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Longitudinal Metabolic Impacts of Perinatal Exposure to Phthalates and Phthalate Mixtures in Mice
Kari Neier1, Drew Cheatham1, Leah D Bedrosian2
1Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan.
Insights
Early-life exposure to phthalates like DEHP and DINP can impact female mice metabolism, affecting body composition and glucose tolerance. Mixture exposures showed fewer effects than single phthalate exposures.
Area of Science:
- Environmental Health
- Endocrinology
- Toxicology
Background:
- Developmental exposure to phthalates is linked to metabolic syndrome risk, but human data is inconsistent.
- Long-term metabolic effects of early-life phthalate and mixture exposures require further investigation.
- Research on newer phthalates like diisononyl phthalate (DINP) and their metabolic impacts is limited.
Purpose of the Study:
- To evaluate the long-term metabolic effects of perinatal exposure to individual phthalates (DEHP, DINP, DBP) and their mixtures in a mouse model.
- To compare the metabolic impacts of single phthalate exposures versus phthalate mixtures.
- To investigate sex-specific differences in metabolic outcomes following developmental phthalate exposure.
Main Methods:
- Longitudinal study using a mouse model with perinatal exposure to diethylhexyl phthalate (DEHP), diisononyl phthalate (DINP), and dibutyl phthalate (DBP) via maternal chow.
- Metabolic phenotyping (body composition, glucose tolerance) at 2 and 8 months, and plasma adipokine analysis at 10 months in offspring.
- Evaluation of individual phthalate exposures (DEHP, DINP, DBP) and mixtures (DEHP+DINP, DEHP+DINP+DBP).
Main Results:
- Perinatal DEHP exposure in female mice led to increased body fat and decreased lean mass.
- Perinatal DINP exposure in female mice resulted in impaired glucose tolerance.
- Phthalate exposures modified the relationship between body fat and adipokines in females; males showed no significant metabolic differences.
- Phthalate mixture exposures were associated with fewer metabolic effects than single exposures.
Conclusions:
- Developmental exposure to specific phthalates can have distinct long-term metabolic consequences in female mice.
- The metabolic impact of phthalate mixtures may be less pronounced or more complex than anticipated, not necessarily additive to single exposures.
- Further research is needed to understand the complexities of phthalate mixture toxicology and sex-specific effects on metabolic health.
Abstract:
Developmental exposures to phthalates are suspected to contribute to risk of metabolic syndrome. However, findings from human studies are inconsistent, and long-term metabolic impacts of early-life phthalate and phthalate mixture exposures are not fully understood. Furthermore, most animal studies investigating metabolic impacts of developmental phthalate exposures have focused on diethylhexyl phthalate (DEHP), whereas newer phthalates, such as diisononyl phthalate (DINP), are understudied. We used a longitudinal mouse model to evaluate long-term metabolic impacts of perinatal exposures to three individual phthalates, DEHP, DINP, and dibutyl phthalate (DBP), as well as two mixtures (DEHP+DINP and DEHP+DINP+DBP). Phthalates were administered to pregnant and lactating females through phytoestrogen-free chow at the following exposure levels: 25 mg of DEHP/kg of chow, 25 mg of DBP/kg of chow, and 75 mg of DINP/kg of chow. One male and female per litter (n = 9 to 13 per sex per group) were weaned onto control chow and followed until 10 months of age. They underwent metabolic phenotyping at 2 and 8 months, and adipokines were measured in plasma collected at 10 months. Longitudinally, females perinatally exposed to DEHP only had increased body fat percentage and decreased lean mass percentage, whereas females perinatally exposed to DINP only had impaired glucose tolerance. Perinatal phthalate exposures also modified the relationship between body fat percentage and plasma adipokine levels at 10 months in females. Phthalate-exposed males did not exhibit statistically significant differences in the measured longitudinal metabolic outcomes. Surprisingly, perinatal phthalate mixture exposures were statistically significantly associated with few metabolic effects and were not associated with larger effects than single exposures, revealing complexities in metabolic effects of developmental phthalate mixture exposures.
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