Longitudinal patterns of urinary biomarkers of placental and renal function in pregnancy and associations with early pregnancy exposure to phthalates and replacements

Phthalates and replacements are endocrine-disrupting chemicals that may interfere with early pregnancy processes such as placentation and renal adaptation. Placental and renal biomarkers may help examine these toxicologic mechanisms. This study aims to characterize longitudinal changes in urinary protein biomarkers of placental angiogenesis (sFlt-1, PlGF, sEng) and renal function (KIM-1, NGAL, nephrin), and investigate associations with early pregnancy exposure to phthalates and replacements. Among 291 participants from the Human Placenta and Phthalates prospective cohort, urinary metabolites of eight phthalates and two replacements were quantified at up to 2 time points from 12 to 15 weeks gestation. Repeated measures were averaged as early pregnancy exposure biomarkers. Placental and renal biomarkers were quantified longitudinally in urine samples from early (median 13 weeks), middle (21 weeks), and late (33 weeks) pregnancy. Linear mixed effects models with participant-specific random effects estimated the percent change in placental or renal biomarker concentrations throughout pregnancy in association with a one interquartile range increase in early pregnancy phthalate and replacement biomarkers. Certain protein biomarkers showed trends across gestation (sFlt-1, PlGF, NGAL), while others did not (sEng, KIM-1, nephrin). Early pregnancy mono-3-carboxypropyl phthalate was associated with decreased urinary concentrations of NGAL (-6.66% [95% confidence interval: -12.23%, -0.74%]), but this association was nonsignificant after multiple comparisons correction. Associations between other phthalate and replacement biomarkers with placental and renal proteins were imprecise. Urinary biomarkers of placental angiogenesis and renal function change dynamically in pregnancy; further research is needed to validate associations between urinary proteins and phthalate metabolites, and to explore additional toxicity mechanisms.