Evaluation of dose additive effects of combined oral maternal exposure to PFOA and PFOS during pregnancy in the Sprague-Dawley rat
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Co-exposure to more than one per- and polyfluoroalkyl substance (PFAS) is common, if not ubiquitous. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are the two most frequently detected and extensively studied PFAS; however, an examination of their cumulative in vivo effects has not been rigorously conducted. We performed a series of oral exposures in pregnant Sprague-Dawley rats (dosed gestation day (GD) 8 – postnatal day (PND) 2) to first characterize individual dose responses to PFOA (10-250 mg/kg/d) and PFOS (0.1-5 mg/kg/d) across a range of endpoints, followed by a binary mixture study in which we repeated a dose response of PFOA (3-80 mg/kg/d) but with a fixed dose of PFOS (2 mg/kg/d) added to each PFOA dose. Numerous apical effects from each chemical and the mixture were significantly altered compared to controls including reduced maternal gestational weight gain, reduced pup body weight at multiple timepoints, reduced pup viability, and increased maternal and pup relative liver weights. As a clear demonstration of cumulative effects, individual exposures to 62.5 mg/kg PFOA and 2 mg/kg PFOS produced 12±7% and 8±6% post-implantation loss (PIL) by PND2, respectively; while a mixture of the two (62.5 mg/kg PFOA+2 mg/kg PFOS) produced 66±15% PIL, which was accurately predicted by dose addition (predicted PIL = 76%), but underestimated by response addition (predicted PIL = 21%). Further, the addition of PFOS significantly shifted the PFOA dose response curve towards effects at lower doses for post-implantation loss, pup body weight, and maternal and pup liver weights. Newborn pup liver glycogen concentration and PND2 maternal and pup serum total T3 and T4 were significantly reduced in all experiments. Clinical chemistry profiles in newborn pups and PND2 moms and pups had numerous dose-responsive alterations indicative of perturbed carbohydrate and lipid metabolism, as well as liver and kidney function. Studies are on-going with additional endpoints in-process including liver and kidney histopathology, liver gene expression, maternal serum metabolomics, and analytical determination of PFOA and PFOS levels in serum in liver. The data here demonstrate dose additive effects of combined exposure to PFOA and PFOS for multiple endpoints. Abstract does not necessarily reflect USEPA views or policy.