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1.    Introduction to Endocrine Disrupting Chemicals
Endocrine-disrupting chemicals (EDCs) are ex- ogenous chemicals that interfere with hormone ac- tions, and which can be encountered through food and water, consumer products, medications, natural sources, industrial products, pesticides, or occupa- tional exposure 1,2 (Figure 1). The Endocrine Society, in their second Scientific Statement on EDCs, defined an EDC as an exogenous chemical, or mixture of chemicals, that interferes with any aspect of hor- mone action 2. The pool of implicated substances with endocrine disrupting activities continues to ex- pand with advancing research and has an indeter- minate reach. Some of the most well-studied EDCs that are discussed in this review are listed below:
•    Bisphenol A (BPA), found in various plastics
•    Phthalates, used in plasticizers and personal care products
•    Polychlorinated biphenyls (PCBs), in coolants and lubricants of electrical equipment
•    Perfluorooctanesulfonic acid (PFOS), found in various consumer products: food packaging, carpeting and upholstery, cleaning, and personal care products
•    Organophosphates (OPs), used in pesticides
•    Dichlorodiphenyltrichloroethane (DDT), in pesticides

Endocrine disrupting chemicals have been impli- cated in a variety of pathologic processes, and their adverse effects may be most significant when ex- posure occurs during early development when sys- tems are changing most rapidly1,3. The purpose of this review is to examine how prenatal exposure to EDCs can result in life-long effects that are very sim- ilar to those that result from prenatal stress. The im- plications for this are that prenatal exposure to both stress and EDCs might have additive or syner- gistic effects on the developing HPA axis, and to- gether, be a greater risk factor for future disease than either alone. We would like to propose that studies be designed specifically to examine whether both types of prenatal exposures result in effects that are different from either alone.

Figure 1. Known source of Endocrine Disrupting Chemical (EDC) from which humans may be exposed

2.    Prevalence of Endocrine Disrupting Chemicals
There are diverse routes of EDC exposure in- cluding ingestion of food, dust, water, and breast milk, skin contact, inhalation of gases and particles, and biological transfer across the placenta. EDCs have been detected in both children and adults in numerous fluids including blood, sweat, urine, breast milk and hair. Pervasive, detectable levels can be found in the blood, serum, and urine of pregnant individuals4,5. Of additional concern, are persistent EDCs, including PCBs, DDT, and PFOS which have been almost universally detected in study samples despite production or use having been banned in the United States for many years5,6. Phthalates are also ubiquitous EDCs; 95–98% of women and chil- dren tested positive for phthalates in two National Health and Nutrition Examination Surveys con- ducted from 1999 to 20147.

3.    The Hypothalamic-Pituitary-Adrenal Axis
The hypothalamic-pituitary-adrenal (HPA) axis is a network of endocrine organs which regulate glucocorticoid secretion and facilitate the stress response8. While acute HPA axis activation results in adaptive physiological responses to chal- lenge, chronic or repeated activation can produce adverse effects on many physiological systems9,10. Acute stressors have been characterized as resulting in allostasis, the result of processes which promote adaptation, while chronic stress results in allostatic load, in which homeostatic processes become over- whelmed11. Activation of the HPA axis is initiated upon perception of an external or internal stressor, or threat to homeostasis which causes the release of corticotropin releasing factor (CRF) from the para- ventricular nucleus (PVN) of the hypothalamus to act on corticotrophs of the anterior pituitary12. The pi- tuitary in turn synthesizes and secretes adrenocorti- cotropic hormone (ACTH) 13. ACTH binds the mela- nocortin 2 receptor in the zona fasciculata of the adrenal cortex, stimulating the production and re- lease of glucocorticoids which bind to mineralocor- ticoid (MR) and glucocorticoid receptors (GR) at many sites throughout the body14,15. Negative feed- back to both the levels of the pituitary and the PVN allows for tight regulation of glucocorticoid produc- tion and secretion16,17 (Figure 2).

Figure 2. The hypothalamic-pituitary-adrenal axis. Negative feedback mechanisms are in place at each organ level. Measured HPA axis dysregulation associated with pre-natal stress and EDC exposure have been observed at all levels of regulation.

The HPA axis and its feedback mechanisms are subject to dysregulation, particularly following chronic or repeated stress9,10. Glucocorticoids are essential for the normal development of many or- gan systems and the timing and amount of glucocor- ticoid secretion are critical factors18. Dysregulation of the HPA axis, including that which results from prenatal toxins, can result in adverse health out- comes and a wide spectrum of human disease, from depression to cardiovascular disease to type II dia- betes and metabolic syndrome later in life19-21.

4.    Prenatal Stress Effects and the Hypothalamic- Pituitary-Adrenal Axis
The role of prenatal stress on the subse- quent dysregulation of HPA axis function and con- comitant disease has been the subject of a number of excellent reviews22-26. Prenatal stress results in not only acute, but long-term dysregulation of the HPA axis. Glucocorticoids, including those released in response to prenatal stress, can have a long-last- ing effect on many regions of the developing brain27. Maternal glucocorticoids can cross the pla- centa and affect programming of the HPA axis as well as that of brain regions such as the hippocam- pus and amygdala, that modulate the activity of the PVN28. Generally, prenatal stress in rodents results in enhanced HPA responses to an acute stressor later in life29-33, an effect that is often found to be sex-specific23,34-36, though not always37. The nota- ble sex differences are likely due, at least in part, to the interactions between the HPA and hypotha- lamic-pituitary-gonad axes in the developing brain22. Specific effects on the fetus which appear to be maintained into adulthood include higher than normal levels of CRF, altered CRF1 receptor density, enhanced glucocorticoid responsivity and reduced glucocorticoid receptor density23. In rodent studies, a number of often sex-dependent changes in the responsivity or basal activity of components of the HPA axis have been found. Maternal stress results in lower levels of mRNA for POMC in female but not male offspring36. In response to a stressor, adult female rats that had experienced PNS, show ele- vated levels of CRF mRNA in the PVN30, unless the rats were selected for a high anxiety-like behavior phenotype38. Application of a stressor in adult male rats that had undergone prenatal stress causes more CRF-immunoreactivity in the PVN than in non- prenatally stressed controls39. CRF protein levels are also elevated in the PVN of prenatally stressed rats40, although this effect is not always observed41. In one study, levels of CRF protein in the PVN are also elevated following prenatal stress in male, but not female rats42, while in another, it was female rats which displayed elevated levels of CRF expres- sion43. Despite the differences in some of the results, it is clear that the CRF system is affected by prena- tal stress, and most likely the system is primed to be more highly reactive to stressors later in life.

In humans, prenatal stress has been associated with behavioral changes and neuropsychiatric dis- orders, including depression, anxiety, ADHD, con- duct disorders, conduct disorders, and autism spec- trum disorder later in life44. Prenatal stress does ap- pear to alter HPA axis function in humans as well as in animals, but the direction of the effect in humans in more variable25,45.

Excessive levels of prenatal glucocorticoids al- ter GR density in a number of brain regions that modulate HPA axis activity, most notably the hippo- campus, which normally inhibits that activity, and the amygdala, which normally enhances that activ- ity22,25. Prenatal stress-induced re-programming of subsequent HPA axis function results in a reduction in glucocorticoid negative feedback to the hypo- thalamus and pituitary24,46. This is thought to be caused by reduced hippocampal glucocorticoid re- ceptor (GR) density which limits hippocampus-in- duced inhibition of the PVN34,47-51. However, it has also been shown that GR mRNA levels in the hippo- campus of female, but not male rats, is greater fol- lowing prenatal stress31. In mice, this elevated level of the message for the receptor is seen in both sexes52. GR protein levels in the hippocampus are also higher in prenatally stressed female rats than in controls53. A second possibility is that excessive CRF release results in CRF receptor down-regulation with less ultimate glucocorticoid release. The amyg- dala is also affected by prenatal stress in ways that have the capacity to alter HPA axis function. Spe- cifically, CRF mRNA levels, CRF protein levels and CRF1 receptor densities are greater in the amyg- dala of prenatally stressed rodents than in con- trols31,34,43,54,55. Although this CRF is not directly af- fecting ACTH release, it is affecting the modulatory input of the amygdala over the PVN. As previously reviewed, CRF, its two receptors, and its binding protein are affected in different nuclei of the amyg- dala following prenatal stress22.

There are a number of mechanisms by which maternal stress during pregnancy might affect or re-program the responsivity of the HPA axis in off- spring and there is evidence for each. These include maternal glucocorticoid-induced alterations of the fetal HPA axis and epigenetic, intergenerational gene modifications14,24,26,28,34,45,47,56-60. Hippocam- pal inhibition of the HPA axis may also be affected by prenatal stress via the long-established effects of glucocorticoids on the hippocampus24,48,61,62. Ad- ditionally, prenatally stressed mice show higher lev- els of CRF in the CA3 region of the hippocampus63. Importantly, GR and CRF receptors, as well as CRF mRNA are affected in the F2 generation of dams that were stressed while pregnant64. This transgen- erational transmission is important evidence for the guidance of future studies.

5.    Prenatal Endocrine Disrupting Chemical Expo- sure and the Hypothalamic-Pituitary-Adrenal Axis: Evidence from Human and Animal Studies 
There is increasing evidence that the offspring of pregnant individuals exposed to endocrine-dis- rupting chemicals may also suffer adverse health outcomes. Here, we highlight the possibility that prenatal EDC exposure may result in adverse health outcomes via a similar mechanism to that of prena- tal stress exposure: through HPA axis dysregulation. Like prenatal stress, prenatal EDC exposure can alter HPA axis programming with health consequences later in life4,65. Prenatal exposure to EDCs ap- pears to disrupt the HPA axis on both the levels of the hypothalamus66 and the adrenals67. Addition- ally, EDCs can directly interact with glucocorticoid receptors68,69. Prenatal BPA exposure has been linked to alterations in basal cortisol levels3,4,70-72, cortisol response to a stressor4,70,71, and behavioral response to a stressor73. Prenatal BPA exposure has also been associated with variations in adrenal mass, composition, and histology70. A series of ad- ditional EDCs have also been observed to disrupt various aspects of the HPA axis. Prenatal PCB ex- posure causes alterations in basal and responsive cortisol72,73, and prenatal PFO contact alters CRF1 receptor gene expression in both the hypothalamus and pituitary74. In many of the cited animal and hu- man studies demonstrating physiologic effects of both prenatal stress and EDC exposure, sexually di- morphic results were appreciated4,70,73. Although outside the scope of this review, further considera- tion of the potential evolutionary and clinical signif- icance of sex-specific differences is warranted.

In addition to the noted effects of prenatal EDC exposure on the components of the HPA axis, the chemicals result in behavioral effects which mimic those produced by stress. These include anxiety-like behaviors in animal models75 as well as anxiety and depression in humans76. A number of neurotransmit- ter systems, as well as HPA axis dysregulation have been implicated in the behavioral effects of EDCs76. Critically, the EDCs may alter the way in which these systems respond to stressors later in life. It has been shown that metals, which are endocrine disruptors, can interact with prenatal stress to affect endocrine and behavioral measures77.
Like prenatal stress, there is evidence that EDCs can cause epigenetic modifications which result in intergenerational changes to the function of the HPA axis78-81. Additionally, prenatal exposure to a mix- ture of EDCs alters the methylation status of the CRF1 receptor gene in the hippocampus of adult mice in a manner correlated with hyperactive be- havioral changes82.

6.    Intersection of Poverty, Stress, and Endocrine Disrupting Chemical Exposure
As reviewed above, both prenatal stress and prenatal exposure of EDCs have been shown to al- ter the responsivity of the HPA axis to challenge. This dysregulation at critical periods in development has the potential to produce adverse outcomes later in life. Systemic stressors, such as low socio-economic status can contribute to allostatic load, rendering in- dividuals highly susceptible to disease11. Of partic- ular concern is the potential for prenatal stress and EDC exposure to overlap in the same pregnancy and cause an additive effect. This summative effect may perpetuate health inequity in the most vulner- able populations. Exposure to many EDCs occurs via water systems, work-place chemicals, and through bioaccumulation. While both scientific and public knowledge of the potential effects of EDCs is a lim- iting factor, efforts to avoid exposure are difficult without financial and logistical resources. Unfortu- nately, populations which face the greatest risk for EDC exposure are often those that also experience increased prevalence of chronic stressors, both of which are especially critical during pregnancy.

A review of the results of human studies high- lighted the need to evaluate the risks posed by dual exposure to EDCs and prenatal stress6. Indeed, there is accumulating evidence that prenatal pesti- cide exposure in the context of low socio-economic status can result in pediatric cognitive and immune deficiencies. In CHAMACOS, a study of Latino farm- worker families with high occupational pesticide ex- posures, maternal levels of OPs were measured throughout pregnancy83. Standardized IQ measure- ments at age 7 in offspring whose mothers had highest levels of urinary OPs during pregnancy showed a 13.3-point decline in boys facing eco- nomic adversity compared with those from a more privileged status. Likewise, an 8.5-point abatement in girls from economically disadvantaged families was observed compared with a 4.7 decrement in those facing less adversity. The intersection of eco- nomic stressors and pesticide exposure was further observed in the South African VHEMBE study. Among 674 households, maternal exposure to the insecticide DDT resulted in higher rates of childhood illness among those below the designated South Af- rican poverty line and in those who had experienced poor nutrient intake during pregnancy84. Given these observations, and the critical role of the HPA axis in both neurocognitive development and im- mune function, it is highly plausible that dual expo- sures to chronic stress and EDCs intersect in their abilities to cause dysregulation of the HPA axis.

7.    Conclusion
It has been well-established that prenatal stress may result in adverse health outcomes, likely via disruption of the maturation of the HPA axis during critical periods of development. There is increasing evidence to suggest prenatal EDC exposure may have very similar effects, which may occur via shared mechanisms. Increased understanding of the effects of EDCs, as well as state and national-level efforts to limit human exposure, will aid intergener- ational health and protect vulnerable populations.

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