Biological Response Profiles of Selected Engineered Nanomaterials after Perinatal Exposure

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PROJECT SUMMARY The steady growth of products containing engineered nanomaterials (ENMs) has outpaced research to determine their impact on biological systems, most importantly human health. Our goal in this Nanomaterials Health Implications Research (NHIR) Consortium proposal is to elucidate how physicochemical properties of ENMs and their molecular interactions affect the immune and hormonal status of exposed animals. We will accomplish this goal by collaborating with NIEHS project scientists and NHIR Consortium members to test ENMs provided by the ENM Resource and Coordination Core (ERCC) first in vitro using a novel air-liquid interface system, and then in vivo for a subset of ENMs using a Pulmonary Tox Protocol and a Developmental Tox Protocol. Each protocol will employ nose-only and whole-body inhalation exposure and a host of outcome measures to assess body condition, cytotoxicity, inflammation, oxidative stress, gene expression, immune modulation, endocrine disruption, and histopathology. We will share our data and methods within the NHIR Consortium and beyond, thereby contributing to the development of comprehensive biological response profiles of selected ENMs and identifying those that pose significant hazards for vulnerable populations including pregnant women and children. Three specific aims will be addressed: AIM 1: Identify which ERCC- characterized ENMs are most likely to induce cytotoxicity, inflammation, or immunomodulation in airway epithelial cells using our established in vitro air-liquid interface model system. AIM2: Characterize comprehensive biological responses to selected ENMs following subchronic inhalation exposure in pregnant compared to non-pregnant mice. AIM 3: Elucidate biological response profiles in male and female offspring following exposure to ENMs in utero and then postnatally by inhalation and lactation. These aims will be accomplished by an experienced research team with expertise in inhalation toxicology of nanomaterials, developmental toxicology, nanoaerosol generation and characterization, and ENM proteomics. Five primary hypotheses will be tested: H1) Inhalation of the ENM under study induces significant biological responses at the selected dose compared with controls. H2) ENM exposure produces adverse effects with a distinct biological response profile that is dependent on pregnancy status. H3) Maternal ENM inhalation exposure from pre-conception to delivery produces adverse developmental responses in fetuses. H4) Pups with further post- natal exposure develop toxicological responses not seen in sham-exposed controls or in ENM-exposed adults. H5) Following in utero and post-natal ENM exposure, maturation without exposure is associated with disease progression. The research proposed herein will significantly advance understanding of the dose-specific toxicity of inhaled ENMs and the operative AOPs and thus, will establish a framework for improving the safety profile of commercial ENMs and guide their safe and sustainable use.