This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The objective of this exploratory research project is to study the effects of chronic exposure to phthalate esters on the infant primate testis in a novel xenograft model system. Environmental exposure to reproductive toxicants is of serious concern to human health and has been implicated in both the apparent decline of male fertility and a rise in testicular neoplasms. Phthalate esters are widely used as plasticizers in consumer products and can leach into the environment, resulting in significant human exposure, especially during childhood and in pediatric patients requiring long-term catheterization or intravenous treatments. Di-(2- ethylhexyl) phthalate (DEHP) is the most ubiquitous phthalate and its metabolite MEHP is a known testicular toxicant. Di-n-butyl phthalate (DBP) is commonly found in personal care products and fetal exposure to DBP affects male reproductive tract development in rats. Historically, research into the reproductive toxicology of phthalates has been evaluated following gestational exposure in rodents, but species-specific differences in metabolism and sensitivity of the reproductive organs suggest that results obtained in rodent models may not extrapolate well to humans. As epidemiological studies link phthalate exposure during childhood to disturbances of human male reproductive development, there is a clear need for studies in primate models, as emphasized by the NTP-CERHR Expert Panel on the Reproductive and Developmental Toxicity of DEHP. In this revised exploratory project we propose to utilize a novel primate testis tissue xenografting system developed in our lab to study the effect of DEHP and DBP on testicular maturation and testis function in immature rhesus monkey testes.
Specific aim 1 will test the hypothesis that exposure to environmentally relevant concentrations of DEHP or DBP will adversely affect testicular somatic cell function and germ cell development. Specifically, testis tissue from infant and juvenile monkeys will be ectopically grafted to mouse hosts and exposed to various doses of DEHP or DBP for 3 months. At various time points, Sertoli cell maturation, steroidogenic function of Leydig cells, and exogenous gonadotropin-induced germ cell differentiation will be compared in treated and control tissue to assess the potential effects of chronic phthalate exposure.
Specific aim 2 will investigate the mechanisms underlying phthalate toxicity in the infant primate testis. Phthalate-induced changes in global gene expression patterns in testis tissue from infant monkeys will be evaluated by microarray analysis and confirmed by RT-PCR. Special attention will be given to differential expression of genes involved in steroidogenesis. Successful completion of this exploratory project will provide insights into the sensitivity to phthalate esters, characterize effects on testicular somatic cell maturation, and begin to elucidate the molecular mechanisms underlying phthalate toxicity in the immature primate testis. Results from the proposed project will provide the basis for future studies performed in the developing primate.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR000169-50
Application #
8357330
Study Section
Special Emphasis Panel (ZRR1-CM-5 (01))
Project Start
2011-05-01
Project End
2012-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
50
Fiscal Year
2011
Total Cost
$50,419
Indirect Cost
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Han, Pengcheng; Nielsen, Megan; Song, Melissa et al. (2017) The Impact of Aging on Brain Pituitary Adenylate Cyclase Activating Polypeptide, Pathology and Cognition in Mice and Rhesus Macaques. Front Aging Neurosci 9:180
Pittet, Florent; Johnson, Crystal; Hinde, Katie (2017) Age at reproductive debut: Developmental predictors and consequences for lactation, infant mass, and subsequent reproduction in rhesus macaques (Macaca mulatta). Am J Phys Anthropol 164:457-476
Zhang, Xinjun; Kanthaswamy, Sree; Trask, Jessica S et al. (2017) Genetic Characterization of a Captive Colony of Pigtailed Macaques (Macaca nemestrina). J Am Assoc Lab Anim Sci 56:390-395
Jensen, Kara; Dela Pena-Ponce, Myra Grace; Piatak Jr, Michael et al. (2017) Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine. Clin Vaccine Immunol 24:
Rose, Destanie R; Careaga, Milo; Van de Water, Judy et al. (2017) Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation. Brain Behav Immun 63:60-70
Hasan, M Kamrul; Feeroz, M Mostafa; Jones-Engel, Lisa et al. (2016) Performing monkeys of Bangladesh: characterizing their source and genetic variation. Primates 57:221-30
Austin, Christine; Smith, Tanya M; Farahani, Ramin M Z et al. (2016) Uncovering system-specific stress signatures in primate teeth with multimodal imaging. Sci Rep 6:18802
Scott, Julia A; Grayson, David; Fletcher, Evan et al. (2016) Longitudinal analysis of the developing rhesus monkey brain using magnetic resonance imaging: birth to adulthood. Brain Struct Funct 221:2847-71
Rueda, Cesar M; Presicce, Pietro; Jackson, Courtney M et al. (2016) Lipopolysaccharide-Induced Chorioamnionitis Promotes IL-1-Dependent Inflammatory FOXP3+ CD4+ T Cells in the Fetal Rhesus Macaque. J Immunol 196:3706-15
Bliss-Moreau, Eliza; Moadab, Gilda (2016) Variation in Behavioral Reactivity Is Associated with Cooperative Restraint Training Efficiency. J Am Assoc Lab Anim Sci 55:41-9

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