Acetamiprid (ACE) and imidacloprid (IMI) are two major members in the family of neonicotinoid pesticides, which are synthesized with a higher selectivity to insects. The present study determined and compared in vitro effects of ACE, IMI and nicotine on mammalian reproduction by using an integrated testing strategy for reproductive toxicology, which covered sperm quality, sperm penetration into oocytes and preimplantation embryonic development. Direct chemical exposure (500 µM or 5 mM) on spermatozoa during capacitation was performed, and in vitro fertilization (IVF) process, zygotes and 2-cell embryos were respectively incubated with chemical-supplemented medium until blastocyst formation to evaluate the reproductive toxicity of these chemicals and monitor the stages mainly affected. Generally, treatment of 500 µM or 5 mM chemicals for 30 min did not change sperm motility and DNA integrity significantly but the fertilization ability in in vitro fertilization (IVF) process, indicating that IVF process could detect and distinguish subtle effect of spermatozoa exposed to different chemicals. Culture experiment in the presence of chemicals in medium showed that fertilization process and zygotes are adversely affected by direct exposure of chemicals (P<0.05), in an order of nicotine>IMI>ACE, whereas developmental progression of 2-cell stage embryos was similar to controls (P>0.05). These findings unveiled the hazardous effects of neonicotinoid pesticides exposure on mammalian sperm fertilization ability as well as embryonic development, raising the concerns that neonicotinoid pesticides may pose reproductive risks on human reproductive health, especially in professional populations.

Background:The impact of combining plasma fibrinogen levels with Epstein–Barr Virus DNA (EBV DNA) levels on the prognosis for patients with nasopharyngeal carcinoma (NPC) was evaluated.Methods:In this observational study, 2563 patients with non-metastatic NPC were evaluated for the effects of circulating plasma fibrinogen and EBV DNA levels on disease-free survival (DFS), distant metastasis-free survival (DMFS), and overall survival (OS).Results:Compared with the bottom biomarker tertiles, TNM stage-adjusted hazard ratios (HR, 95% confidence intervals (CIs)) for predicting DFS in fibrinogen tertiles 2 to 3 were 1.26 (1.00 to 1.60) and 1.81 (1.45 to 2.26), respectively; HR for EBV DNA tertiles 2 to 3 were 1.49 (1.12 to 1.98) and 4.24 (3.27 to 5.49), respectively. After additional adjustment for established risk factors, both biomarkers were still associated (P for trend <0.001) with reduced DFS (HR: 1.79, 95% CI, 1.43 to 2.25 for top fibrinogen tertiles; HR: 4.04, 95% CI: 3.10 to 5.27 for top EBV DNA tertiles compared with the bottom tertiles). For patients with advanced-stage disease, those with high fibrinogen levels (⩾3.34 g l−1) presented with worse DFS, regardless of EBV DNA ⩾4000 or <4000 copies ml−1 subgroup. Similar findings were observed for DMFS and OS.Conclusions:Circulating fibrinogen and EBV DNA significantly correlate with NPC patients survival. Combined fibrinogen and EBV DNA data lead to improved prognostic prediction in advanced-stage disease.

Multiple sclerosis (MS) is a complex autoimmune disease, and several therapies for MS have been developed and widely used. However, existing medications for MS were far from satisfactory due to their failure to suppress relapses and alleviate disease progression. Novel drug targets for MS prevention are still needed. We performed Mendelian randomization (MR) to explore potential drug targets for MS using summary statistics from the International Multiple Sclerosis Genetics Consortium (NCase = 47,429, NControl = 68,374) and further replicated in UK Biobank (NCase = 1,356, NControl = 395,209) and FinnGen cohorts (NCase = 1,326, NControl = 359,815). Genetic instruments for 734 plasma and 154 cerebrospinal fluid (CSF) proteins were obtained from recently published genome-wide association studies (GWAS). The reverse causality detection using bidirectional MR analysis and Steiger filtering, Bayesian colocalization, and phenotype scanning that searched previously-reported genetic variant-trait associations were implemented to consolidate the MR findings further. In addition, the protein-protein interaction (PPI) network was performed to reveal potential associations among proteins and/ or present MS medications. At Bonferroni significance (P &lt; 5.63×10−5), MR analysis revealed six protein-MS pairs. In plasma, per SD increase in FCRL3, TYMP and AHSG had a protective effect. Odds ratio (OR) for the proteins above were 0.83 (95% confidence interval [CI], 0.79-0.89), 0.59 (95% CI, 0.48-0.71), and 0.88 (95% CI, 0.83-0.94), respectively. In CSF, per 10-fold increase in MMEL1 (OR, 5.03; 95% CI, 3.42-7.41) increased the risk of MS, while SLAMF7 (OR, 0.42; 95% CI, 0.29-0.60) and CD5L (OR, 0.30; 95%CI, 0.18-0.52) decreased the risk. None of the six above proteins had reverse causality. Bayesian colocalization suggested that FCRL3 (coloc.abf-posterior probability of hypothesis 4 [PPH4] = 0.889), TYMP (coloc.susie-PPH4 = 0.896), AHSG (coloc.abf-PPH4 = 0.957, coloc.susie-PPH4 = 0.973), MMEL1 (coloc.abf-PPH4 = 0.930), and SLAMF7 (coloc.abf-PPH4 = 0.947) shared the same variant with MS. FCRL3, TYMP, and SLAMF7 interacted with target proteins of current MS medications. MMEL1 was replicated in both UK Biobank and FinnGen cohorts. Our integrative analysis suggested that genetically-determined levels of circulating FCRL3, TYMP, AHSG, CSF MMEL1, and SLAMF7 had causal effects on MS risk. These findings suggested those five proteins might be promising drug targets for MS and warrant further clinical investigation, especially FCRL3 and SLAMF7.

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