Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Pinkas, A., Slotkin, T. A., Brick-Turin, Y., Van der Zee, E. A., & Yanai, J. (2010). Neurobehavioral teratogenicity of perfluorinated alkyls in an avian model. Neurotoxicology and Teratology, 32(2), 182-186. https://doi.org/10.1016/j.ntt.2009.11.004 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Perfluorinated alkyls are widely-used agents that accumulate in ecosystems and organisms because of their slow rate of degradation. There is increasing concern that these agents may be developmental neurotoxicants and the present study was designed to develop an avian model for the neurobehavioral teratogenicity of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Fertilized chicken eggs were injected with 5 or 10 mg/kg of either compound on incubation day 0. On the day of hatching, imprinting behavior was impaired by both compounds. We then explored underlying mechanisms involving the targeting of protein kinase C (PKC) isoforms (α, β, γ) in the intermedial part of the hyperstriatum ventrale, the region most closely associated with imprinting. With PFOA exposure, cytosolic PKC concentrations were significantly elevated for all three isoforms; despite the overall increase in PKC expression, membrane-associated PKC was unaffected, indicating a defect in PKC translocation. In contrast, PFOS exposure evoked a significant decrease in cytosolic PKC, primarily for the β and γ isoforms, but again without a corresponding change in membrane-associated enzyme; this likely partial, compensatory increases in translocation to offset the net PKC deficiency. Our studies indicate that perfluorinated alkyls are indeed developmental neurotoxicants that affect posthatch cognitive performance but that the underlying synaptic mechanisms may differ substantially among the various members of this class of compounds, setting the stage for disparate outcomes later in life.

The identification of mechanisms and outcomes for neurobehavioral teratogenesis is critical to our ability to develop therapies to ameliorate or reverse the deleterious effects of exposure to developmental neurotoxicants. We established mechanistically-based complementary models for the study of cholinergic systems in the mouse and the chick, using both environmental neurotoxicants (chlorpyrifos, perfluoroalkyls) and drugs of abuse (heroin, nicotine, PCP). Behavioral evaluations were made using the Morris maze in the mouse, evaluating visuospatial memory related to hippocampal cholinergic systems, and imprinting in the chick, examining behavior dependent on cholinergic innervation of the IMHV. In both models we demonstrated the dependence of neurobehavioral deficits on impairment of cholinergic receptor-induced expression, and translocation of specific PKC isoforms. Understanding this mechanism, we were able to reverse both the synaptic and behavioral deficits with administration of neural progenitors. We discuss the prospects for clinical application of neural progenitor therapy, emphasizing protocols for reducing or eliminating immunologic rejection, as well as minimizing invasiveness of procedures through development of intravenous administration protocols. KeywordsChick; Induction of endogenous cells; Mouse; Neural progenitor transplantation; Neurobehavioral teratogenicity Complementary neurobehavioral teratogenicity modelsAn inherent methodological obstacle in studies of the mechanisms of neurobehavioral teratogenicity is the problem of specificity; most neuroteratogens affect multiple regions and processes, resulting in plethora of behavioral defects. It is thus critical to develop exposure models that produce functional (behavioral) deficits linked to specific neurotransmitter and synaptic mechanisms. Accordingly, the principal approach taken in our studies has been to

The GELF criteria and NCI guidelines are accepted for treatment initiation for indolent lymphomas and CLL. However, the lower toxicity of single agent rituximab (SAR) compared with chemotherapy may affect treatment initiation. We sought to evaluate what criteria hematologists (n=12) in our institution used when treating indolent lymphoma and CLL with SAR. Methods: A complete data set of all patients(pts)receiving rituximab (R) at MSKCC from 05/02 through 05/07 was compiled. Pts were eligible for this study if they received SAR for indolent lymphoma or CLL without prior R for at least 6 months. A second treatment cycle given ≥6 months later after progression of disease (POD) was included. In contrast, in the absence of POD, subsequent courses of R maintenance to consolidate or maintain a prior response were excluded. Pts with previously transformed lymphoma were ≥five years from any aggressive lymphoma. The presence or absence of GELF criteria, FLIPI score, IPI score, Rai stage and NCI guidelines for the treatment of SLL/CLL was assessed. Results: SAR was given 285 times in 240 pts. 92 (32%) were treatment naive. Histologies included follicular lymphomas (FL) grades 1 and 2 (n=107), FL grade 3 or not otherwise specified (n=31), SLL/CLL (n=59), marginal zone (=54) and other indolent lymphomas (n=34). The pts ranged in age from 22 to 90, with a median age of 66. IPI scores: low risk in 159 (56%); FLIPI scores: low risk in 66 (58%). Additionally, among SLL/CLL patients, 42 out of 59 (71%) were classified as having Rai Low Risk disease. At treatment initiation 167/285 (59%) met no GELF criteria. Within histologic subsets the prevalence of GELF treatment indications did not differ substantially with respect to prior therapy, although NCI treatment guidelines were more prevalent among treatment naive patients with SLL/CLL than in relapsed pts. GELF and NCI Criteria by Histologic Subset and Prior Treatment Prior Prior RX No GELF GELF No NCI SLL/CLLIndication NCI SLL/CLLIndication FL (n=138) No (n=50) 31 (62%) 19 (38%) Yes (n=88) 52 (59%) 37 (41%) Non-FLL/SLL/CLL(n=88) No (n=43) 29 (67%) 14 (33%) Yes (n=45) 28 (62%) 17 (38%) SLL/CLL (n=59) No (n=30) 8 (27%) 22 (73%) 12 (40%) 18 (60%) Yes (n=29) 11 (38%) 18 (62%) 15 (52%) 14 (48%) For the subset of SLL/CLL pts, the presence of newer, adverse prognostic factors was determined including high ZAP-70, high CD38+, and unmutated VH gene. VH gene mutation status was not evaluated in any patient before immunotherapy. CD38 levels were checked in 28/59: 19 high positive, 2 low positive, and 7 negative. ZAP-70 was evaluated in 13/59 cases: 6 high positive, 3 low positive, and 4 negative. Physicians often stated more than one indication for therapy. The most common stated impetus for treatment was progression (63%). The justification for therapy involved symptoms in 6% of cases, threatened end-organ function in 16%, cytopenias in 10%, bulky disease in 5%, patient preference in 4%, histologic transformation in 1%, and other reasoning in 19%. Conclusions: At our institution, expert hematologists treating indolent lymphomas and CLL used criteria beyond GELF and NCI indications to justify therapy with SAR in more than half the patients receiving such therapy. This likely reflects the drug’s low toxicity and, possibly, a desire to spare patients from future chemotherapy. This finding has significant implications for resource allocation. Future studies may demonstrate whether relatively early use of SAR results in diminished chemotherapy usage over a patient’s lifetime.