Prenatal organophosphate esters exposure and neurodevelopment trajectory in infancy: Evidence from the Shanghai Maternal-Child Pairs Cohort.

BACKGROUND: Concerns remain about the neurotoxic properties of the ubiquitous organophosphate esters (OPEs), the replacement of the toxicant polybrominated diphenyl ethers. OBJECTIVES: We examined the associations of prenatal exposure to OPEs and their mixtures with early-life neurodevelopment trajectories. METHODS: Totally 1276 mother-child pairs were recruited from the Shanghai Maternal-Child Pairs Cohort. A high-performance liquid chromatography-triple quadrupole mass spectrometer was used to measure the levels of 7 OPEs in cord serum. Ages and Stages Questionnaires was used to examine children's neuropsychological development at 2, 6, 12, and 24 months of age. Group-based trajectory models were applied to derive the neurodevelopmental trajectories. Multiple linear regression and logistic regression model were performed to assess the relationships between OPEs exposure and neurodevelopment and trajectories. Mixtures for widely detected OPEs (n = 4) were investigated using quantile-based g-computation. RESULTS: Tributyl phosphate (TBP), tris (2-butoxy ethyl) phosphate (TBEP), tris(1,3-dichloro-2-propyl) phosphate (TDCPP), and 2-ethylhexyl diphenyl phosphate (EHDPP), had detection rates >50 %. TDCPP had the highest median concentration (1.02 µg/L) in cord serum. EHDPP concentrations were negatively associated with scores in most domains at 12 months of age, with effect values (ß) ranging from -1.89 to -0.57. EHDPP could negatively affect the total ASQ (OR = 1.07, 95 % CI: 1, 1.15) and gross-motor (OR = 1.09, 95 % CI: 1.02, 1.17) trajectory in infancy. Joint exposure to OPEs was associated with decreased scores in the total ASQ, gross-motor, fine-motor and problem-solving domain of 12-month-old infants, with ß ranging from -5.93 to -1.25. In addition, the qgcomp models indicated significant positive associations between the concentrations of OPEs mixtures and risks of the persistently low group of the total ASQ, gross-motor and fine-motor development in early childhood. The impact of OPEs was more pronounced in boys. DISCUSSION: Our findings suggested OPEs, especially EHDPP, had a persistently negative effect on neurodevelopment during the first 2 years.

Sex-specific effects of organophosphate ester exposure on child growth trajectories in the first two years.

The connections between urinary organophosphate ester (OPE) metabolites and child growth have been identified in prior research, but there is currently a dearth of epidemiological evidence regarding the sex-specific impact of OPEs on child growth trajectories. This study enrolled 804 maternal-child pairs, and five OPE congeners were quantified in maternal serum during pregnancy. In this study, the impact of prenatal OPE exposure on child growth trajectories was assessed using linear mixed-effect models and a group-based trajectory model (GBTM), with consideration given to sex-specific effects. Fetuses were frequently exposed to OPEs in utero, and tris(2-butoxyethel) phosphate (TBEP) exhibited the highest concentration levels in maternal serum. Among male children, an increase of 2.72 ng/g lipid in TBEP concentration was associated with a 0.11-unit increase in head circumference-for-age z-score (HCAZ), and the effect was mainly concentrated at 1 and 2 months of age. Among female children, an increase of 2.72 ng/g lipid in tris(2-chloro-1-(chloromethyl) ethyl) phosphate (TDCPP) concentration was associated with a 0.15-unit increase in length-for-age z-score (LAZ) and a 0.14-unit increase in weight-for-age z-score (WAZ), and the effects were mainly concentrated at 9 months of age. For HCAZ trajectories, higher prenatal TBEP exposure was associated with higher odds for the fast growth group in male children. For the LAZ and WAZ trajectories, higher prenatal TDCPP exposure was associated with higher odds for the fast growth group in female children. The trajectory analysis approach provided insight into the complex associations between OPE exposure and child growth.

MICALL2 as a substrate of ubiquitinase TRIM21 regulates tumorigenesis of colorectal cancer.

BACKGROUND: Molecule interacting with CasL-like protein 2 (MICALL2) is believed to regulate cytoskeleton dynamics, tight junction formation, and neurite outgrowth. However, its biological role and the underlying mechanism in colorectal cancer (CRC) remain largely elusive. METHODS: qRT-PCR, Western blotting and immunohistochemistry assays were used to detect the expression levels of different genes. Next, mass spectrometry, co-immunoprecipitation and immunofluorescence staining were used to detect the interactions of proteins. Furthermore, MTT assay, colony formation assay, wound-healing assays and xenograft tumor models were performed to demonstrate the functions of MICALL2 in CRC. In addition, transcriptome sequencing and Western blotting were conducted to verify the mechanism of MICALL2 in CRC. RESULTS: We found that both mRNA and protein levels of MICALL2 are up-regulated in colorectal cancer tissues compared with non-tumor tissues and that its overexpression is closely correlated with poor prognosis. Ubiquitin E3 ligase Tripartite motif-containing protein 21 (TRIM21) mediated MICALL2 ubiquitination and proteasome-dependent degradation, negatively correlated with MICALL2 levels, and reversely regulated the tumorigenic activity of MICALL2 in CRC. Functional studies confirmed that MICALL2 promoted colorectal cancer cell growth and migration via the Wnt/ß-catenin signaling pathway. CONCLUSIONS: As a substrate of ubiquitinase TRIM21, MICALL2 enhances the growth and migration of colorectal cancer cells and activates the Wnt/ß-catenin signaling pathway. Video abstract.