Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and associations with hypertensive disorders of pregnancy in the Atlanta African American Maternal-Child cohort.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are man-made chemicals that are slow to break down in the environment and widely detected in humans. Epidemiological evidence suggests that prenatal exposure to perfluorooctanoic acid (PFOA), a legacy PFAS, is linked to gestational hypertension and preeclampsia. However, the relationship between other PFAS, which are structurally similar, and these outcomes remains largely understudied, despite biologic plausibility. Here, we examined associations between serum PFAS mixtures in relation to hypertensive disorders of pregnancy within a birth cohort of African Americans. METHODS: Participants in the present study were enrolled in the Atlanta African American Maternal-Child cohort between 2014 and 2020 (n = 513). Serum samples collected between 8 and 14 weeks gestation were analyzed for four PFAS. Logistic regression was used to assess associations between individual natural log transformed PFAS and specific hypertensive disorders of pregnancy (preeclampsia, gestational hypertension), while quantile g-computation was used to estimate mixture effects. Preeclampsia and gestational hypertension were treated as separate outcomes in individual models. All models were adjusted for maternal education, maternal age, early pregnancy body mass index, parity, and any alcohol, tobacco, or marijuana use. RESULTS: The geometric mean of PFOS and PFHxS was slightly lower among those with preeclampsia relative to those without a hypertensive disorder (e.g., geometric mean for PFOS was 1.89 and 1.94, respectively). Serum concentrations of PFAS were not strongly associated with gestational hypertension or preeclampsia in single pollutant or mixture models. For example, using quantile g-computation, a simultaneous one quartile increase in all PFAS was not associated with odds of gestational hypertension (odds ratio = 0.86, 95% CI = 0.60, 1.23), relative to those without a hypertensive disorder of pregnancy. CONCLUSIONS: In this birth cohort of African Americans, there was no association between serum PFAS measured in early pregnancy and hypertensive disorders of pregnancy, which may be reflective of the fairly low PFAS levels in our study population.

A brainstem to circadian system circuit links Tau pathology to sundowning-related disturbances in an Alzheimer's disease mouse model.

Alzheimer's disease (AD) patients exhibit progressive disruption of entrained circadian rhythms and an aberrant circadian input pathway may underlie such dysfunction. Here we examine AD-related pathology and circadian dysfunction in the APPSwe-Tau (TAPP) model of AD. We show these mice exhibit phase delayed body temperature and locomotor activity with increases around the active-to-rest phase transition. Similar AD-related disruptions are associated with sundowning, characterized by late afternoon and early evening agitation and aggression, and we show TAPP mice exhibit increased aggression around this transition. We show such circadian dysfunction and aggression coincide with hyperphosphorylated Tau (pTau) development in lateral parabrachial (LPB) neurons, with these disturbances appearing earlier in females. Finally, we show LPB neurons, including those expressing dynorphin (LPBdyn), project to circadian structures and are affected by pTau, and LPBdyn ablations partially recapitulate the hyperthermia of TAPP mice. Altogether we link pTau in a brainstem circadian input pathway to AD-related disturbances relevant to sundowning.