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Close relationships exist between metal(loid)s exposure and embryo implantation failure (EIF) from animal and epidemiological studies. However, there are still inconsistent results and lacking of sensitive metal(loid) exposure biomarkers associated with EIF risk. We aimed to ascertain sensitive metal(loid) biomarkers to EIF and provide potential biological explanations. Candidate metal(loid) biomarkers were measured in the female hair (FH), female serum (FS), and follicular fluid (FF) with various exposure time periods. An analytical framework was established by integrating epidemiological association results, comprehensive literature searching, and knowledge-based adverse outcome pathway (AOP) networks. The sensitive biomarkers of metal(loid)s along with potential biological pathways to EIF were identified in this framework. Among the concerned 272 candidates, 45 metal(loid)s biomarkers across six time periods and three biomatrix were initially identified by single-metal(loid) analyses. Two biomarkers with counterfactual results according to literature summary results were excluded, and a total of five biomarkers were further determined from 43 remained candidates in mixture models. Finally, four sensitive metal(loid) biomarkers were eventually assessed by overlapping AOP networks information, including Se and Co in FH, and Fe and Zn in FS. AOP networks also identified key GO pathways and proteins involved in regulation of oxygen species biosynthetic, cell proliferation, and inflammatory response. Partial dependence results revealed Fe in FS and Co in FH at their low levels might be potential sensitive exposure levels for EIF. Our study provided a typical framework to screen the crucial metal(loid) biomarkers and ascertain that Se and Co in FH, and Fe and Zn in FS played an important role in embryo implantation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The relationship between heavy metal(loid)s exposure and oxidative stress damage is a matter of research interest. Our study aimed to investigate the distribution patterns of the nine heavy metal(loid)s in blood of pregnant women, including four toxic heavy metal(loid)s [arsenic (As), cadmium (Cd), lead (Pb) and mercury (Hg)] and five typical heavy metal(loid)s [manganese (Mn), cobalt (Co), copper (Cu), zinc (Zn), and selenium (Se)] in blood. Blood samples of 348 women were collected and their concentrations in the serum (sr) and blood cells (bc) were measured, as well as serum heme oxygenase-1 (HO-1) (an oxidative stress marker). Total blood (tb) concentrations of these metal(loid)s and serum-to-blood cell concentration ratios (sr/bc) were further calculated. We found Cu mainly accumulated in the serum compared to the blood cells with Cu sr/bc  = 2.30, whereas Co, Se, and As evenly distributed between these two fractions. Other metal(loid)s mainly concentrated in the blood cells. Co sr , Cu sr , Cu bc , Mn bc , Zn bc , Cd bc , Co tb , Cu tb , Mn tb , Zn tb , Cd tb , and Cu sr/bc were negatively associated with serum HO-1, whereas As sr , As bc , As tb , Zn sr/bc , Cd sr/bc , and Hg sr/bc were positively, indicating of their potential toxicity. We concluded that the distribution patterns of blood heavy metal(loid)s, in particular for Cd, Hg and Zn, which either increased in serum or decreased in blood cells, might be associated with elevated serum oxidative stress, should be considered in environmental health assessments., (Copyright © 2021 Elsevier Ltd. All rights reserved.)