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Department of Biology, Molecular and Cellular Biology Graduate Program, University of Massachusetts—Amherst, Amherst, Massachusetts 01003
Address all correspondence and requests for reprints to: Sandra L. Petersen, 611 North Pleasant Street, Department of Biology, University of Massachusetts–Amherst, Amherst, Massachusetts 01003. E-mail: sandyp{at}bio.umass.edu.
Abstract
Historically, much of the research on health effects of environmental pollutants focused on ascertaining whether compounds were carcinogenic. More recent findings show that environmental contaminants also exert insidious effects by disrupting hormone action. Of particular concern are findings that developmental exposure to dioxins, chemicals that act through the aryl hydrocarbon receptor pathway, permanently alters sexually differentiated neural functions in animal models. In this review, we focus on mechanisms through which dioxins disrupt neuroendocrine development as exemplified by effects on a brain region critical for ovulation in rodents. We also provide evidence that dysregulation of GABAergic neural development may be a general mechanism underlying a broad spectrum of effects seen after perinatal dioxin exposure.
THE RECOGNITION THAT chemicals released into the environment adversely affect human health is not new, but judgments about what effects constitute the most serious and global consequences of exposure are changing. For decades, toxicologists have tested environmental contaminants for carcinogenicity and examined adults for other adverse effects of exposure. However, accumulating evidence suggests that exposure to some environmental contaminants during fetal and neonatal life may have even more profound and long-term effects on individuals and society.
Of particular concern are findings that certain pollutants alter neuroendocrine functions during development in animal models. Because these functions are critical for normal brain development, neuroendocrine disruption produces permanent effects. Similar human effects are difficult to assess because they are not likely to be observable until adulthood. Moreover, effects may be difficult to measure because of poorly defined outcomes and the complexity of neuroendocrine systems. Therefore, it is important to identify mechanisms and sites of action of various neuroendocrine disruptors in animal models to develop appropriate diagnostic tools.
Herein, we review evidence that a group of chemicals that act through the aryl hydrocarbon receptor (AhR) pathway produce permanent impairments by interfering with neuroendocrine development. We also present a new hypothesis to explain seemingly diverse neural effects of AhR ligands.
AhR Ligands: Prototypic Endocrine Disruptors
Numerous environmental contaminants can alter endocrine physiology and neuroendocrine functions, but those that exert their effects through the AhR are among the best studied. Early work identified some AhR ligands as carcinogens (1) and also showed that they induce a battery of genes important for metabolism of xenobiotics (2, 3). As more studies were performed to characterize molecular mechanisms of AhR action, it became clear that the AhR pathway also cross-talks with estrogen (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16), progestin (17), androgen (18, 19), glucocorticoid (20), and thyroid (21) hormone receptor pathways. Therefore, it is not surprising that exposure to AhR ligands disrupts a wide range of endocrine-mediated functions (22). Importantly, endocrine disruption is seen at much lower exposure levels than are associated with carcinogenesis (23), and developmental exposure produces particularly dramatic and long-lived effects (24, 25, 26, 27, 28, 29, 30). For these reasons, AhR ligands have attracted the attention of a growing number of endocrinologists, neuroendocrinologists, and developmental biologists.
The AhR Pathway
The AhR is a member of the basic-helix-loop-helix/period (per)/arylhydrocarbon nuclear translocator (ARNT)/single-minded (Sim) (bHLH-PAS) family of ligand-activated transcription factors and was first identified nearly 30 yr ago (31). Hypoxia factor 1
(HIF), ARNT2, clock, MOP3 (also called brain and muscle ARNT-like protein 1; BMAL1), MOP4, MOP9, and BMAL2 are also members of this family (32). Pertinent to this review, most of these proteins play key roles in the development and/or adult regulation of neuroendocrine systems and are found in the preoptico-hypothalamus (33, 34, 35, 36, 37, 38, 39, 40).
A number of excellent reviews have described the AhR signaling pathway in detail (32, 41, 42, 43, 44). According to the classical model, unliganded AhR resides in the cytoplasm bound to heat shock protein 90, X-associated protein 2, and co-chaperone p23 (45). Ligand binding triggers conformational changes that facilitate translocation to the nucleus where the AhR dimerizes with ARNT or ARNT2 (46). AhR-ARNT dimers bind to dioxin response elements (also called xenobiotic response elements or aryl hydrocarbon receptor response elements), attract coregulatory proteins (44), and alter transcription of target genes (2, 3, 47, 48). In addition to the classical mode of AhR action, some evidence suggests that activation of the AhR induces rapid nongenomic effects through activation of protein kinases (49). Moreover, the AhR pathway exhibits cross-talk with a number of other signaling pathways including estrogen receptor (ER), retinoblastoma protein, hypoxia, nuclear factor-
B, and TGF-ß (50). Thus, there are multiple mechanisms through which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can interfere with endocrine functions during development and in adulthood.
As is the case for a number of transcription factors, posttranscriptional modifications are important mechanisms for regulating the AhR pathway (50, 51, 52). The AhR as well as dimerization partners and chaperones are phosphoproteins, and phosphorylation status regulates the AhR pathway at multiple levels. First, phosphorylation of the AhR inhibits translocation of the AhR to the nucleus (53, 54). Phosphorylation of ARNT is required for dimerization with the AhR (55), and both AhR and ARNT must be phosphorylated for heterodimer binding to DNA (56, 57, 58, 59) and also for initiation of transcription (54, 60, 61). Finally, recent work using ERK kinase inhibitors indicates that phosphorylation of the AhR also targets the receptor for degradation (54).
AhR Ligands: Diverse and Ubiquitous
AhR can be activated by hundreds of ligands ingested by humans daily. These ligands are not only substances produced as by-products of human activity but also naturally occurring substances and endogenous ligands. Among the man-made ligands that cause concern are halogenated aromatic hydrocarbons that bind to the AhR with high affinity (pico- to nanomolar range), bioaccumulate through the food chain, and are poorly metabolized. Polyhalogenated dibenzodioxins, dibenzofurans, and coplanar polyhalogenated biphenyls are in this category (43). Nonhalogenated polycyclic aromatic hydrocarbons including benzo(a)pyrene, benzanthracenes, and benzoflavones and 3-methylcholanthrene are also AhR agonists but have a somewhat lower affinity for the receptor (48). AhR ligands in the polycyclic aromatic hydrocarbon and halogenated aromatic hydrocarbon family have been linked to carcinogenicity (62), induction of oxidative stress (48, 63), immunotoxicity (64), cardiotoxicity (65, 66), and reproductive toxicity (7, 67, 68) in adults. However, evidence that developmental exposure to these compounds produces a constellation of more lasting effects is even more troubling (24, 69, 70).
In addition to these environmental pollutants, a number of naturally occurring substances found in plants are also potent AhR ligands (43). The largest group of compounds in this category is the flavonoid class of which most members are AhR antagonists (71, 72). Previous work showed that flavone derivatives bind the AhR with high affinity but fail to induce translocation of the receptor to the nucleus (73). Because flavones and flavonols suppress the dioxin-induced transformation of AhR required for binding to DNA (74), it has been suggested that flavonoids might prevent adverse effects of dioxins (71, 74, 75). Resveratrol, a phytoalexine found in grape skins, also binds the AhR with high affinity and inhibits AhR transformation. This compound may prevent dioxin-induced tumorigenesis (76, 77, 78) and inhibitory effects of dioxin on osteogenesis (79) as well as benzo[a]pyrene-induced lung damage (80) and sperm apoptosis (81).
In contrast to the flavonoids, other plant substances with demonstrated health benefits are AhR agonists. Indolo[3,2-b]carbazole (ICZ) is an anticarcinogenic flavone formed from acid digestion of indole-3-carbinol found in cruciferous vegetables (i.e. cabbage, cauliflower, broccoli, and brussel sprouts) (82). This substance is an AhR agonist, and it binds with an affinity similar to that of TCDD, the most potent and highly toxic AhR ligand known (83). Although both TCDD and ICZ bind the AhR with high affinity when administered at the same dosage, toxic effects are elicited only by TCDD (84). The fact that AhR activation induces a battery of detoxification genes that rapidly metabolize ICZ, but not TCDD, may be at least partially responsible for these differences (85). Alternatively, ligand-based differences in the recruitment of coactivators by AhR may play a role in the elicitation of cellular events that lead to toxicity.
Although adult exposure to ICZ did not elicit demonstrable toxicity, a single oral dose of the ICZ precursor, indole-3- carbinol (I3C), to pregnant rats decreases daily sperm production in male offspring in adulthood (86). Likewise, a daily dose of I3C interferes with the preovulatory surge release of LH and FSH and blocks ovulation in an immature rat model (87). These findings are consistent with recent evidence that after ingestion, I3C, not just its metabolites, is rapidly taken up by a number of organs, including the brain (88).
The AhR is generally considered an orphan receptor, but the search for an endogenous AhR ligand identified several agonists including bilirubin, biliverdin, metabolites of tryptophan, indirubin, indigo, and other compounds (43). Of these, indirubin and indigo, produced by oxidation of indole (89), demonstrate the highest affinity (90, 91, 92, 93, 94, 95, 96). These substances are found in urine and serum (89) and are able to induce expression of metabolizing enzymes typically induced by AhR activation, albeit with less potency than TCDD (97). More recently, another endogenous ligand, 2-(1'H- indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester, was purified from lung tissue and shown to compete with TCDD for binding to fish, murine, and human AhR (98). The functions of these and other endogenous AhR ligands remain to be determined.
Dioxins: Sources of Exposure
Dioxins and dioxin-like compounds have a halogen substitution pattern that produces a planar structure important for AhR binding (99). Dioxins are produced as by-products of waste incineration, pulp and paper bleaching, wood preservation, metallurgy, petroleum refinement, ethylene dichloride (component of polyvinyl chloride, PVC) synthesis, and manufacturing of other chemicals (100). Some human populations have been heavily contaminated with dioxins and dioxin-like compounds as a result of specific incidents (100); however, most individuals receive daily low-dose exposure through ingestion and inhalation. Daily exposure in industrialized countries is expressed in toxic equivalency units (units used to express toxic potency of chemicals and mixtures relative to TCDD) (101), and estimates of exposure depend on models used and populations examined. A detailed discussion of this topic and current exposure levels throughout the world can be found at www.epa.gov/ncea/pdfs/dioxin/nas-review. Because of the ubiquitous distribution, lipid solubility, and a half-life in adult humans of approximately 9–10 yr (100, 102), measurable concentrations are present in virtually all humans as well as other mammals. In addition, people in highly contaminated regions that have not received much attention may be exceeding the daily tolerable dioxin intake dose of 1–4 pg toxic equivalency units per kilogram body weight per day established by the World Health Organization (103).
There is evidence that dioxins cross the placenta and begin accumulating before birth (104). Of even more concern, breast milk is widely contaminated (105, 106, 107, 108, 109, 110), and infants in the United States and United Kingdom may be receiving doses as much as 20- to 40-fold higher than the tolerable limit established for adults by the World Health Organization (105, 111) (limits based on risk assessment for cancer). Consistent with the idea that transfer occurs through breast milk, TCDD concentrations in adipose tissue are two to five times higher in breast-fed than in formula-fed infants (104).
The postnatal rate of accumulation of TCDD is dramatic in breast-fed infants, peaking at 5–6 months and then slowing around 2 yr of age (106). By around 50 yr of age, body burdens in breast-fed and formula-fed individuals are similar (104), leading to the suggestion that individuals with higher developmental exposure may not be at a greater risk for cancer. Nonetheless, it is important to note that the initial and relatively high-dose exposure, as well as the rapid acquisition of body burdens of dioxins, occurs during the time of irreversible changes in brain development. Considering that developmental effects of TCDD may not manifest until adulthood, appropriate end points for evaluating consequences of developmental exposure must be established. This will require a better understanding of where and how TCDD might alter early neural functions.
Fetal Exposure to TCDD Permanently Alters Reproductive Functions
In animal models, perinatal exposure to dioxins or dioxin-like chemicals produces a number of sex-specific physiological changes that become apparent in adulthood (24). Of these, changes in reproductive potential are of particular concern. Pioneering work by Peterson and Gray (112, 113, 114) showed that male offspring of dams treated perinatally with TCDD show poor masculine sexual behaviors and have increased propensity to show female mating behaviors (115). In some rat strains, treated males also exhibit feminine cyclic rather than tonic patterns of gonadotropin release (114). In female rats, a single prenatal exposure to TCDD delays the onset of puberty, prolongs the time required to achieve pregnancy in continuous breeding situations, and increases the incidence of premature constant estrus (113, 116, 117).
The altered behavioral and gonadotropin patterns seen after developmental exposure to TCDD in rodent models also occur after perinatal manipulation of gonadal hormones. During the perinatal period, the developing testes actively secrete testosterone (T), and some of this hormone is aromatized to estradiol (E2) in the preoptico-hypothalamus (POA-HYP). As a result, neural circuitry in this region is masculinized such that male sexual behaviors can be elicited by androgens in adulthood. Perinatal exposure also defeminizes the POA-HYP so that feminine behavioral potentials and cyclic gonadotropin release patterns are suppressed. Thus, it is possible that altered reproductive capacity in males exposed to TCDD during development is a result of interference with T or E2 action in the POA-HYP.
The idea that TCDD blocks masculinization and defeminization of the POA-HYP by antagonizing T and/or E2 actions is consistent with abundant evidence for inhibitory cross-talk between AhR and steroid receptor pathways (9, 18, 118, 119, 120). However, antiestrogenic or antiandrogenic actions of TCDD cannot easily explain the syndrome it evokes in female rodents exposed during development. In fact, treated females develop symptoms similar to those seen in the delayed anovulatory syndrome (DAS), a syndrome resulting from low-dose T or E2 exposure in the perinatal period (121, 122, 123, 124). Both TCDD-treated (116) and DAS (121, 122, 123, 124) females have normal ovulatory cycles that stop prematurely. Studies of DAS animals show that this syndrome is a result of neuroendocrine rather than ovarian impairments (124). Based on this indirect evidence, it appears that TCDD acts as an ER or androgen receptor agonist, rather than an antagonist, in the POA-HYP of developing females. Such an interpretation fits with evidence that in the absence of E2, AhR ligand binding activates ER (10).
It is well established in rodent models that altered sexual behaviors and gonadotropin release patterns seen after steroid manipulation during development result from permanent changes in neural structures and functions (125). Because the symptoms resulting from developmental exposure to TCDD are similar, and because TCDD can alter hormone action, it is logical to suggest that TCDD has neural effects. However, until recently, there was little evidence that TCDD acts directly in the brain.
Evidence for Neural Targets of TCDD
Most, if not all, effects of TCDD are exerted through the AhR pathway. Therefore, as a first step to test whether TCDD exerts its effects in the brain, we mapped the distributions of AhR, ARNT, and ARNT2 gene expression in adult rats. Relevant to the present discussion, we found these genes expressed in sexually dimorphic nuclei of the POA (126, 127) that contain ER (128, 129) and are sensitive to perinatal steroid hormone manipulations. Most notably, expression was apparent in the anteroventral periventricular nucleus (AVPV), a structure critical for sex-specific and E2-dependent LH surge release (130, 131). AhR, ARNT, and ARNT2 mRNAs were also seen in sexually dimorphic medial preoptic regions and the ventromedial hypothalamus, structures important for the expression of male (132, 133) and female (134) sexual behaviors.
We observed the same distribution of AhR, ARNT, and ARNT2 mRNAs in rat brains collected during the critical period when sexually dimorphic patterns develop (Mac- Abee, M., and S. L. Petersen, unpublished observation). Levels of AhR expression appear to be higher in fetuses and neonates than in adults (MacAbee, M., and S. L. Petersen, unpublished observation), suggesting that the AhR pathway may be important for POA-HYP development. This idea is supported by findings that AhR knockout mice have reduced fertility (135). However, it is not yet clear whether the reproductive deficits noted result from faulty neuroendocrine development. Such determinations await elucidation of the neural developmental processes regulated by the AhR pathway.
-Aminobutryic Acid (GABA) Neurons Are Targets of TCDD
To understand the role of the AhR pathway in neural development and to determine how inappropriate activation of the pathway disrupts sexual differentiation of the brain, it is important to know the phenotype of the target cells. After mapping AhR gene expression in the rat brain (38), we noted that the pattern of distribution resembles that of genes encoding glutamic acid decarboxylase (GAD) 65 and 67, the enzymes critical for GABA synthesis (137). Dual-label in situ hybridization studies verified that nearly all AhR gene expression in the brains of adult and developing rats (138) is in GAD-expressing neurons.
The link between GABA and AhR suggested by neuroanatomical findings appears to be evolutionarily conserved. In Caenorhabditis elegans, a developmental model in which cells are well characterized, orthologs of AhR and ARNT direct the cell fate of specific GABAergic neurons (139). In mammals, evidence that the AhR is important for GABA neuronal development is mainly indirect. For example, GABA, GAD isoforms (140, 141, 142), and AhR (143) all appear around embryonic d 10–15, before specific brain nuclei differentiate in the rat brain. In addition, the basic-helix-loop-helix protein, Hairy and Enhancer of Split homolog-1 (HES-1), plays a role in GABAergic neuronal development in mammals (144), and HES-1 was recently identified as a target of the AhR (145). Finally, our recent work, described below, shows that inappropriate activation of the AhR during development permanently alters the number of a unique type of GABAergic neuron in the AVPV. Based on these pieces of evidence, we hypothesize that GABA neurons are the targets through which TCDD interferes with neuroendocrine development.
Dual-Phenotype GABA/Glutamate (Glu) Neurons in the AVPV Are Developmental Targets of E2 and TCDD
It is possible that changes in sexual behavior potentials seen after developmental exposure to TCDD may be secondary to effects on genitalia (116). However, peripheral changes cannot explain how TCDD blocks defeminization of gonadotropin release patterns such that males show LH surge release in response to E2 and progesterone (114). Abundant evidence indicates that E2 signals necessary for the LH surge are communicated to GnRH neurons indirectly through the AVPV (146). Our recent work shows that all ER- and ER-ß expression in the region is in unique dual-phenotype GABAergic neurons that are also glutamatergic (147). Importantly, AVPV GABA neurons also express AhR, and perinatal exposure to TCDD alters GAD 67 expression in these neurons (138). Thus, accumulating evidence supports our hypothesis that GABA neurons are targets of TCDD during neuroendocrine development.
The AhR- and ER-containing GABA neurons of the AVPV are unique in that they are also glutamatergic (147). Previous work shows that both inhibition of GABA release and stimulation of Glu release are required for the LH surge (reviewed in Refs. 146 , 148 , and 149). Therefore, it is significant that at the onset of the surge, GABAergic vesicles decrease and Glu vesicles increase in dual-phenotype terminals contacting GnRH neurons (147) (see Fig. 1
). In line with evidence that the AVPV regulates the female-specific LH surge release pattern, females have 2.5 times more GABA/Glu neurons in the AVPV than do males (147). Because GABA/Glu neurons comprise the bulk of the AVPV, it is likely that they account for the previously described sex difference in the volume of the AVPV (150, 151). It is also likely that they are the AVPV neurons shown previously to provide most of the E2-sensitive input to GnRH neurons (152). In support of this idea, the number of dual-phenotype GABA/Glu contacts on GnRH neurons (147) is similar to estimates of total synaptic contacts detected on these neurons, and females have significantly more such contacts (153). Together these findings indicate that dual-phenotype GABA/Glu neurons of the AVPV are important sexually differentiated targets through which E2 stimulates the LH surge release.
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The volume of the adult AVPV is determined by the perinatal hormonal milieu. E2 administered perinatally to females or derived from aromatization of T in developing males decreases the volume of the AVPV (125, 151, 154, 155). Moreover, perinatal T or E2 exposure abolishes the potential for LH surge release (156), and females become anovulatory (157, 158). Consistent with evidence that GABA/Glu neurons make up most of the AVPV, we found that perinatal T treatment reduces the number of AVPV GABA/Glu neurons in females to levels seen in males (Krishnan, S., and S. L. Petersen, in preparation). This novel finding further substantiates the importance of GABA/Glu neurons in LH surge release.
In view of evidence that prenatal exposure to TCDD interferes with defeminization of LH patterns in males (114), we examined its effect on the number of GABA/Glu neurons in the AVPV. We found that TCDD-treated males had significantly higher numbers of GABA/Glu neurons than controls (159). In fact, the levels seen in TCDD-treated males were similar to those detected in control females. These findings indicate that TCDD acts as an antiestrogen in the brain of developing males as it does in nonneural tissues (160); however, the exact mechanism is not yet clear. AhR ligands decrease ER expression (161, 162) and may affect aromatase activity (163, 164, 165) in some tissues. However, these mechanisms probably do not account for the observed effects in the AVPV, because TCDD did not affect sex differences in progestin receptor expression (138) that depend on ER activation (166, 167, 168).
Mechanisms Underlying Sexual Differentiation of GABA/Glu Neuronal Populations
In a series of studies, Arai and others established that sex differences in the number of neurons in the AVPV results from apoptosis that is dependent on T conversion to E2 in males (169, 170, 171, 172, 173, 174, 175). This concept was validated recently by findings that sex differences in AVPV cell number were absent in mice lacking functional BAX, a key cell death protein (176). Our recent findings, described above, indicate that the cells responsible for sex differences in the size of the AVPV are GABA/Glu neurons. Thus, it is likely that E2 and TCDD impact the number of AVPV and GABA/Glu neurons through the apoptotic pathway.
It is unclear whether genes encoding proteins in the apoptotic pathway are direct or indirect targets of E2 and TCDD in the development of the AVPV. There are a large number of molecules involved in both the death receptor-mediated and mitochondrial pathways of apoptosis (177), any of which might be direct targets of E2 and TCDD. Moreover, E2 and TCDD might indirectly affect the cell death cascade by altering any number of cell signaling pathways that ultimately induce or prevent apoptosis (48, 70, 178, 179). Because of the large number of potential targets, we are currently using cDNA microarrays to identify sex-specific genes that are also regulated by TCDD.
It’s Not Just about the AVPV
The data described above suggest that TCDD exposure during the perinatal period permanently alters reproductive potentials. However, developmental exposure to TCDD also affects nonreproductive functions and does so in a sex- specific manner. For example, exposure to low doses of TCDD during development decreases errors in radial maze performance in males (180, 181). Other researchers showed that schedule-controlled operant performance was affected in opposite ways in males and females exposed to environmentally relevant doses of TCDD during development (182, 183). Alterations of the GABA, Glu, or dual-function neurons in the hippocampus, cortex, striatum, and/or brain stem could explain these outcomes, and each of these regions contain AhR, ARNT, and/or ARNT2 (38) as well as ER (128, 129, 185, 186, 187, 188, 189, 190, 191). Similarly, TCDD alters cortical dominance in a sex-specific manner (192), and GABA neurons play a key role in cortical development (193). Finally, TCDD exposure during development also has permanent effects on body temperature set point (194, 195), a function controlled by GABA and glutamate (196, 197).
It is also interesting to note that GABA is found in testes where it is important for proliferation of Leydig cells (198, 199), cells that also contain the AhR pathway (200) as well as ERs (201, 202). Similarly, the oviduct contains the AhR and ARNT (203) as well as GAD and GABA (204, 205, 206, 207, 208, 209, 210), which are regulated by ovarian hormones in the oviduct (208, 211, 212). Outside the reproductive tract, AhR gene expression is also very high in the pancreas (213), and regulated release of GABA (214) and glutamate (215) in pancreatic cells is critical for glucose regulation. Finally, activation of the AhR during development results in cleft palate (216, 217, 218, 219), a deformity also seen in animals with disrupted GABAergic signaling (220, 221, 222, 223, 224). Although it is premature to say that interactions between the AhR and GABAergic signaling pathways underlie TCDD-induced pathologies as diverse as endometriosis (14), impaired glucose use (136), and cleft palate, the idea certainly warrants additional investigation.
Conclusion and Recommendations
It is becoming clear that developmental exposure to dioxins and dioxin-like compounds can permanently impair neuroendocrine functions. This is exemplified by findings that when male rats are exposed to TCDD during the perinatal period, they can show female-typical LH surge release as adults. Our recent findings indicate that TCDD exerts this effect by interfering with E2-dependent cell death of GABA/Glu neurons in a brain region critical for the LH surge, the AVPV. This interpretation is consistent with other findings that most AhR is found in GABAergic neurons in the AVPV of developing brain. Moreover, other laboratories have demonstrated that developmental exposure to TCDD also exerts sex-specific effects on learning and memory (29, 180, 182, 184), other functions regulated by GABA and Glu. Importantly, comparative neurodevelopmental studies verify evolutionary conservation of the link between the AhR pathway and GABA neuronal development. Based on these findings, we suggest that dysregulation of GABAergic neuronal development may be a general mechanism underlying TCDD-induced neurodevelopmental reproductive toxicity.
In addition to reproductive and learning and memory functions, GABA and Glu regulate social behaviors, mood, and stress responses. Unfortunately, little is known about the developmental effects of dioxins and other neurotoxicants on these functions, despite the impact their dysregulation has on society. Therefore, it is important to include them as end points in future studies investigating the effects of exposure to AhR ligands in animal models and human populations.
It remains to be determined whether the recently characterized effects of TCDD on neural development in animal models are relevant to human health. However, it is notable that observed effects of TCDD on neural structure and function occur at doses that do not produce overt toxicity in animals exposed during development. Moreover, the well characterized nonneural effects of TCDD occur at similar body burdens in humans and animal models (23), and although concentrations of TCDD in the environment may be decreasing, this is probably not the case for all AhR ligands. Therefore, it is critical that neuroendocrinologists and neurotoxicologists work together to fully characterize the molecular mechanisms of AhR action in developing brain. With this information, we can identify appropriate end points for use by epidemiologists and public health officials to accurately evaluate the impact of AhR ligands on human brain development.
Footnotes
This work was supported by National Institutes of Health Grants ES008774, ES013885, and HD27305 to S.L.P.
S.L.P., S.K., and E.D.H. have nothing to disclose.
First Published Online May 11, 2006
Abbreviations: AhR, Aryl hydrocarbon receptorAVPV, anteroventral periventricular nucleus; DAS, delayed anovulatory syndrome; E2, estradiol; ER, estrogen receptor; GABA, -aminobutyric acid; GAD, glutamic acid decarboxylase; Glu, glutamate; I3C, indole-3-carbinol; ICZ, indolo[3,2-b]carbazole; POA-HYP, preoptico-hypothalamus; T, testosterone.
Received September 9, 2005.
Accepted for publication January 26, 2006.
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