Endocrine Disruption of the Follicle-Stimulating Hormone Receptor Signaling During the Human Antral Follicle Growth

Abstract

An increasing number of pollutants with endocrine disrupting potential are accumulating in the environment, increasing the exposure risk for humans. Several of them are known or suspected to interfere with endocrine signals, impairing reproductive functions. Follicle-stimulating hormone (FSH) is a glycoprotein playing an essential role in supporting antral follicle maturation and may be a target of disrupting chemicals (EDs) likely impacting female fertility. EDs may interfere with FSH-mediated signals at different levels, since they may modulate the mRNA or protein levels of both the hormone and its receptor (FSHR), perturb the functioning of partner membrane molecules, modify intracellular signal transduction pathways and gene expression. In vitro studies and animal models provided results helpful to understand ED modes of action and suggest that they could effectively play a role as molecules interfering with the female reproductive system. However, most of these data are potentially subjected to experimental limitations and need to be confirmed by long-term observations in human.

Keywords: FSH; FSHR; GPER; LHCGR; endocrine disruptors.

Figure 1

Complexity of the FSHR signaling regulation. Molecules with disrupting activity might potentially interfere with the FSH-induced signaling, impacting FSHR expression levels, receptor conformational assembly and cis/trans-activation, the compartmentalization of ligand-receptor complexes, and biased signaling, acting as allosteric modulators. Finally, disrupting molecules may modulate serum FSH levels or hormone binding to the receptor.

Figure 2

Action of EDs in disrupting FSH-dependent endocrine signals in the ovary. Depending on the type of EDs, the FSH signal may be modulated due to changes of FSH levels, FSHR expression and attenuation of active conformation, perturbation of interaction with membrane GPCR partners, intracellular signaling cascades and target gene expression, synthesis of steroids and granulosa cell viability.

Figure 3

Point of action of EDs in the antral stage of folliculogenesis. Variations of hormone and receptor expression levels are shown together with follicle growth. EDs are located within coloured squares indicating the endpoint that they may modulate directly (green) or indirectly (orange). MEHP, mono(2-ethylhexyl) phthalate; DEHP, di(2-ethylhexyl) phthalate; DBP, dibutyl phthalate; DMP, dimethyl phthalate; MXC, Methoxychlor; TCDD, 2,3,7,8-Tetrachlorodibenzo-p-Dioxin; BPA, bisphenol A; 4-NP, 4-Nonylphenol; p’p-DDT, methoxychlor, dichlorodiphenyltrichloroethane; MOH, 1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(4-methoxyphenyl) ethane; HPTE, 1,1,1-trichloro-2,2-bis(4-hydroxyphenyl).