Target Exposome for Characterizing Early Gestational Exposure to Contaminants of Emerging Concern and Association with Gestational Diabetes Mellitus

Abstract

Characterization of gestational exposure to complex contaminants of emerging concern (CECs) is critical to the identification of environmental risk factors for pregnancy complications. However, determination of various CECs with diverse physicochemical properties in biological fluids is technically challenging. In the present study, we developed a target exposome protocol, consisting of simple liquid−liquid extraction-based sample preparation and sensitive liquid chromatography−tandem mass spectrometry (LC-MS/MS) analysis, to determine 325 CECs covering 11 subclasses, including poly-and perfluoroalkyl substances, organophosphate esters, ultraviolet (UV) stabilizers, synthetic antioxidants, phthalate esters, and several others. The protocol exhibits exceptional advantages over traditional approaches in the coverage of chemicals, sample volume demand, and time and financial cost. The protocol was applied in a prospective nested gestational diabetes mellitus (GDM) study including 120 cases and 240 matched healthy controls. Thirty-three CECs were detected in >70% of the samples, with a combined concentration of 17.0−484.7 ng/mL. Bayesian kernel machine regression analysis showed that exposure to the CEC mixture was significantly associated with a higher GDM risk. For example, when increasing all CECs in the mixture from 50th percentile to 75th percentile, the estimated probit of GDM incidence had an increase of 92% (95% CI: 56%, 127%). Meanwhile, perfluorohexanesulfonic acid, 1,3-diphenylguanidine, and dibutyl fumarate were identified as the key CECs driving the joint effect. This work demonstrates great potential of our target exposome protocol for environmental risk factor identification in large-scale epidemiology or biomonitoring studies.

Suspect-Screening Analysis of Environmental Chemicals in Paired Human Cerebrospinal Fluid and Serum Samples

“… Note: Quantitative analysis was conducted on an LC-30A ultra-high performance liquid chromatograph interfaced with a Triple Quad 7500 mass spectrometer (SCIEX). 4 Detailed information on instrumental analysis is available on GitHub ( https://github.com/ZL1695/EHP-SI ). 6:2 Cl-PFESA, 6:2 chlorinated perfluoroalkyl ether sulfonic acid; BHT, 2,6-di- tert -butyl-4-hydroxytoluene; BPA, 2,2-bis(4-hydroxyphenyl)propane; BPF, ; BPS, ; BuP, butyl paraben; DF, detection frequency; EtP, ethyl paraben; IQR, interquartile range; LOD, limit of detection; max, maximum; MeP, methyl paraben; M(i)BP, mono-(iso)butyl phthalate; min, minimum; MK, ; MMP, monomethyl phthalate; PFBA, perfluorobutanoic acid; PFBS, perfluorobutanesulfonic acid; PFDA, perfluorodecanoic acid; PFDoA, perfluorododecanoic acid; PFHpA, perfluoroheptanoic acid; PFHpS, perfluoroheptanesulfonic acid; PFHxA, perfluorohexanoic acid; PFHxS, perfluorohexanesulfonic acid; PFNA, perfluorononanoic acid; PFOA, perfluorooctanoic acid; PFOS, perfluorooctanesulfonic acid; PFUdA, perfluoroundecanoic acid; PI-651, 2,2-dimethoxyphenyl acetophenone; TBP, tributyl phosphate; TCIPP, tris(2-chloroisopropyl) phosphate; TCS, triclosan; TPHP, triphenyl phosphate.…”

“…The CSF and serum samples were pretreated following the method described by Huang et al., with minor modifications. 4 Briefly, of serum/CSF was spiked with 21 internal standards ( each) and extracted with a mixture of ethyl acetate and hexane ( ; 3:2, vol/vol, 0.6% formic acid) in three cycles. 4 The supernatants were collected after each cycle and combined, concentrated to , frozen overnight, and centrifuged to collect the supernatant for analysis.…”

“… 4 Briefly, of serum/CSF was spiked with 21 internal standards ( each) and extracted with a mixture of ethyl acetate and hexane ( ; 3:2, vol/vol, 0.6% formic acid) in three cycles. 4 The supernatants were collected after each cycle and combined, concentrated to , frozen overnight, and centrifuged to collect the supernatant for analysis. It is noted that the modified methodology has not previously been reported to test CSF, to our knowledge.…”

“…Third, a quantitative method was established based on using an LC-30A UHPLC coupled to a Triple Quad 7500 MS (SCIEX). 4 Quality assurance/control (QA/QC) tests revealed that the analyte recoveries from spiking tests ranged from 72% to 128%, matrix effects 74% to 119%, interbatch coefficients of variation (50 samples per batch), and absence of background contamination in field and procedural blanks (1 blank processed with 10 samples) for target analytes, except for tributyl phosphate (TBP), triphenyl phosphate (TPHP), tris(2-chloroisopropyl) phosphate (TCIPP), methyl paraben (MeP), mono-(iso)butyl phthalate [M(i)BP], and 2,6-di- tert -butyl-4-hydroxytoluene (BHT). Detailed information on quantitative and qualitative analysis and QA/QC procedures are available on GitHub ( https://github.com/ZL1695/EHP-SI ).…”