Fig. 4: TDCIPP inhibits human oligodendrocyte development and is associated with abnormal neurodevelopmental outcomes in children.

a-d. Human cortical organoids were treated with DMSO or TDCIPP at IC₇₅ (18.7 μM). a. Representative images of human cortical organoids showing DAPI, SOX10, and CC1 immunostaining. Scale bars, 50 μm. Quantification total cell number (DAPI+ per mm²) (b), oligodendrocytes (SOX10+CC1+ per mm²) (c), and oligodendrocyte progenitors (SOX10+CC1− per mm²) (d), in whole cortical organoids. Data are mean ± SD, n = 21 or 29 biological replicates (individual organoids generated from 4 independent batches). Data points are colored based on organoid batch. p-values were calculated using unpaired two-tailed t test. e. Pie chart showing the number of children ages 3-11 years old from the NHANES 2013-2014, 2015-2016, and 2017-2018 datasets with undetectable and detectable levels of BDCIPP, the urine metabolite of TDCIPP. f. Creatinine-normalized levels of BDCIPP in children (3-11 years old), n = 1762, and adults (>18 years), n = 4988. p-value calculated using the two-sided Mann-Whitney U-test. g. Creatinine-normalized levels of BDCIPP in children 3-11 years of age across three NHANES data cycles, n = 337, 675 or 749. p-values were calculated using the Kruskal-Wallis test with Dunn’s multiple comparisons test. h. Range and quartiles of urine BDCIPP levels in children ages 3-11 years old from the NHANES 2013-2014, 2015-2016, and 2017-2018 datasets. i. Proportions of all US children in each urinary BDCIPP quartile, who utilize special education or have motor dysfunction. j. Fully adjusted odds ratio for the neurodevelopmental outcomes: special education and motor dysfunction, n = 1564 or 1566. Significant odds ratios (p-value ≤ 0.05) are indicated by closed circles (BDCIPP Q4 v Q1 OR 2.0 [95% CI = 1.0-3.8] for special education; BDCIPP Q3 v Q1 OR 4.2 [95% CI = 1.1-16.2], and BDCIPP Q4 v Q1 OR 6.0 [95% CI = 1.7-21.9] for motor dysfunction). Closed and open circles are the odds ratio and error bars indicate the 95% CI. Odds ratios and p-values were using the “survey” and “gtsummary” R packages. The Wald test was used to calculate p-values. Data for odds ratios and p-values calculated for all covariates are shown in Extended Data Fig. 5 d,e.