Environmental thallium exposure and the risk of early embryonic arrest among women undergoing in vitro fertilization: thallium exposure and polymorphisms of mtDNA gene interaction and potential cause exploring

Abstract

Early embryonic arrest (EEA) leads to cancelation of fresh cycles among infertile women undergoing in vitro fertilization (IVF), bringing a great challenge for IVF. Whether exposure to thallium (Tl) is associated with an increased risk of EEA, especially its interaction with polymorphisms of mitochondria DNA (mtDNA) gene, is worthy of study. A case-control design was performed, including 74 EEA cases with 123 IVF cycles and 157 age and BMI-matched controls with 180 IVF cycles. Levels of Tl and other toxic metals (lead (Pb), (mercury) Hg, and (arsenci) As) were assessed by measuring them in blood samples collected on the day of oocyte retrieval; PCR amplification and sequencing were performed to screen the polymorphic sites of mtDNA gene in D-loop region. Bayesian kernel machine regression (BKMR) was used to confirm that Tl played a leading role in the situation of combined exposure; generalized estimating equation (GEE) models were used to evaluate the associations of Tl concentrations, polymorphisms of mtDNA gene, and their interactions with the risk of EEA. The impact of Tl exposure or polymorphisms of mtDNA gene on the oogenesis and embryonic development was also evaluated. BKMR analysis revealed that PIP (posterior inclusion probability) value of T1 was 0.9096, indicating that it played a leading role in the situation of combined exposure. Compared to the first quartile of Tl, the adjusted ORs (95% CIs) of EEA risk were 0.66 (0.26, 1.70), 1.18 (0.52, 2.64), and 4.53 (2.11, 9.69) for the second, third, and fourth quartile, respectively (p trend < 0.001). Compared to the wild type of mtDNA 16,519 gene (T 16,519 T), the adjusted OR (95% CI) of EEA risk for the variant type (T 16,519 C) was 3.11 (1.70, 5.72), and the variant types of the other sites with a minor allele frequency > 10% were not significantly related with the risk of EEA after FDR (False Discovery Rate) correction. With respect to interaction, compared to women at low Tl exposure level & wild type of mtDNA 16,519 gene group, the adjusted OR (95% CI) of EEA risk for women at high Tl exposure level & variant type of mtDNA 16,519 gene group was 9.28 (3.33, 25.81). Additionally, Tl exposure and polymorphisms of mtDNA 16,519 gene are inversely associated with the outcomes of oogenesis and embryonic development significantly. Our study indicated that high Tl exposure level was associated with the increased risk of EEA and Tl played a leading role in the situation of combined exposure; the strength of association was much higher when Tl exposure interacted with polymorphism of 16,519 mtDNA gene. These relationships might originate from the impact of Tl exposure or polymorphism of 16,519 mtDNA gene on the oogenesis and early embryonic development in vitro. Infertile women should keep high vigilant against Tl exposure especially those with variant type of mtDNA 16,519 gene.

Keywords: Early embryonic arrest; Exposure; Interaction; Mitochondrion; Thallium.