Placental origins of phthalate-induced changes in fetal reproductive development

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1 During pregnancy, the maternal brain and the fetal-placental unit are connected by way of an understudied 2 hypothalamic-pituitary-placental (HPP) axis. This axis may shed light on the differential effects of stress 3 exposure on maternal and fetal well-being complementing what we already know about the hypothalamic- 4 pituitary-adrenal (HPA) axis. The COVID-19 pandemic has aggravated the chronic maternal stressors arising 5 from structural racism and discrimination in the U.S., and has also heightened disparities in food insecurity and 6 SARS-CoV-2 infection. Stress and adversity in pregnancy not only increase risks of preterm birth, growth 7 restriction and infant mortality, but they also heighten risk of postpartum maternal mortality and morbidity too 8 (i.e., diabetes, heart disease, depression). To gain insight into the etiology of these dramatic changes in 9 exposure and susceptibility at the population level, we propose to ‘join the army’ organized by the NIH 10 Maternal Mortality Task Force, of interdisciplinary investigators generating and analyzing data in racially and 11 economically diverse populations, at different stages of reproduction, and in different tissue types. We will 12 extend our R01 (ES029336-03) research in the following ways: 1) to broaden the definition of maternal 13 environmental exposure to the endocrine disrupting chemicals phthalates to include food insecurity and 14 changing food environments (correlated with consumption of ultra-processed and packaged foods which 15 contain phthalates), maternal stress, structural racism and discrimination, and SARS-CoV-2 exposure and 16 related immune and inflammatory effects at the maternal-placental interface; 2) to examine a novel endocrine 17 axis that connects the maternal hypothalamus and pituitary with the fetal placenta by studying gonadotropins in 18 maternal serum (prenatal/postnatal) and in placental tissue; and 3) to estimate and compare the direct and 19 indirect pathways (through placental-pituitary gonadotropins) from maternal prenatal exposures to maternal 20 postpartum health. Postpartum health will be measured as pregnancy complications (preeclampsia and 21 hypertension, gestational diabetes and glucose regulation, placental accrete and abruptio, preterm labor and 22 gestational age at delivery) and by follow-up measures in the first year postpartum (glucose levels, 23 anthropometrics related to weight gain and metabolism, measures of depression, anxiety, stress, 24 discrimination and food insecurity). We will use existing R01 data from two cohorts (UPSIDE MPIs Barrett, 25 O’Connor and Magee CT PI Simhan) to establish a conceptual model, and apply this model to the context of 26 the COVID-19 pandemic and SRD in Pittsburgh with collection of new data from 100 pregnancies of Black and 27 White women, who conceived since March 2020 and delivered since June 2020. In sum, this work will 28 generate insight into sources of adversity in pregnancy, unique to being Black and/or pregnant during the 29 COVID-19 pandemic; and to offer a public health strategy applicable to a city at the 97th percentile of 30 postpartum maternal mortality among Black women in the U.S