Phthalate monoesters act through peroxisome proliferator-activated receptors in the mouse ovary

• Published in: Reproductive toxicology (Elmsford, N.Y.) N.Y.), 2022-06, Vol.110, p.113-123
• Main Authors: Meling, Daryl D., De La Torre, Kathy M., Arango, Andres S., Gonsioroski, Andressa, Deviney, Ashley R.K., Neff, Alison M., Laws, Mary J., Warner, Genoa R., Tajkhorshid, Emad, Flaws, Jodi A.
• Format: Article
• Language: English
• Subjects: Animals; Environmental Exposure - analysis; Environmental Pollutants - analysis; Female; Granulosa cells; Mice; Nuclear receptor; Ovary; Ovary - metabolism; Phthalates; Phthalic Acids - analysis; Plasticizers - toxicity; PPAR; PPAR alpha - genetics; PPAR gamma - genetics; Toxicants
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/j.reprotox.2022.04.002

Widespread use of phthalates as solvents and plasticizers leads to everyday human exposure. The mechanisms by which phthalate metabolites act as ovarian toxicants are not fully understood. Thus, this study tested the hypothesis that the phthalate metabolites monononyl phthalate (MNP), monoisononyl phthalate (MiNP), mono(2-ethylhexyl) phthalate (MEHP), monobenzyl phthalate (MBzP), monobutyl phthalate (MBP), monoisobutyl phthalate (MiBP), and monoethyl phthalate (MEP) act through peroxisome proliferator-activated receptors (PPARs) in mouse granulosa cells. Primary granulosa cells were isolated from CD-1 mice and cultured with vehicle control (dimethyl sulfoxide) or MNP, MiNP, MEHP, MBzP, MBP, MiBP, or MEP (0.4–400 μM) for 24 h. Following culture, qPCR was performed for known PPAR targets, Fabp4 and Cd36. Treatment with the phthalate metabolites led to significant changes in Fabp4 and Cd36 expression relative to control in dose-dependent or nonmonotonic fashion. Primary granulosa cell cultures were also transfected with a DNA plasmid containing luciferase expressed under the control of a consensus PPAR response element. MNP, MiNP, MEHP, and MBzP caused dose-dependent changes in expression of luciferase, indicating the presence of functional endogenous PPAR receptors in the granulosa cells that respond to phthalate metabolites. The effects of phthalate metabolites on PPAR target genes were inhibited in most of the cultures by co-treatment with the PPAR-γ inhibitor, T0070907, or with the PPAR-α inhibitor, GW6471. Collectively, these data suggest that some phthalate metabolites may act through endogenous PPAR nuclear receptors in the ovary and that the differing structures of the phthalates result in different levels of activity. •phthalate metabolites activate PPAR nuclear receptors in granulosa cells.•higher molecular weight phthalates show more PPAR activity than low molecular weight phthalates.•phthalate structure affects the preferred PPAR isoform.•phthalates of identical molecular weight can have very different activity profiles.