Long-term effects of environmental endocrine disruptors on reproductive physiology and behavior

Abstract

It is well established that, over the course of development, hormones shape the vertebrate brain such that sex specific physiology and behaviors emerge. Much of this occurs in discrete developmental windows that span gestation through the prenatal period, although it is now becoming clear that at least some of this process continues through puberty. Perturbation of this developmental progression can permanently alter the capacity for reproductive success. Wildlife studies have revealed that exposure to endocrine disrupting compounds (EDCs), either naturally occurring or man made, can profoundly alter reproductive physiology and ultimately impact entire populations. Laboratory studies in rodents and other species have elucidated some of the mechanisms by which this occurs and strongly indicate that humans are also vulnerable to disruption. Use of hormonally active compounds in human medicine has also unfortunately revealed that the developing fetus can be exposed to and affected by endocrine disruptors, and that it might take decades for adverse effects to manifest. Research within the field of environmental endocrine disruption has also contributed to the general understanding of how early life experiences can alter reproductive physiology and behavior through non-genomic, epigenetic mechanisms such as DNA methylation and histone acetylation. These types of effects have the potential to impact future generations if the germ line is affected. This review provides an overview of how exposure to EDCs, particularly those that interfere with estrogen action, impacts reproductive physiology and behaviors in vertebrates.

Keywords: bisphenol; development; estrogen receptors; genistein; sexual differentiation; soy.

Figure 1

Chemical structures and uses of common endocrine disruptors. DES, bisphenol-a and genistein are classified as estrogen agonists while both of the phthalates are androgen antagonists. DDT is classified as both an estrogen agonist and an androgen antagonist.

Figure 2

Frequently observed ovarian malformations in rats following neonatal exposure to endocrine disruptors. (A) An ovary from an unexposed adult female contains follicles at all stages of folliculogenesis and numerous corpora lutea (CLs), indicative of successful ovulation. (B) Ovaries from females neonatally treated with the synthetic estrogen estradiol benzoate (25 μg) show no signs of folliculogenesis, are undersized and lack CLs. The presence of numerous, large antral-like follicles (AF) most of which contain a degenerating or no oocyte and are frequently reminiscent of ovarian cysts, are commonly observed following neonatal exposure to (C) BPA (50 mg/kg bw) or (D) genistein (10 mg/kg bw). CLs are often absent or significantly reduced in number when numerous AFs are present. A multi-oocyte follicle (E) in a pre-pubertal ovary following neonatal treatment with estradiol benzoate (10 μg).

Figure 3

Effects of neonatal exposure to genistein (GEN, 10 mg/kg bw) compared to an oil based vehicle (OIL), and estradiol benzoate (EB, 50 μg) on reproductive physiology and behavior in female rats. (A) GEN significantly advanced the timing of pubertal onset as measured by day of vaginal opening compared to control females. (B) This corresponded with anovulation (by 15 weeks of age) in 43% of GEN females, compared to none of the OIL females and all of the EB females. (C) There was no effect of GEN on sexual receptivity (following ovariectomy and hormone priming) however (D) the number of GnRH neurons also immunopositive for Fos was significantly reduced indicating an impaired capacity to display steroid positive feedback. (Panels (A) and (D) adapted from Bateman and Patisaul, 2008).