Introduction: The prevalence of psychosocial neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) is rising at an alarming rate. ASD etiology is multifactorial, resulting from sex-specific genetic susceptibilities that may interact with environmental toxicant exposures during critical developmental periods. In humans, PBDEs are thyroid-disrupting chemicals associated with altered socioemotional behavior, decreased IQ and hyperactivity. We have previously demonstrated autistic-like effects produced by perinatal exposure to PBDEs in female mice (Kozlova et al, 2022; PMID: 34687351). Maternal thyroid hormone (TH) status affects fetal brain development and has been linked to ASD. Since thyroid hormones regulate oxytocin (OXT) and/or vasopressin neuroendocrine systems critical for social behavior, PBDEs may produce autistic-like actions via disruption of the thyroid system. Therefore, this study tested the hypothesis that developmental exposure to PBDEs produce neurobehavioral and hypothalamic OXT deficits in a TH-dependent manner. Materials and Methods: C57BL/6N dams were exposed human relevant doses of the penta-PBDE mixture, DE-71, at 0.1 mg/kg/d (L-DE-71), 0.4 mg/kg/d (H-DE-71) or with corn oil vehicle control (VEH/CON) for 10 wks (pre-conception: 4 wk, gestation: 3 wk, lactation: 3 wk). A subset of dams was treated with levothyroxine, a synthetic analogue of thyroxine (T4) (8 μg/100 g bw; GD 12-PND 21). Other dams were administered the thyroid synthesis inhibitor, 6-propyl-2-thiouracil (PTU; 50 mg/L; GD 14-PND 21). Results: Compared to VEH/CON, T4 and insulin-like growth factor-1 were attenuated in L-DE-71 dams at PND 0 but normalized in L-DE-71 + T4. In contrast, dam plasma OXT was not altered by DE-71 and elevated by T4 supplementation. L-DE-71 adult male and female offspring showed deficient social novelty preference; maternal T4 supplementation prevented this only in females. In contrast, T4 supplementation was equally effective at normalizing exaggerated repetitive behavior in L-DE-71 male and female offspring. DE-71 reduced OXT immunofluorescence IOD in the paraventricular nucleus of the hypothalamus (PVH) in male (L- and H-DE-71) and female offspring (L-DE-71) and in supraoptic nucleus (SON) in male offspring (L-DE-71) at PND 30. T4 supplementation normalized OXT content in L-DE-71 female and H-DE-71 male PVH. DE-71 had no effect on plasma OXT but was upregulated in VEH/CON +T4 female and DE-71+T4 male offspring. RT-qPCR analysis performed at PND15-30 showed that L-DE-71 downregulated hypothalamic Trh and cortical Oatp1c1 and Dio3 in females and upregulated hypothalamic Dio2, Esr1 and Esr2 and cortical Oatp1c1 in males. PTU’s actions do not exactly mimic those of DE-71. Conclusions: These results suggest that PBDEs disrupt social behavior and central OXT in a TH-dependent and sex-dependent manner. We provide novel information about possible TH-responsive genes that may contribute to neurodevelopmental disorders such as ASD. This work is supported by a Society of Toxicology Syngenta Fellowship Award in Human Health Applications of New Technologies and University of California President's Pre-Professoriate Fellowship to E.V.K. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Background Allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-matched sibling donor for patients with sickle cell disease (SCD) provides excellent curative potential with acceptable rates of graft rejection and other common post transplant complications. However, in the United States, only 18% of patients with SCD have an HLA-matched sibling donor. Hence, multiple studies adopted various strategies to figure out alternative donors with favorable outcomes. Poor engraftment, graft versus host disease (GVHD) and regimen related toxicities are the main obstacles following alternative-donor transplant. To overcome these complications, different modalities had been experimented targeting the source of the stem cell, CD34 and TNC cell counts, pre-transplant conditioning regimens and adding immunosuppressive drugs pre/post transplant. However, so far there is no worldwide consensus about robust strategy for alternative donor HSCT. Aim The aim of this review is to systematically evaluate the outcomes of alternative-donor HSCT in patients with SCD in pediatric population, and correlate the outcomes with experimented interventional regimens. Methods We searched PubMed, SCOPUS, Embase, Cochrane and Clinical trials.gov from 2000 till February 2018. We utilized the Systematic Reviews and Meta-Analyses guidelines for Preferred Reporting Results (PRISMA). Two reviewers independently screened titles/abstracts, assessed full-text articles, extracted data from included articles, and assessed their quality. Risk of bias in the included studies was assessed using ROBINS-I tool. Data of platelet/neutrophil recovery, acute/chronic GvHD incidence and overall survival were pooled in a single-arm meta-analysis approach. Results Of the 2886 records examined, 19 met predefined criteria. 16 studies were included in the meta-analysis. 12 clinical trials, 5 cohort observational studies and 2 case reports. All studies had a sample size <50. The pooled times of platelet and neutrophil recovery were 31.55 and 20.15 days, respectively. The pooled incidences of acute and chronic GvHD were 36.1% and 21.7, respectively (Figure 1). The pooled one-year overall survival was 90.3% and two-years was 88.3%. Neutrophil engraftment was earlier and more sustained after using Reduced Intensity Conditioning, 16 days (7-32) compared to 23 days (12-42) after Myelo-ablative Conditioning, (P=0.013). Platelet engraftment was earlier and more sustained after using Reduced Intensity Conditioning, 29 days (15-204) in comparison to 62 days (18-123) after Myelo-ablative Conditioning, (P=0.026). The median duration of neutrophil engraftment after mismatched related donors was 14 days (14-17), after unrelated donors was 14 days (9-25) , after haplo-identical transplantation was 14 days (12-16), after umbilical cord blood transplantation (UCBT) was 23 days (7-42), (P=0.001). The median duration of platelet engraftment after haplo-identical and mismatched related transplantation was 19 days, after matched unrelated donors was 19 days (18-24), after mismatched unrelated donors was 22 day (19-37) and after UCBT was 47 days (15-204), (P=.001). There was no significant difference in acute/chronic GvHD between different types of alternative donors but acute GvHD was significantly less in Myelo-ablative Conditioning compared to Reduced Intensity Conditioning (P=.036) Conclusion Our systematic review showed better outcomes with using Myelo-ablative Conditioning and post transplant cyclophosphamide in haplo-identical transplantation compared to using Reduced Intensity Conditioning. Adding pre-transplant immunosuppressive drugs in haplo-identical transplantation didn't significantly improve the outcomes. In unrelated donor no significant difference between Myelo-ablative Conditioning and Reduced Intensity Conditioning but adding Mesenchymal Stem Cell to the reduced intensity regimen improved the outcomes. In UCBT and mismatched related donors, Reduced Intensity Conditioning had better outcomes especially with high doses of TNC and CD34 cell counts and with applying Mesenchymal Stem Cell or adequate dose of Alemtuzumab. Randomized controlled trials are mandated to generate standardized regimen in the setting of alternative-donor HSCT. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
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