Pharmacological Reports Copyright © 2012 2012, 64, 12851290 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences
Review
Flowers for Algernon: steroid dysgenesis, epigenetics and brain disorders
Bryan K. Sanders
College of Letters and Science (Alumnus), University of California, Durant Hall, MC 2920, Berkeley, CA 94720, USA
Correspondence: Bryan K. Sanders, e-mail: [email protected].
Abstract: While a recent study has reported that early citalopram exposure alters cortical network function and produces autistic-like behaviors in male rats, when evaluating antidepressant animal models of autism spectrum disorder (ASD) it is important to note that some se- lective serotonin (5-HT) reuptake inhibitors alter 3a-hydroxysteroid dehydrogenase activity, and thus steroidogenesis. At least one study has examined the effect of repeated citalopram administration on the serum and brain concentration of testosterone (T) and its metabolites and shown that citalopram increases serum T. Several in vitro studies also suggest that sex steroid can alter 5-HT homeo- stasis. While research efforts have demonstrated that transgenic mice expressing the most common of multiple gain-of-function 5-HT reuptake transporter (SERT) coding variants, SERT Ala56, previously identified in children with ASD, exhibit autistic-like be- haviors, elevated p38 MAPK-dependent transporter phosphorylation, enhanced 5-HT clearance rates and hyperserotonemia, a few studies provide some evidence that 5-HT may alter gonadal steroidogenesis. T, 17b-estradiol and synthetic estrogens are known in- hibitors of AKR1C21 (BRENDA, E.C. 1.1.1.209), the epitestosterone (epiT) producing enzyme in rodents. EpiT is a naturally oc- curring steroid in mammals, including man. An analysis of the literature suggests that epiT may be the central mediator in the epigenetic regulation of gene expression. Over thirty years ago, it was shown that rat brain epiT production is higher in females than in males. A similar finding in humans could explain the sex differences in the incidence of autism and other brain disorders. Despite this, the role of epiT in brain development remains a long neglected area of research.
Key words: autism, antidepressants, behavior, epigenetic, rodents, serotonin, sex differences, valproic acid
Introduction ders. Although spatial learning, memory and prepulse inhibition of the startle response (PPI) in rats were shown to be unaffected by 5-HT depletion after pre- Extensive research suggests a role for serotonin treatment with desipramine (an active metabolite of (5-HT) in learning and memory processes, both in imipramine) [34, 40], limited involvement of chronic healthy individuals and pathological disorders includ- 5-HT depletion on spatial learning, memory and PPI ing depression, autism spectrum disorder (ASD) and does not exclude the possibility that the neurotrans- schizophrenia, most of which have a developmental mitter has an important neuromodulatory role in these onset [40]. Therefore, 5-HT dysfunction in develop- functions. On the contrary, preservation of these func- ment may be involved in the etiology of these disor- tions in this context despite 5-HT depletion, which is
Pharmacological Reports, 2012, 64, 12851290 1285 known to alter adult sexual partner preference in rats perserotonemia, altered basal firing of raphe 5-HT [12, 23, 24], further implicates male gender as a com- neurons, and 5-HT1A and 5-HT2A receptor hypersensi- mon risk factor for some brain cognitive disorders tivity [51]. On this basis, Veenstra-Vanderweele et al. that show serotonergic imbalance. Interestingly, concluded that their efforts provide strong support for female-type sexual orientation in rats was shown to be the hypothesis that altered 5-HT homeostasis can im- converted to male-type sexual orientation by admini- pact risk for ASD traits and thus provide a model with stration of the dopamine agonist and mixed 5-HT ago- construct and face validity that can support further nist/antagonist lisuride to androgen-treated, prepuber- analysis of ASD mechanisms and potentially novel tally castrated adult females and adult males castrated treatments [51]. This position, however, is problem- at birth [16]. Neonatal castration of male rats at birth atic given that in vitro rodent studies on the effects of results in a female pattern of spatial learning [44], and 5-HT on sex steroid metabolism suggest that the pur- ehanced brain 5-HT level compared to intact males [25], ported role of 5-HT dysfunction in ASD may be sec- with 5-HT content and uptake in the hypothalamus in- ondary to the effect of steroid dysgenesis. Moreover, creased to levels found in females [53]. When ovariec- in vitro studies have shown that excess 5-HT can alter tomized at birth, females were found to have lower sex steroid metabolism by affecting placental aroma- 5-HT levels compared to normal females [25]. As this tization [52], enhancing follicular estrogen production review will demonstrate, these findings strengthen the [48], or inhibiting testicular androgen synthesis [19, association between androgens, 5-HT and ASD. 20] or disrupting T metabolism in other organs of the In a recent, well-publicized, study published in male rodent [33]. These findings support the notion Proceedings of the National Academy of Sciences that endocrine disruption during critical periods in (PNAS) [45], the investigators argue that, “There is early brain development may be the causative factor some evidence that leads us to propose that dysfunc- in the development of autistic-like behaviors in both tion of the raphe 5-HT system during perinatal devel- the SERT Ala56 mouse and the rat perinatally ex- opment may be one of the most important factors con- posed to citalopram. tributing to pervasive developmental disorders, espe- cially to ASD.” Indeed, the SERT Ala56, valproate and antidepressant rodent models of ASD appear to support this [17, 45, 51]. SERT Ala56, previously identified in children with ASD, is the most common of multiple Discussion gain-of-function serotonin reuptake trasporter (SERT) coding variants [51]. Although another study also pub- lished in PNAS demonstrated that transgenic mice ex- There is some evidence that the 5-HT receptor re- pressing SERT Ala56 exhibit autistic-like behaviors, sponses to some antidepressant drugs is dependent, at elevated p38 MAPK-dependent transporter phosphory- least in part, on the hormonal state of rodents [31]. In lation, enhanced 5-HT clearance rates and hyperseroto- fact, transient sex differences in cerebral 5-HT levels nemia [51], the medical literature further shows that of neonatal rats can be modified by androgens and es- 5-HT disrupts sex steroid production. trogens [25], with estradiol (E2 or 17b-E2) adminis- While the PNAS study of early citalopram exposure tered at a pharmacological dose on postnatal day (PN) demonstrated that the antidepressant alters cortical net- 1 increasing the brain 5-HT level by PN 8–14 and T work function and produces autistic-like behaviors in decreasing it [25]. When administered on PN 11, E2 rats, when evaluating this animal model it is important increases the brain 5-HT level in females [25]. Both to note that some selective serotonin reuptake inhibi- E2 and T are without effect in males on PN 11 [25]. tors (SSRIs) alter 3a-hydroxysteroid dehydrogenase E2 administered on PN 20 is without effect in either activity [26], and thus steroidogenesis. Furthermore, sex [25]. Finally, it has been demonstated that Przegaliñski et al. [41] studied the effect of repeated castration on PN 50 increases brain 5-HT synthesis in antidepressant administration on the serum and brain male rats, whereas T exerts an inhibitory influence concentration of testosterone (T) and its metabolites in [21]. Hence, the emphasis that the PNAS authors rats and found that citalopram increases serum T. Nev- place on hyperserotonemia [45, 51] and the sex differ- ertheless, SERT Ala56 mice also displayed autistic-like ence in mouse brain 5-HT levels on PN 3 [45], as they alterations in social function, communication and re- relate to their results and conclusions, may be mis- petitive behavior [51], effects accompanied by hy- placed given that brain 5-HT may rise as T falls in
1286 Pharmacological Reports, 2012, 64, 12851290 Flowers for Algernon: steroid dysgenesis, epigenetics and brain disorders Bryan K. Sanders
males after the well-documented postnatal T surge research. EpiT is a naturally occurring steroid in [11]. In view of these findings, excess postnatal E2 on mammals, including humans. It is regarded as an in- PN 1–2 or PN 8–21 to intact male rats would then be active epimer of T without medical significance out- expected to produce results similar to those reported side the realm of sports where it is used as a biological in the PNAS studies under review [1, 45]. T admini- marker in doping control [47]. Structurally, epiT dif- stration during the same periods, however, would be fers from T only in the configuration at the OH- expected to produce both autistic-like behaviors and bearing carbon, C17. It is herein proposed that epiT a male partner preference in adult male rats exposed deficiency disrupts the action of sex steroids and other neonatally to excess T [12, 29]. hormones (e.g., glucocorticoids) at their target sites, In humans, blood platelets have been suggested as and may trigger the expression, overexpression or a model for 5-HT uptake and storage in the brain, and downregulation of the myriad genes implicated in the effects of the various steroids on 5-HT uptake several brain disorders. Moreover, the timing and du- -3 were measured [18]. At 10 M, it was reported that ration of this steroid dysgenesis may affect the pres- E2, T and dihydrotestosterone (DHT) decreased 5-HT entation and outcome of ASD and other brain disor- uptake by 70, 49, and 25%, respectively [18]. Con- ders such as schizophrenia. Because epiT is anti- versely, both E2 and T showed maximal enhancement androgenic [46, 47], a finding of markedly decreased -6 of uptake at 10 M, with E2 and T increasing 5-HT epiT concentrations in autistic subjects would recon- uptake by 41%, and 60% respectively [18]. DHT cile the extreme male brain theory [3] with the fact maximally facilitated uptake by 40% at a concentra- -4 that researchers have yet to find evidence of markedly tion of 10 M [18]. No sex differences were found in increased androgen levels in ASD. As of this writing, either direction or in magnitude of change in uptake there are no published studies of urinary or plasma/ due to any hormone [18]. Given these results, the ac- serum epiT concentrations in brain disorders, includ- tion of sex steroids may be the most important factor ing ASD. contributing to hyperserotonemia in ASD. A critical Over fifty years of animal studies on the hormonal review of these and other findings may lead us to regulation of sex behavior have established that either a more meaningful, unified theory of autism. T or E2 can masculinize behavior and brain develop- Michael Baum of Boston University recently pro- ment [39]. However, not one has recognized that T, vided extensive commentary on the significance of 17b-E2 and synthetic estrogens inhibit AKR1C21 a study implicating an epigenetic mechanism in the (BRENDA, E.C. 1.1.1.209), the epiT producing mediation of T-dependent brain masculinization [4]. enzyme in rodents. In 2008, it was demonstrated that Specifically, the critical observation was that neonatal select inhibitors of aldose reductase (BRENDA, E.C. administration of the anticonvulsant drug valproic 1.1.1.21) also inhibit AKR1C21 [15]. In like manner, acid (VPA), a histone deacetylase inhibitor, com- VPA, an aldose reductase inhibitor, may block epiT pletely blocked the masculinizing action of either ex- formation. According to one study, VPA showed ogenous, neonatal T in female mice or of testicular T dose-dependent (1–800 µM) inhibition of progesterone- secreted neonatally in males on the development of bed nucleus of the stria terminalis (BNSTp) morphol- induced progesterone receptor (PR) and T-induced an- ogy [4]. According to Baum, authors who have pro- drogen receptor (AR) activity but had no estrogen re- vided evidence of a contribution of epigenetic modu- ceptor (ER) antagonist bioactivity and no significant lation of gene expression to brain and behavioral sex- PR, AR or ER agonist bioactivity [14]. Prenatal VPA ual differentiation in rats and mice all point to the exposure was shown to cause transient histone hyper- well-known sex differences in the incidence of autism acetylation [30] and autistic-like behaviors in rats [2, spectrum disorder and attention deficit disorder (male 17, 30, 32]. Hence, epiT may modulate both histone > female), as well as bipolar disorder and Rhett’s syn- acetylation and deacetylation by competing with T for drome (female > male), in humans [4]. AR binding sites [4]. Lastly, these findings and those Over thirty years ago, Gustafsson et al. [27] of Gustafsson et al. may serve to explain why exoge- showed that rat brain epitestosterone (epiT) produc- nous E2 at a dose known to masculinize behavior in tion is higher in females than in males. A similar find- female rats was shown to cause autistic-like behaviors ing in humans could explain the sex difference in the in intact males but not in intact females [1]. For these incidence of autism. Despite this, the role of epiT in reasons, inhibition of epiT synthesis in rats by either brain development remains a long neglected area of VPA exposure or a citalopram-induced increase in se-
Pharmacological Reports, 2012, 64, 12851290 1287 rum T or 17b-E2 during a critical period in brain de- support the notion that an epigenetic change in epiT velopment raises the question of whether epiT is the synthesis triggered by excess androgens or estrogens central mediator of the epigenetic regulation of gene may provide an alternate explanation for the develop- expression. If so, endocrine disrupting agents that im- ment of autistic-like behaviors in both SERT Ala56 pair epiT synthesis may be the most important factors mice or in rats administered a postnatal dose of citalo- contributing to pervasive developmental disorders. pram, estradiol or valproic acid. Additionally, they implicate potential environmental factors that may al- ter epiT action or synthesis in man, thereby leading to the development of ASD. Lastly, epiT or one of its Conclusion metabolites may be the endogenous ligand acting on the [3H]-imipramine-recognition site to modulate the In 2002, Havlíková, Hill, Hampl and Stárka were the first 5-HT transporter [35, 36]. This notion is supported by to reported that the plasma ratio of epiT-to-T in childhood studies showing that imipramine administration in is ³ 1, but dramatically decreases in males during prepu- adult rats decreases serum and brain DHT levels [41] berty and puberty, remaining constant in adulthood [28]. and reverses lasting behavior changes cause by neo- With the exception of prepubertal levels, serum T levels natal citalopram exposure [38]. Taken together, these in males are 5 to 10 times higher than epiT [37]. So far, results suggest that epiT may play a role in the patho- researchers have failed to consider the significance of this genesis of not only ASD but also depression [38]. Ac- beyond speculating that epiT may contribute to the regu- cordingly, it is predicted that exogenous epiT may re- lation of androgen dependent events such as the control verse or ameliorate the behavior changes characteris- of prostate growth or body hair distribution [47]. Both T and epiT are of similar molecular weight tic of the rat models of citalopram-induced ASD and [22, 49], raising the possibility that epiT produced by depression, as well as prove effective in humans suf- the kidneys in mice [6], male liver [27] and testes [46] fering from depression, ASD or related disorders. in rats and gonads and adrenals in humans [28, 37] Several lines of investigation exploring the mecha- crosses the blood-brain barrier to exert its effects on nism of T action in male-typical brain development brain development. Also likely is the possibility that have evolved since 1973 [4]. Unfortunately, the large brain epiT is synthesized de novo in humans as in body of literature developed around them represents mice and female rats, possibly from androstenedione missed opportunities to clarify the significance of (4-dione) [6, 50]. These possibilities are of particular Gustafsson et al. findings and, by extension, the po- interest given that Ruta et al. showed that autism tential role of epiT in the development, diagnosis and spectrum conditions (ASC) diagnosis (i.e., Asperger’s treatment of brain disorders. Consequently, the infer- syndrome or high functioning autism), without any ential discovery that epiT plays a central role in the interaction with sex, strongly predicted 4-dione levels sexual differentiation of the brain presented here and < (p 0.01) that were significantly elevated in ASC elsewhere [43] serves to clarify the influence of gender (Mann-Whitney W = 2677, p = 0.002), a result con- on the nature and expression of brain disorders includ- firmed by permutation testing in females (permuta- ing but not limited to ASD. As Bejerot et al. [5] re- tion-corrected p = 0.02) [42]. 4-Dione is the interme- ported, women with ASD were found to have elevated diate precursor of and is converted into T, DHT or es- T levels and several masculinized characteristics com- trogen (e.g., estrone and E2). EpiT, however, is pared with female controls (i.e., less feminine facial known to inhibit: 1) T biosynthesis and its reduction features and larger head circumference), whereas men to DHT in rats, mice and human tissues [46, 47]; 2) the conversion of T to 17b-E2 in human placental with ASD displayed several feminized characteristics microsomes [10]; 3) renal and testicular 11b-hydroxy- (i.e., less masculine body characteristics and voice steroid dehydrogenase [9]; 4) 5a-reductase [13, 46] in quality, and higher 2D:4D ratios) but similar T levels to rats; and 5) 17a-hydroxylase and C17,20 lyase in mi- controls. The present author anticipates that these and crosomal preparations of both rat and human testis [7, the previously discussed findings will ultimately sup- 8]. Further, a significant negative correlation between port our recognition of epiT’s role in health, gender ex- epiT and estradiol in human male serum was reported pression and androgen-mediated differences in sexual by Bicíková et al. [10]. Collectively, these findings development.
1288 Pharmacological Reports, 2012, 64, 12851290 Flowers for Algernon: steroid dysgenesis, epigenetics and brain disorders Bryan K. Sanders
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