Long-Term Effects of Environmental Endocrine Disruptors on Reproductive Physiology and Behavior

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

Influence of ERβ selective agonism during the neonatal period on the sexual differentiation of the rat hypothalamic-pituitary-gonadal (HPG) axis

<p>Abstract</p> <p>Background</p> <p>It is well established that sexual differentiation of the rodent hypothalamic-pituitary-gonadal (HPG) axis is principally orchestrated by estrogen during the perinatal period. Here we sought to better characterize the mechanistic role the beta form of the estrogen receptor (ERβ) plays in this process.</p> <p>Methods</p> <p>To achieve this, we exposed neonatal female rats to three doses (0.5, 1 and 2 mg/kg) of the ERβ selective agonist diarylpropionitrile (DPN) using estradiol benzoate (EB) as a positive control. Measures included day of vaginal opening, estrous cycle quality, GnRH and Fos co-localization following ovariectomy and hormone priming, circulating luteinizing hormone (LH) levels and quantification of hypothalamic kisspeptin immunoreactivity. A second set of females was then neonatally exposed to DPN, the ERα agonist propyl-pyrazole-triol (PPT), DPN+PPT, or EB to compare the impact of ERα and ERβ selective agonism on kisspeptin gene expression in pre- and post-pubescent females.</p> <p>Results</p> <p>All three DPN doses significantly advanced the day of vaginal opening and induced premature anestrus. GnRH and Fos co-labeling, a marker of GnRH activation, following ovariectomy and hormone priming was reduced by approximately half at all doses; the magnitude of which was not as large as with EB or what we have previously observed with the ERα agonist PPT. LH levels were also correspondingly lower, compared to control females. No impact of DPN was observed on the density of kisspeptin immunoreactive (-ir) fibers or cell bodies in the arcuate (ARC) nucleus, and kisspeptin-ir was only significantly reduced by the middle (1 mg/kg) DPN dose in the preoptic region. The second experiment revealed that EB, PPT and the combination of DPN+PPT significantly abrogated preoptic Kiss1 expression at both ages but ARC expression was only reduced by EB.</p> <p>Conclusion</p> <p>Our results indicate that selective agonism of ERβ is not sufficient to completely achieve male-typical HPG organization observed with EB or an ERα agonist.</p

Endocrine Disruption of Vasopressin Systems and Related Behaviors

Endocrine disrupting chemicals (EDCs) are chemicals that interfere with the organizational or activational effects of hormones. Although the vast majority of the EDC literature focuses on steroid hormone signaling related impacts, growing evidence from a myriad of species reveals that the nonapeptide hormones vasopressin (AVP) and oxytocin (OT) may also be EDC targets. EDCs shown to alter pathways and behaviors coordinated by AVP and/or OT include the plastics component bisphenol A (BPA), the soy phytoestrogen genistein (GEN), and various flame retardants. Many effects are sex specific and likely involve action at nuclear estrogen receptors. Effects include the elimination or reversal of well-characterized sexually dimorphic aspects of the AVP system, including innervation of the lateral septum and other brain regions critical for social and other non-reproductive behaviors. Disruption of magnocellular AVP function has also been reported in rats, suggesting possible effects on hemodynamics and cardiovascular function

Neonatal Bisphenol-A Exposure Alters Rat Reproductive Development and Ovarian Morphology Without Impairing Activation of Gonadotropin-Releasing Hormone Neurons1

Developmental exposure to endocrine-disrupting compounds is hypothesized to adversely affect female reproductive physiology by interfering with the organization of the hypothalamic-pituitary-gonadal axis. Here, we compared the effects of neonatal exposure to two environmentally relevant doses of the plastics component bisphenol-A (BPA; 50 μg/kg and 50 mg/kg) with the ESR1 (formerly known as ERalpha)-selective agonist 4,4′,4″-(4-propyl-[1H]pyrazole-1,3,5-triyl)trisphenol (PPT; 1 mg/kg) on the development of the female rat hypothalamus and ovary. An oil vehicle and estradiol benzoate (EB; 25 μg) were used as negative and positive controls. Exposure to EB, PPT, or the low dose of BPA advanced pubertal onset. A total of 67% of females exposed to the high BPA dose were acyclic by 15 wk after vaginal opening compared with 14% of those exposed to the low BPA dose, all of the EB- and PPT-treated females, and none of the control animals. Ovaries from the EB-treated females were undersized and showed no evidence of folliculogenesis, whereas ovaries from the PPT-treated females were characterized by large antral-like follicles, which did not appear to support ovulation. Severity of deficits within the BPA-treated groups increased with dose and included large antral-like follicles and lower numbers of corpora lutea. Sexual receptivity, examined after ovariectomy and hormone replacement, was normal in all groups except those neonatally exposed to EB. FOS induction in hypothalamic gonadotropic (GnRH) neurons after hormone priming was impaired in the EB- and PPT-treated groups but neither of the BPA-treated groups. Our data suggest that BPA disrupts ovarian development but not the ability of GnRH neurons to respond to steroid-positive feedback