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Deepwater Horizon spilled over 200 million gallons of oil into the waters of the Gulf of Mexico in 2010. In an effort to contain the spill, chemical dispersants were applied to minimize the amount of oil reaching coastal shorelines. However, the biological impacts of chemically-dispersed oil are not well characterized, and there is a particular lack of knowledge concerning sublethal long-term effects of exposure. This study examined potential estrogenic effects of CWAF, Corexit 9500-enhanced water-accommodated fraction of oil, by examining its effect on estrogen receptors and sex determination in the American alligator, Alligator mississippiensis. The alligator exhibits temperature-dependent sex determination which is modulated by estrogen signals, and exposure to 17β-estradiol (E2) and estrogenic compounds in ovo during the thermosensitive period of embryonic development can induce ovarian development at a male-producing temperature (MPT). CWAF induced transactivation up to 50% of the maximum induction by E2 via alligator estrogen receptors in vitro. To determine potential endocrine-disrupting effects of exposure directly on the gonad, gonad-adrenal-mesonephric (GAM) organ complexes were isolated from embryos one day prior to the thermosensitive period and exposed to E2, CWAF, or medium alone in vitro for 8–16 days at MPT. Both CWAF and E2 exposure induced a significant increase in female ratios. CWAF exposure suppressed GAM mRNA abundances of anti-Mullerian hormone (AMH), sex determining region Y-box 9, and aromatase, whereas E2 exposure suppressed AMH and increased Forkhead box protein L2 mRNA abundances in GAM. These results indicate that the observed endocrine-disrupting effects of CWAF are not solely estrogenically mediated, and further investigations are required.

e15008 Background: The oncotherapeutic promise of IL-15, a potent immune stimulant, is limited by short serum half-life. The fusion protein N-803 is an IL-15 superagonist complex that has > 20-fold longer half-life in vivo vs IL-15. This study characterized the pharmacokinetic (PK) profile, biological activity, and safety of N-803 after subcutaneous administration to healthy human volunteers. Methods: Volunteers were randomized 1:1 to receive 1 mg/mL or 2 mg/mL N-803. Each subject received 2 doses of N-803: 10 µg/kg followed 24 days later by 20 µg/kg. After each dose, PK and safety measures were assayed for 9 successive days. Primary endpoint was the PK profile of N-803; secondary was safety; and exploratory endpoints were cytokine levels, immune cell characterization, and immunogenicity. Results: N-803 resulted in no grade ≥3 or serious adverse events (AEs). Mild injection site reactions, chills, and pyrexia were the most common AEs. Serum N-803 concentrations peaked 10.3-15.4 hours after administration and declined with a half-life of 20.0-20.7 hours. Peak N-803 serum concentrations were dose-dependent, with a 1.5-fold increase in Cmax after administration of 20 µg/kg vs 10 µg/kg. In the peripheral blood, N-803 induced a transient decline, followed by a significant increase (3-fold) in NK cell number that persisted for ≥24 days. N-803 also caused a significant proliferation of NK (22-fold increase in Ki-67+ cells), CD8+ (27-fold) and CD4+ T (11-fold) cells; however, increased cell number occurred only in NK cells. N-803 administration also increased serum levels of interferon gamma, IL-10, and IL-6. One of 14 evaluable subjects had measureable anti-N-803 antibodies at the end-of-study visit. Conclusions: N-803 results in prolonged elevation of drug serum concentrations, contrasting with rapid clearance of recombinant human IL-15 (ie, half-life of ~20 vs < 1 hour). N-803 administration was well-tolerated in healthy volunteers, without evidence of adverse systemic inflammatory responses, and resulted in proliferation of NK cells and CD8+ T cells, as well as sustained increases in NK cell number. Findings in this study are consistent with published results from N-803 administration in treating liquid tumors and lung cancer. Our results demonstrate N-803 administration potentiates the proliferation and activity of lymphocytes with antitumor and antivirus properties, and suggest this investigational product holds promise in treatment of cancer as well as infectious disease such as HIV. Clinical trial information: NCT03381586 .

Dr. Louis J. Guillette Jr. thought of himself as a reproductive biologist. However, his interest in reproductive biology transcended organ systems, life history stages, species, and environmental contexts. His integrative and collaborative nature led to diverse and fascinating research projects conducted all over the world. He doesn’t leave us with a single legacy. Instead, he entrusts us with several. The purpose of this review is to highlight those legacies, in both breadth and diversity, and to illustrate Dr. Guillette’s grand contributions to the field of reproductive biology. He has challenged the field to reconsider how we think about our data, championed development of novel and innovative techniques to measure endocrine function, helped define the field of endocrine disruption, and lead projects to characterize new endocrine disrupting chemicals. He significantly influenced our understanding of evolution, and took bold and important steps to translate all that he has learned into advances in human reproductive health. We hope that after reading this manuscript our audience will appreciate and continue Dr. Guillette’s practice of open-minded and passionate collaboration to understand the basic mechanisms driving reproductive physiology and to ultimately apply those findings to protect and improve wildlife and human health.