The impact of persistent organic pollutants on fertility: exposure to the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin alters reproductive tract immune responses

Abstract

Exposure to environmental contaminants can result in profound effects on the host immune system. One class of environmental toxicants, known as dioxins, are persistent environmental contaminants termed "forever chemicals". The archetype toxicant from this group of chemicals is 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), an immunotoxicant that activates the aryl-hydrocarbon receptor pathway leading to a variety of changes in immune cell responses. Immune cell functions are crucial to the development and maintenance of healthy reproduction. Immune cells facilitate tolerance between at the maternal-fetal interface between the parent and the semi-allogenic fetus and help defend the gravid reproductive tract from infectious assault. Epidemiological studies reveal that exposure to environmental contaminants (such as TCDD) are linked to adverse reproductive health outcomes including endometriosis, placental inflammation, and preterm birth. However, little is known about the molecular mechanisms that underpin how environmental toxicant exposures impact immune functions at the maternal-fetal interface or within the reproductive tract in general. This review presents the most recent published work that studies interactions between dioxin or TCDD exposure, the host immune system, and reproduction.

Keywords: TCDD; dioxin; environmental toxicant; innate immunity; reproduction.

Figure 1

Conceptual model of TCDD exposure and endometriosis. TCDD exposure leads to adverse effects in the uterus including repression of progesterone production and inhibition of progesterone receptor (PGR) signaling. TCDD synergizes with 17-beta-estradiol leading to signaling cascades that enhance risk for development of endometriosis. TCDD-dependent inhibition of progesterone results in de-repression/enhanced activity of matrix metalloproteinses (MMP-3 and MMP-7). TCDD exposure is associated with enhanced levels of gonadotrophin releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) which enhance risk of endometriosis. TCDD-dependent signaling through the aryl-hydrocarbon receptor (AhR) results in enhanced inflammation leading to endometriosis. Endometriosis is characterized as lesions of ectopic implantation of functional tissue lining the uterus. Figure created with Biorender.

Figure 2

Conceptual model of reproductive immune cell disruption as a consequence of TCDD exposure during pregnancy. TCDD exposure leads to adverse effects on reproduction including inflammation, infertility, and preterm birth. TCDD alters immune cell functions in gravid reproductive tissues and in circulating immune cell populations. TCDD exposure inhibits placental macrophage phagocytosis and cytokine responses to bacterial infection. TCDD enhances dendritic cell surface expression of I-CAM-1, CD-24, and MHC Class II molecules. Dendritic cell exposure to TCDD inhibits IL-10, IL-12 and TNF-α secretion. TCDD exposure inhibits CD11a and CD26L expression and production of IL-2, IL-10, IFN-γ, and IL-4 cytokines in CD4+ T cell populations. Figure created with Biorender.

Figure 3

Conceptual model of the consequences of TCDD exposure to the reproductive tract. TCDD exposure leads to adverse effects in the reproductive tract including repression of progesterone production and inhibition of progesterone receptor (PGR) signaling. TCDD enhances the activity of 17-beta-estradiol. TCDD enhances the activity of tissue remodeling matrix metalloproteinases (MMP-3 and MMP-7). TCDD enhances hormones such as: gonadotrophin releasing hormone (GnRH), follicle-stimulating hormome (FSH), and luteinizing hormone (LH). TCDD-dependent signaling through the aryl-hydrocarbon receptor (AhR) results in enhanced inflammation in the reproductive tract. TCDD exposure inhibits placental macrophage phagocytosis of bacterial cells and cytokine responses to infection. Dendritic cell exposure to TCDD inhibits IL-10, IL-12 and TNF-α secretion. TCDD exposure inhibits CD11a and CD26L expression and production of IL-2, IL-10, IFN-γ, and IL-4 cytokines in CD4+ T cell populations. Figure created with Biorender.