Transgenerational neuroendocrine disruption of reproduction

Abstract

Exposure to endocrine disrupting chemicals (EDCs) is associated with dysfunctions of metabolism, energy balance, thyroid function and reproduction, and an increased risk of endocrine cancers. These multifactorial disorders can be 'programmed' through molecular epigenetic changes induced by exposure to EDCs early in life, the expression of which may not manifest until adulthood. In some cases, EDCs have detrimental effects on subsequent generations, which indicates that traits for disease predisposition may be passed to future generations by nongenomic inheritance. This Review discusses current understanding of the epigenetic mechanisms that underlie sexual differentiation of reproductive neuroendocrine systems in mammals and summarizes the literature on transgenerational epigenetic effects of representative EDCs: vinclozolin, diethylstilbesterol, bisphenol A and polychlorinated biphenyls. The article differentiates between context-dependent epigenetic transgenerational changes--namely, those that require environmental exposure, either via the EDC itself or through behavioral or physiological differences in parents--and germline-dependent epigenetic mechanisms. These processes, albeit discrete, are not mutually exclusive and can involve similar molecular mechanisms including DNA methylation and histone modifications and may predispose exposed individuals to transgenerational disruption of reproductive processes. New insights stress the crucial need to develop a clear understanding of how EDCs may program the epigenome of exposed individuals and their descendants.

Figure 1

The hypothalamic–pituitary–gonadal (HPG) axis. The HPG axis of mammals is shown with hypothalamic-releasing factor neurons of the hypothalamus terminating in the median eminence above the anterior pituitary gland, where the portal capillary system communicates signals from the hypothalamus to the pituitary. The release of gonadotropin-releasing hormone from hypothalamic neurons specifically targets the anterior pituitary gonadotropes to synthesize and secrete luteinizing hormone and follicle-stimulating hormone. From there, these circulating gonadotropins act upon receptors in the gonad, ovary or testis, to activate gonadal steroidogenesis and gametogenesis. Steroid hormones in the circulation act upon peripheral targets and also feed back upon steroid-sensitive neurons in the brain and hypothalamus. Endocrine disrupting chemicals can disrupt HPG systems through interference with any or all of these pathways, particularly during developmental exposures. Shown in the figure is how endocrine disrupting chemicals may disrupt the hypothalamic level of the HPG axis through actions on neurons containing steroid hormone receptors.

Figure 2

DNA methylation and histone modifications. Two major epigenetic mechanisms, DNA methylation and histone modifications, act in concert to regulate gene transcription. The DNA double helix backbone is shown in blue. In DNA methylation, methyl groups are added to a cytosine that is immediately 5′ to a guanine. In general, an increase in DNA methylation leads to a decrease in mRNA transcription. Histone modifications occur when functional groups are added to the tails of histones (histones shown in pink, with blue tails), leading to a ‘relaxed’ or ‘condensed’ chromatin state. Depending on the modification, the DNA will be more or less tightly wound around the histone thereby increasing or decreasing the likelihood of gene transcription. Adapted with permission from Macmillan Publishers Ltd © Qiu, J. Nature 441, 143–145 (2006).

Figure 3

Context-dependent epigenetic transmission. EDC effects can be passed from one generation to another through actions on genes and proteins that control hormone levels, neurobiological physiological functions, and behaviors, particularly maternal behaviors towards the offspring. As depicted here, prenatal exposure to an EDC in a dam can alter the hypothalamic control of her hormone levels and her behaviors towards her F1 pups. The F2 generation may exhibit differences in their own hormones and behavior due to the context of what they were exposed to during postnatal development from their F1 mother. Abbreviation: EDC, endocrine disrupting chemical.

Figure 4

Programming of methylation in the germline. a | Methylation reprogramming in the germ line. Primordial germ cells (PGCs) in the mouse become demethylated early in development. Remethylation begins in prospermatogonia on embryonic day 16 in male germ cells and after birth in growing oocytes. Some stages of germ cell development are shown. b | Methylation reprogramming in preimplantation embryos. The paternal genome (blue) is demethylated by an active mechanism immediately after fertilization. The maternal genome (red) is demethylated by a passive mechanism that depends on DNA replication. Both are remethylated around the time of implantation to different extents in the embryonic and extra-embryonic lineages. Methylated imprinted genes and some repeat sequences (dashed line) do not become demethylated. Unmethylated imprinted genes (dashed line) do not become methylated. Abbreviations: EM, embryonic lineages; EX, extra-embryonic lineages; PGC, primordial germ cells. Permission obtained from the American Association of the Advancement of Science © Reik, W. et al. Science 293, 1089–1093 (2001).

Figure 5

Transgenerational inheritance of epigenetic traits across three generations. Depiction of how exposure of a pregnant dam (F0) exposes the fetal F1 offspring, as well as germ cells within the F1 that will develop into the F2 generation. The first generation devoid of any personal exposure is F3.

Figure 6

Effects of endocrine disrupting chemicals on mate preference in the F3 generation. A partner preference test is depicted. The testing chamber is partitioned on either end with acrylic glass, with an opening covered with mesh wire. In this figure, a male from each lineage (F3-vehicle, F3-vinclozolin) is housed in each opposite end chamber. In the center, a female from one of the lineages is videotaped for a 10-minute trial, during which time the nature and location of her behaviors relative to each male is recorded. A preference is indicated by a significantly greater amount of time spent towards one male over the other.