition in the Rhesus Macaque Fetal Oviduct.

Bisphenol A (BPA) is an endocrine disrupting compound that is a pervasive environmental contaminant. Although it has been reported to affect the development of a variety of fetal reproductive tissues, data on the effect of fetal BPA exposure on oviducts were extremely limited and were only available in mice. To determine if there are adverse effects of gestational BPA exposure on fetal oviduct, we exposed pregnant rhesus macaques with female fetuses to oral or nonoral BPA during the last trimester of gestation (day 100 to term).

Transcriptome analysis of rhesus monkey failed-to-mature oocytes: deficiencies in transcriptional regulation and cytoplasmic maturation of the oocyte mRNA population.

Study Question: Which different pathways and functions are altered in rhesus monkey oocytes that fail to mature after an ovulatory stimulus?

Summary Answer: Failed to mature (FTM) oocytes complete a large portion of the transition in transcriptome composition associated with normal maturation, but also manifest numerous differences that indicate incomplete transcriptional repression and cytoplasmic maturation affecting multiple processes.

What Is Known Already: Oocyte maturation defects contribute to unexplained female infertility. Failure of some oocytes to undergo germinal vesicle breakdown or progress to second meiotic metaphase in response to an ovulatory stimulus can limit the number of high quality oocytes available for ART.

Adiposity and weight gain during pregnancy associate independently with behavior of infant rhesus monkeys (Macaca mulatta).

Growing evidence identifies maternal adiposity as a potentially modifiable risk factor for adverse neurodevelopment. This retrospective cohort analysis examined whether maternal prepregnancy adiposity and gestational weight gain were associated with behavioral outcomes in 173 rhesus macaque infants at the California National Primate Research Center. Dams conceived indoors, had uncomplicated pregnancies, delivered vaginally, and reared infants indoors.

Determination of single embryo sex in Macaca mulatta and Mus musculus RNA-Seq transcriptome profiles.

To account for sex as a biological variable, it is sometimes necessary to identify the sex of an embryo or embryonic cell that was used to generate libraries for RNA sequencing, without the sex being known a priori. The preferred approach for this would take advantage of the mRNA data, rather than relying on other methods that require separation and analysis of genomic DNA or diversion of limiting RNA for other assays. We describe here a method that has been optimized for this purpose in samples of rhesus monkey and mouse embryos.

Changes in gene expression following long-term in vitro exposure of Macaca mulatta trophoblast stem cells to biologically relevant levels of endocrine disruptors.

Trophoblast stem cells (TSCs) are crucial for embryo implantation and placentation. Environmental toxicants that compromise TSC function could impact fetal viability, pregnancy, and progeny health. Understanding the effects of low, chronic EDC exposures on TSCs and pregnancy is a priority in developmental toxicology.

Quantitative assessment of timing, efficiency, specificity and genetic mosaicism of CRISPR/Cas9-mediated gene editing of hemoglobin beta gene in rhesus monkey embryos.

Gene editing technologies offer new options for developing novel biomedical research models and for gene and stem cell based therapies. However, applications in many species demand high efficiencies, specificity, and a thorough understanding of likely editing outcomes. To date, overall efficiencies, rates of off-targeting and degree of genetic mosaicism have not been well-characterized for most species, limiting our ability to optimize methods.

The contraceptive efficacy of intravas injection of Vasalgel™ for adult male rhesus monkeys.

Background: Options for male contraception are limited. The purpose of this study was to use a nonhuman primate model to evaluate Vasalgel™, a high molecular weight polymer being developed as a contraceptive device for men.

Methods: Sixteen adult male rhesus monkeys received intravas injections of Vasalgel, consisting of 25% styrene maleic acid in dimethyl sulfoxide.

Maternal and Fetal Pharmacokinetics of Oral Radiolabeled and Authentic Bisphenol A in the Rhesus Monkey.

The present study was conducted in pregnant rhesus monkeys to determine the rapidity and extent to which BPA reaches the fetal compartment following oral ingestion, and the 24-hr fate of BPA. To assess metabolism changes during the course of pregnancy, we compared BPA biotransformation during the second and third trimesters in the same animals, measuring the levels of sulfated, gluronidated, and free BPA in maternal serum, amniotic fluid, and fetal serum. All animals showed measurable unconjugated and conjugated BPA in the fetal compartment and slow clearance compared to maternal serum.

Effects of long-term endocrine disrupting compound exposure on Macaca mulatta embryonic stem cells.

Endocrine disrupting chemicals (EDCs) exert significant effects on health and physiology, many traceable to effects on stem cell programming underlying development. Understanding risk of low-level, chronic EDC exposure will be enhanced by knowledge of effects on stem cells. We exposed rhesus monkey embryonic stem cells to low levels of five EDCs [bisphenol A (BPA), atrazine (ATR), tributyltin (TBT), perfluorooctanoic acid (PFOA), and di-(2-ethylhexyl) phthalate (DEHP)] for 28days, and evaluated effects on gene expression by RNAseq transcriptome profiling.

Disruptions in follicle cell functions in the ovaries of rhesus monkeys during summer.

Oocytes isolated from female rhesus monkeys following standard ovarian stimulation protocols during the summer months displayed a reduced capacity to mature compared with stimulation during the normal breeding season. Because the gene expression profiles of oocyte-associated cumulus cells and mural granulosa cells (CCs and GCs) are indicative of altered oocyte quality and can provide insight into intrafollicular processes that may be disrupted during oogenesis, we performed array-based transcriptome comparisons of CCs and GCs from summer and normal breeding season stimulation cycles. Summer CCs and GCs both display deficiencies in expression of mRNAs related to cell proliferation, angiogenesis, and endocrine signaling, as well as reduced expression of glycogen phosphorylase.

Transgenerational effects of binge drinking in a primate model: implications for human health.

Objective: To determine if binge ethanol consumption before ovulation affects oocyte quality, gene expression, and subsequent embryo development.

Design: Binge levels of ethanol were given twice weekly for 6 months, followed by a standard in vitro fertilization cycle and subsequent natural mating.

Setting: National primate research center.

Invalid controls undermine conclusions of FDA studies.

This issue of Toxicological Sciences features several exciting changes: a redesigned cover, revised category subheadings, and this "Look Inside ToxSci" feature. Together with my esteemed colleagues in the field of green chemistry, we have outlined some exciting opportunities for the field of toxicology in the editorial on green chemistry and toxicology. There are insightful articles on the regulatory challenges regarding mixtures that are being addressed by the European Union and on risk assessment of carbon nanotubes.

Bisphenol a and reproductive health: update of experimental and human evidence, 2007-2013.

Background: In 2007, an expert panel reviewed associations between bisphenol A (BPA) exposure and reproductive health outcomes. Since then, new studies have been conducted on the impact of BPA on reproduction.

Objective: In this review, we summarize data obtained since 2007, focusing on a) findings from human and animal studies, b) the effects of BPA on a variety of reproductive end points, and c) mechanisms of BPA action.

Dietary sugar in healthy female primates perturbs oocyte maturation and in vitro preimplantation embryo development.

The consumption of refined sugars continues to pose a significant health risk. However, nearly nothing is known about the effects of sugar intake by healthy women on the oocyte or embryo. Using rhesus monkeys, we show that low-dose sucrose intake over a 6-month period has an impact on the oocyte with subsequent effects on the early embryo.

Maternal bisphenol a exposure impacts the fetal heart transcriptome.

Conditions during fetal development influence health and disease in adulthood, especially during critical windows of organogenesis. Fetal exposure to the endocrine disrupting chemical, bisphenol A (BPA) affects the development of multiple organ systems in rodents and monkeys. However, effects of BPA exposure on cardiac development have not been assessed.

Bisphenol A (BPA) pharmacokinetics with daily oral bolus or continuous exposure via silastic capsules in pregnant rhesus monkeys: Relevance for human exposures.

We measured serum dBPA in non-pregnant and pregnant female rhesus monkeys, fetuses and amniotic fluid. dBPA was administered by a daily oral bolus or sc implantation of Silastic capsules; both resulted in daily average serum unconjugated dBPA concentrations of <1ng/ml. We observed lower serum concentrations of unconjugated dBPA in pregnant females relative to pre-pregnancy values, and generally lower concentrations in fetal serum than in maternal serum.

Bisphenol A exposure alters developmental gene expression in the fetal rhesus macaque uterus.

Bisphenol A (BPA) exposure results in numerous developmental and functional abnormalities in reproductive organs in rodent models, but limited data are available regarding BPA effects in the primate uterus. To determine if maternal oral BPA exposure affects fetal uterine development in a non-human primate model, pregnant rhesus macaques carrying female fetuses were exposed orally to 400 µg/kg BPA or vehicle control daily from gestation day (GD) 50-100 or GD100-165. Fetal uteri were collected at the completion of treatment (GD100 or GD165); tissue histology, cell proliferation, and expression of estrogen receptor alpha (ERα) and progesterone receptor (PR) were compared to that of controls.

Binge drinking prior to pregnancy detection in a nonhuman primate: behavioral evaluation of offspring.

Background: Minimal scientific information is available to inform public health policy on binge drinking prior to pregnancy detection. The nonhuman primate provides a valuable animal model for examining consequences to reproduction and offspring function that may result from this common pattern of alcohol abuse.

Methods: Adult female rhesus monkeys were dosed with 1.