Perinatal Exposure to Phthalates and Phthalate Mixtures Results in Metabolic Alterations in Weanling and Young Adult Mice

Presentation Number: SAT 245
Date of Presentation: April 1st, 2017

Kari Neier*1, Drew Cheatham1, Leah Danielle Bedrosian1, Brigid Gregg2 and Dana C Dolinoy1
1University of Michigan School of Public Health, Ann Arbor, MI, 2University of Michigan, Ann Arbor, MI

Abstract

Phthalates are chemical plasticizers found in a wide variety of consumer products, and have been classified as endocrine disruptors, primarily due to their anti-androgenic effects.1 Two high-molecular weight phthalates, diethylhexyl phthalate (DEHP) and diisononyl phthalate (DINP), and one low-molecular weight phthalate, dibutyl phthalate (DBP), are the largest sources of human exposures to phthalates.2 In recent years, exposure to DINP has been increasing while exposure to DEHP has been decreasing, due to DINP increasingly being used as a replacement for DEHP.2 Developmental exposures to phthalates are known to have adverse reproductive impacts,3 but effects of exposures to phthalates and phthalate mixtures on metabolic outcomes have not been fully characterized. We utilized a perinatal exposure mouse model to investigate whether developmental exposures to phthalates and/or phthalate mixtures impact metabolism and obesity-related outcomes. The viable agouti (Avy) strain of mice was used with forced heterozygosity for the Avy allele, resulting in approximately half a/a wildtype (93% C57BL/6) and half Avy/a offspring. Mice were perinatally exposed 2 weeks prior to mating and throughout gestation and lactation to 1 of 6 diets: Control, 25mg DEHP/kg chow, 25mg DBP/kg chow, 75mg DINP/kg chow, 25mg DEHP + 75mg DINP/kg chow, or 25mg DEHP + 25mg DBP + 75mg DINP/kg chow. Approximately half of the a/a wildtype offspring were sacrificed at weaning (PND21), and the other half were weaned onto the control diet and followed into adulthood for metabolic phenotyping. At PND21, male and female mice exposed to DINP weighed significantly more than controls (p=0.01, 0.03, respectively). Males exposed to DEHP+DINP, but not those exposed to all three phthalates, weighed more than controls (p=0.05), while females exposed to all three phthalates, but not those exposed to DEHP+DINP, weighed moderately more than controls (p=0.09). At 2 months of age, both DINP and DEHP were associated with increased body weight (p=0.006, 0.01, respectively) and increased body fat percentage (p=0.02, both), as modeled with multiple linear regression controlling for sex-effects. Glucose tolerance testing (GTT) at 2 months of age revealed that overall insulin levels post-glucose administration were moderately elevated in DINP-exposed males (p=0.09). In females, fasting plasma insulin levels at PND21 were elevated in mice exposed to all three phthalates (p=0.08), and GTT at 2 months also revealed that insulin levels 30 minutes post-glucose administration were elevated in DBP-exposed females (p=0.03). These results suggest that perinatal exposure to phthalates and phthalate mixtures may impact metabolic function in weanling and young adult mice, and that some effects differ by sex. Ongoing studies include in-depth metabolic phenotyping into late adulthood and tissue-specific epigenomic and oxidative stress analyses.

 

Nothing to Disclose: KN, DC, LDB, BG, DCD