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Perinatal exposures to phthalates and phthalate mixtures result in sex-specific effects on body weight, organ weights and intracisternal A-particle (IAP) DNA methylation in weanling mice

Published online by Cambridge University Press:  11 July 2018

K. Neier ,
D. Cheatham ,
L. D. Bedrosian  and
D. C. Dolinoy
K. Neier
Affiliation:
Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
D. Cheatham
Affiliation:
Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
L. D. Bedrosian
Affiliation:
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA
D. C. Dolinoy*
Affiliation:
Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
*
Address for correspondence: Dana C. Dolinoy, Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA. E-mail: [email protected]
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Abstract

Developmental exposure to phthalates has been implicated as a risk for obesity; however, epidemiological studies have yielded conflicting results and mechanisms are poorly understood. An additional layer of complexity in epidemiological studies is that humans are exposed to mixtures of many different phthalates. Here, we utilize an established mouse model of perinatal exposure to investigate the effects of three phthalates, diethylhexyl phthalate (DEHP), diisononyl phthalate (DINP) and dibutyl phthalate (DBP), on body weight and organ weights in weanling mice. In addition to individual phthalate exposures, we employed two mixture exposures: DEHP+DINP and DEHP+DINP+DBP. Phthalates were administered through phytoestrogen-free chow at the following exposure levels: 25 mg DEHP/kg chow, 25 mg DBP/kg chow and 75 mg DINP/kg chow. The viable yellow agouti (Avy) mouse strain, along with measurement of tail DNA methylation, was used as a biosensor to examine effects of phthalates and phthalate mixtures on the DNA methylome. We found that female and male mice perinatally exposed to DINP alone had increased body weights at postnatal day 21 (PND21), and that exposure to mixtures did not exaggerate these effects. Females exposed to DINP and DEHP+DINP had increased relative liver weights at PND21, and females exposed to a mixture of DEHP+DINP+DBP had increased relative gonadal fat weight. Phthalate-exposed Avy/a offspring exhibited altered coat color distributions and altered DNA methylation at intracisternal A-particles (IAPs), repetitive elements in the mouse genome. These findings provide evidence that developmental exposures to phthalates influence body weight and organ weight changes in early life, and are associated with altered DNA methylation at IAPs.

Keywords

chemical mixturesDNA methylationepigeneticsphthalates
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 10 , Issue 2 , April 2019 , pp. 176 - 187
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Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2018. 

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Footnotes

†

These authors contributed equally to this work.

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