Imprinting and Reproductive Health: A Toxicological Perspective

Abstract

This overview discusses the role of imprinting in the development of an organism, and how exposure to environmental chemicals during fetal development leads to the physiological and biochemical changes that can have adverse lifelong effects on the health of the offspring. There has been a recent upsurge in the use of chemical products in everyday life. These chemicals include industrial byproducts, pesticides, dietary supplements, and pharmaceutical products. They mimic the natural estrogens and bind to estradiol receptors. Consequently, they reduce the number of receptors available for ligand binding. This leads to a faulty signaling in the neuroendocrine system during the critical developmental process of 'imprinting'. Imprinting causes structural and organizational differentiation in male and female reproductive organs, sexual behavior, bone mineral density, and the metabolism of exogenous and endogenous chemical substances. Several studies conducted on animal models and epidemiological studies provide profound evidence that altered imprinting causes various developmental and reproductive abnormalities and other diseases in humans. Altered metabolism can be measured by various endpoints such as the profile of cytochrome P-450 enzymes (CYP450's), xenobiotic metabolite levels, and DNA adducts. The importance of imprinting in the potentiation or attenuation of toxic chemicals is discussed.

Keywords: development; endocrine disrupting chemicals; epigenetics; imprinting; toxicants; xenoestrogens.

Figure 1

Schematic of the role of xenoestrogens on the developmental imprinting process and the consequences on reproductive system. Xenoestrogens or endocrine-disrupting chemicals contribute to imprinting through direct (genomic pathway) and indirect (epigenomic pathway) effects by acting on hypothalamo–hypophyseal axis. Since hypothalamus controls the secretion of reproductive hormones, faulty imprinting will result in aberrations in hormone-mediated pathways causing altered sexual behavior, infertility, and cancers of the reproductive system by triggering oncogenes and silencing tumor suppressor genes. Some of the hormones also influence the expression of cytochrome P450 (CYP) biotransformation enzymes, which, in a mixture exposure scenario, could alter the chemical metabolism causing either attenuation or potentiation of toxic effect. Some of the CYPs are also involved in the synthesis of hormones. The indirect effect of imprinting proceeds through the epigenetic pathway causing DNA methylation and histone modifications, further causing disruptions in the differentiation and functioning of sexual organs and culminating in infertility and/or cancer. LH: Luteinizing hormone; FSH: Follicle stimulating hormone; CYP: Cytochrome P450 enzymes.