Prenatal exposure to perfluoroalkyl substances modulates neonatal serum phospholipids, increasing risk of type 1 diabetes

Abstract

In the last decade, increasing incidence of type 1 diabetes (T1D) stabilized in Finland, a phenomenon that coincides with tighter regulation of perfluoroalkyl substances (PFAS). Here, we quantified PFAS to examine their effects, during pregnancy, on lipid-related and immune markers of T1D risk in children. In a mother-infant cohort (264 dyads), high PFAS exposure during pregnancy associated with decreased cord serum phospholipids and progression to T1D-associated islet autoantibodies in the offspring. This PFAS-lipid association was exacerbated by increased human leukocyte antigenconferred risk of T1D in infants. Exposure to a single PFAS compound or a mixture of organic pollutants in non-obese diabetic mice resulted in a profile characterized by a similar decrease in phospholipids, a marked increase of lithocholic acid, and accelerated insulitis. Our findings suggest that PFAS exposure during pregnancy contributes to risk and pathogenesis of T1D in offspring.3

Metabolic alterations in immune cells associate with progression to type 1 diabetes

“…Metabolic modelling of sphingolipid metabolism in islet autoimmunity and type 1 diabetes Given that (1) in our previous study, we observed persistent downregulation of plasma sphingolipids in children who progressed to type 1 diabetes [16,42], (2) in the present study, SMM was over-represented in PBMCs isolated from the PT1D, and (3) we recently found that prenatal chemical exposure modulates postnatal SM levels and increases type 1 diabetes risk [9], we examined SMM in PBMCs using genome-scale metabolic modelling (ESM Fig. 10).…”

“…In addition to genetic predisposition, other exogenous environmental factors affect risk, such as intestinal dysbiosis, reduced gut microbial diversity [5], level of hygiene [6] and infant-feeding regimen [7,8] are implicated in the initiation of beta cell autoimmunity. Our recent data also suggest that prenatal exposure to environmental chemicals modulates lipid metabolism in newborn infants and increases their subsequent risk of type 1 diabetes [9]. However, the early pathogenesis of type 1 diabetes is still poorly understood and of the molecular signatures and related pathways predictive of progression to overt type 1 diabetes have yet to be identified.…”

Exposure To Persistent Organic Pollutants Alters The Serum Metabolome In Non-Obese Diabetic Mice

“…A counterintuitive dysregulation pattern where 11 BAs were dysregulated in high exposure versus low exposure groups compared to only two dysregulated bile acids in high exposure vs control group may be explained by the observation that in the low exposure group, BAs showed upregulation trend, whereas in the high exposure group they were signi cantly downregulated (Supplementary Figure A3), suggesting a non-monotonic response pattern. Observed alteration of bile acids in our study may explain the dysregulation of speci c lipid classes that were associated with T1D development in human studies (Oresic et al, 2008;McGlinchey et al, 2020).…”

“…Conversely, elevated PFOS levels were reported in young patients newly diagnosed with T1D (Predieri et al, 2015), while another birth-cohort study found no evidence that fetal and early life exposure to POP (including 14 PFAS) was a signi cant risk factor for later T1D development (Salo et al, 2019). Other studies suggest that PFAS exposure is associated with hyperglycemia, serum HDL cholesterol and increased blood insulin (Lin et al, 2009), may lead to immunotoxicity (Borg et al, 2013), and modulates neonatal serum phospholipids associated with increased risk of T1D (McGlinchey et al, 2020). Overall, the molecular mechanisms underlying the effects of exposure are still not well characterized.…”

New insights on the effects of endocrine-disrupting chemicals on children

“…Interaction between human leukocyte antigens risk genotype and pre-natal PFAS exposure was highlighted as to play a potential role in altered lipid profiles in newborn infants at-risk of developing T1D. 76 …”