Pregnancy provides a blueprint of highly synchronized maternal responses involving endocrine-immuneangiogenic mechanisms that are significantly influenced by gene-environment interactions. Although reproductive and neurocognitive anomalies have been reported in humans in response to environmental toxicants, experimental evidence in support of these observations is still elusive. Despite their discontinued industrial use, polychlorinated biphenyls (PCBs) are ubiquitous environmental toxicants and pose a health threat as they either mimic or block the actions of hormones. Since exposure to toxicants is mostly to mixtures, PCBs offer an ideal model system to delineate the unknown pathways and targets that underlie toxicant-induced reproductive health effects. PCBs affect either aryl hydrocarbon receptor (AhR) or estrogen receptor (ER) signaling pathways and may possess antagonistic or synergistic effects depending on the coplanar or non-co-planar structures. We hypothesize that in the context of in utero exposure, inflammation through Toll-like receptors (TLRs), angiogenesis, and fluid regulation are the key targets of PCBs at the maternal-fetal interface, and anomalies associated with these pathways become further manifested in response to genetic stress. Our recent results clearly provide support to this notion in that IL-10 deficiency in mice potentiates reproductive complications in response to Aroclor 1254. IL-10 is a potent anti-inflammatory cytokine and has been shown to be a critical factor for normal pregnancy outcome in humans. It is further hypothesized that in utero exposure to PCBs entails compromised pregnancy outcome and postnatal health. To understand the mechanistic underpinnings of PCB-induced in utero effects, we have recently established a mouse model and demonstrated that water channel Aquaporins and angiogenic functions are the novel targets of PCBs at the maternal-fetal interface. We propose to pursue the following specific aims to address our hypothesis and to extend our preliminary observations.
Specific Aim 1 : To determine the dosedependent effect of individual PCB congeners representing co-planar or non-co-planar structures on pregnancy outcome, amniotic fluid regulation, fetal development, spiral artery transformation, and local immune functions.
Specific Aim 2 : To delineate the role of novel pathways for PCB-induced effects, including aquaporins and angiogenesis.
Specific Aim 3 : To rescue PCB-induced pregnancy disruption by IL-10, estradiol, or human chorionic gonadotropin (hCG).
Specific Aim 4 : To evaluate the PCB-mediated inflammatory trigger through Toll-like receptors (TLRs). Evaluating the novel targets of PCBs in an experimental model with reproductive and neurocognitive health risks will lead us to understand novel mechanisms involved in gene-environment interactions and their health complications.
The over-arching goal of this Superfund Basic Research Program is to address health concerns, and to design novel remediation techniques, related to mixed exposures arising from contaminated lands and buildings, using Rhode Island as a model for appropriate research, educational, and training interventions.
|Qiu, Yang; Guo, Fei; Hurt, Robert et al. (2014) Explosive thermal reduction of graphene oxide-based materials: mechanism and safety implications. Carbon N Y 72:215-223|
|Shen, Rui; Suuberg, Eric M (2014) Analytical Quantification of the Subslab Volatile Organic Vapor Concentration from a Non-uniform Source. Environ Model Softw 54:1-8|
|Clift, Danielle; Richendrfer, Holly; Thorn, Robert J et al. (2014) High-throughput analysis of behavior in zebrafish larvae: effects of feeding. Zebrafish 11:455-61|
|Qin, Xiaoli; Liu, Xiaorui; Shan, Bin et al. (2014) Inhibition of eIF5A results in aberrant uterine natural killer cell function and embryo loss in mice. Am J Reprod Immunol 71:229-40|
|Rodd, April L; Creighton, Megan A; Vaslet, Charles A et al. (2014) Effects of surface-engineered nanoparticle-based dispersants for marine oil spills on the model organism Artemia franciscana. Environ Sci Technol 48:6419-27|
|Velazquez-Jimenez, Litza Halla; Hurt, Robert H; Matos, Juan et al. (2014) Zirconium-carbon hybrid sorbent for removal of fluoride from water: oxalic acid mediated Zr(IV) assembly and adsorption mechanism. Environ Sci Technol 48:1166-74|
|Catlin, Natasha R; Huse, Susan M; Boekelheide, Kim (2014) The stage-specific testicular germ cell apoptotic response to low-dose radiation and 2,5-hexanedione combined exposure. II: qRT-PCR array analysis reveals dose dependent adaptive alterations in the apoptotic pathway. Toxicol Pathol 42:1229-37|
|Catlin, Natasha R; Huse, Susan M; Boekelheide, Kim (2014) The stage-specific testicular germ cell apoptotic response to low-dose X-irradiation and 2,5-hexanedione combined exposure. I: Validation of the laser capture microdissection method for qRT-PCR array application. Toxicol Pathol 42:1221-8|
|Shen, Rui; Pennell, Kelly G; Suuberg, Eric M (2014) Analytical modeling of the subsurface volatile organic vapor concentration in vapor intrusion. Chemosphere 95:140-9|
|Sharma, Surendra (2014) Natural killer cells and regulatory T cells in early pregnancy loss. Int J Dev Biol 58:219-29|
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