Early life trauma is associated with decreased peripheral levels of thyroid-hormone T3 in adolescents

Int. J. Devl Neuroscience 47 (2015) 304–308

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Early life trauma is associated with decreased peripheral levels of thyroid-hormone T3 in adolescents T.D. Machado a,∗ , G.A. Salum b , V.L. Bosa a , M.Z. Goldani a , M.J. Meaney c,d , M. Agranonik e , G.G. Manfro b , P.P. Silveira a a Departments of Pediatrics, Faculty of Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil b Departments of Psychiatry, Faculty of Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil c Department of Psychiatry and Neurology, McGill University, Montreal, Quèbec, Canada d Singapore Institute for Clinical Sciences, Singapore e Statistics Information Center, Fundac¸ão de Economia e Estatística, Porto Alegre, Rio Grande do Sul, Brazil

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Article history: Received 18 August 2015 Received in revised form 13 October 2015 Accepted 14 October 2015 Available online 30 October 2015 Keywords: Trauma Triiodothyronine T3 Thyoxine T4 Thyroid hormones Maternal care

a b s t r a c t An adverse early life environment can induce changes on behavioral and metabolic responses later in life. Recent studies in rats showed that the quality of maternal care as measured by high levels of pup licking and grooming (LG) was associated with changes in the relationship between the precursor thyroid-hormone T4 and the more active T3. Here we investigated if early exposure to childhood abuse is associated with thyroid-hormone levels in human adolescents. Given the empirical evidence from animal models showing that good maternal care was associated with increased conversion of T4 to T3, we hypothesized that early adversity would be associated with a decreased peripheral conversion of T4 to T3. A sample of 80 adolescents (10–18 years) participated in this study. We used the Childhood Trauma Questionnaire to investigate early life stress. We calculate the body mass index (BMI) assessing weight and height and sexual maturation stage was determined by self-assessment. Blood samples were collected to measure T3 and T4 levels. ANCOVA were used to evaluate the influence of the Physical Abuse domain of the Childhood Trauma Questionnaire as the early life stress variable in T3 and T4 separately, adjusted for potential confounders such as pubertal status, gender, socioeconomic status and BMI. Early life trauma was associated with reduced T3 levels in adolescents, when adjusted for potential confounders (p = 0.013), but not with peripheral T4 levels (p = 0.625). We extended findings from animal models showing that adverse early experience persistently impacts on the individual’s responses to stress, which is marked by an abnormal metabolism of thyroid hormones. Further studies are needed to further investigate the nature of such associations. © 2015 Elsevier Ltd. All rights reserved.

1. Introduction Early life stress (ELS) has shown to have profound impacts on health throughout the lifespan (Alastalo et al., 2013; Etter et al., 2013; MacMillan et al., 2001) and it can induce changes on behavioral and metabolic responses later in life (Pervanidou and Chrousos, 2012). Studies have shown that ELS is associated with

∗ Corresponding author at: Programa de Pós-Graduac¸ão em Saúde da Crianc¸a e do Adolescente – FAMED – Universidade Federal do Rio Grande do Sul. Ramiro Barcelos, 2350, Largo Eduardo Zaccaro Faraco, Porto Alegre, Rio Grande do Sul 90035-903, Brazil. Fax: +55 51 3359 8001. E-mail address: [email protected] (T.D. Machado). http://dx.doi.org/10.1016/j.ijdevneu.2015.10.005 0736-5748/© 2015 Elsevier Ltd. All rights reserved.

depression, personality disorders (Sudbrack et al., 2015; Weber et al., 2008), temperament traits (Sudbrack et al., 2015), anxiety, drug addiction and antisocial behavior in adulthood (MacMillan et al., 2001) as well as a variety of other medical problems (Fergusson et al., 2008; Spitzer et al., 2013). Among the different types of trauma, physical abuse is consistently associated with poor outcomes (Bailer et al., 2014; Bailey et al., 2012; Fuller-Thomson and Hooper, 2015; Petrenko et al., 2012; Schneiderman et al., 2014). Despite that, the mechanistic links between ELS and poor health are still poorly understood. One prominent hypothesis is that stress early in life may cause persistent programming changes on the hypothalamic–pituitary–adrenal (HPA) axis functioning. The HPA activation culminates with glucocorticoid release, being

T.D. Machado et al. / Int. J. Devl Neuroscience 47 (2015) 304–308 Table 1 Characteristics distribution of the subjects for T3 and T4.

highly adaptive for survival in facing an acute stress situation. However, chronic/persistent hyperactivation of this axis can cause damage (Herman et al., 2003). ELS such as maltreatment (physical, sexual or emotional abuse and neglect) may persistently enhance the HPA activity (Mello et al., 2009; Trickett et al., 2010) and evidences from experimental studies propose a hyper-reactivity of HPA axis in adulthood caused by ELS (Machado et al., 2013). In animal models, it was shown that the poor quality of maternal care, as measured by low levels of pup licking and grooming (LG) over the first week of life, decreases hippocampal glucocorticoid receptor (GR) expression, diminishes glucocorticoid feedback sensitivity over hypothalamic corticotrophin-releasing factor (CRF) synthesis and leads to more exuberant adrenal glucocorticoid responses to stress in comparison with those reared by High-LG mothers (Francis et al., 1999; Liu et al., 1997; Toki et al., 2007; van Hasselt et al., 2012; Weaver et al., 2004, 2005). A broad range of in vivo and in vitro studies demonstrates that pup LG increases GR gene transcription in the offspring through epigenetic mechanisms, specifically through effects on DNA methylation in the exon 17 GR promoter. This is suggested to occur in response to an increase in NGFIA as a consequence of a thyroid-hormonedependent increase in 5-HT activity at 5-HT7 receptors and the subsequent activation of cyclic adenosine monophosphate (cAMP) and cAMP-dependent protein kinase A (PKA) (Champagne et al., 2003; Laplante et al., 2002; Meaney et al., 1987, 2000; Mitchell et al., 1992, 1990a,b; Weaver et al., 2007). Previous experimental studies implicate thyroid hormones in the regulation of hippocampal 5-HT activity and GR expression (Meaney et al., 1987, 2000), and it was recently demonstrated that an increased frequency of pup LG in rats associates with an increased conversion of the T4 precursor to the more active T3 (Hellstrom et al., 2012). Therefore, maternal care regulates GR expression through increases in hippocampal 5-HT that lie downstream of the dynamic T3 signaling. In humans, similarly to pup LG, maternal stroking in infancy is able to modify the effect of maternal prenatal depression on infant reactivity (Sharp et al., 2012). More specifically, low maternal stroking in those women that had prenatal depression is related to increased infant negative emotionality and decreased physiological adaptability (Sharp et al., 2012). It is described decreased levels of glucocorticoid receptor mRNA, as well as mRNA transcripts bearing the glucocorticoid receptor 1F splice variant in human hippocampal samples from suicide victims with a history of childhood abuse (McGowan et al., 2009). This suggests that the effect of parental care on the epigenetic regulation of hippocampal glucocorticoid receptor expression also happens in humans. Despite that, the effects of early life stress on thyroid hormones metabolism are not well known. The objective of our study was to investigate whether changes in thyroid hormone metabolism could be good candidates to explain mechanistic links between early life stress

200,0

305

T3 N Mean SD

T4 p-Value

CTQ-physical abuse score 0.004** Low 44 152.3a 30.38 Intermediate 10 158.7a 27.95 High 26 130.4b 24.75

N Mean SD

0.539** 44 9.6 10 9.3 26 9.9

1.50 1.27 1.32

14 10.0 31 9.3 35 9.9

1.06 1.51 1.39

45 9.7 86 9.7

1.25 1.50

24 9.8 56 9.6

1.56 1.35

0.002**

Pubertal status Pre-puberty Puberty Post-puberty

14 159.7a 28.31 31 154.2a 28.67 35 133.2b 27.77

Gender Male Female

29 150.7 27.71 51 143.3 31.36

Socioeconomic status Low High

24 135.2 28.53 56 150.6 29.85

BMI

80 r = 0.246

0.127**

0.292*

0.931*

0.036*

0.028#

p-Value

0.512*

80 r = 0.270

0.015#

Data presented as mean ± SD. * p Value for Student’s t test. ** p Value for one-way analysis of variance (ANOVA), means followed by the same letter are not significantly different by Bonferroni test. # p Value for pearson’s correlation.

and negative health outcomes. Here, we hypothesize that exposure to childhood abuse (specifically physical abuse) could predict abnormal thyroid-hormone metabolism later in life, being related to decreased peripheral conversion of T4 to T3 as seen in the animal model (pups reared by Low-LG mothers). Recent studies show that among the different types of trauma, the adverse consequences of childhood physical abuse persist in different systems, affecting the inflammatory response, cardiovascular function, lipid metabolism (Friedman et al., 2015), obesity risk (Francis et al., 2015) and even telomere length (Mason et al., 2015). Therefore, we focused on this specific type of trauma for its long-term consequences on physical health. 2. Materials and methods 2.1. Participants The current study addressed a sample of 80 students between 10 and 18 years old (63.8% female; mean age 13.6 years, SD = 2.44) that were evaluated at school. Detailed description of the sample selection can be found elsewhere (Salum et al., 2011). The objective of this study was to investigate anxiety disorders and therefore, anxiety cases were privileged, so that the sample included all children classified in the upper quartile of the SCARED instrument

12,0

*

10,0

160,0

8,0

T3

T4

120,0 80,0

6,0 4,0

40,0

2,0 0,0

0,0 Low

Intermediate

High

CTQ- Physical abuse score

Intermediate High Low CTQ- Physical abuse score

Fig. 1. Adjusted mean and CI-95% for T3 and T4 according to CTQ- Physical abuse score. * ANCOVA adjusted for pubertal status, gender, socioeconomic status and BMI, p < 0.05.

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T.D. Machado et al. / Int. J. Devl Neuroscience 47 (2015) 304–308

Table 2 Remaining domains of the Childhood Trauma Questionnaire (CTQ) and their relationship to thyroid hormones levels. T3

T4

N

Mean

SD

CTQ-physical abuse score Low Intermediate High

44 10 26

152.3a 158.7a 130.4b

30.38 27.95 24.75

CTQ-emotional abuse score Low Intermediate High

30 24 26

151.4 150.6 135.5

29.93 36.45 20.88

72

145.7

8

CTQ-physical neglect score Low Intermediate High

p-Value*

N

Mean

SD

44 10 26

9.6 9.3 9.9

0.539 1.50 1.27 1.32

30 24 26

9.7 9.6 9.8

0.091 1.46 1.38 1.42

30.11

72

9.7

0.867 1.42

148.6

32.22

8

9.8

1.42

45 25 10

147.9 143.3 144.3

30.79 29.97 29.91

45 25 10

9.7 9.6 9.8

0.888 1.43 1.47 1.29

CTQ-emotional neglect score Low Intermediate High

30 23 27

144.5 153.8 141.0

26.68 37.40 26.39

30 23 27

9.6 9.4 9.9

0.495 1.52 1.38 1.32

CTQ-total trauma score Low Intermediate High

27 27 26

153.1 144.4 140.3

30.66 31.99 27.12

27 27 26

9.8 9.3 9.9

0.247 1.62 1.25 1.30

CTQ-sexual abuse score Low Intermediate High

0.004

0.095

0.799

0.820

0.308

0.289

p-Value*

Data presented as mean + SD. * p Value for one-way analysis of variance (ANOVA), means followed by the same letter are not significantly different by Bonferroni test.

(Screen for Child and Anxiety Related Emotional Disorders—valid for Brazilian population (Isolan et al., 2011), and 10% of individuals from the other 3 quartiles as controls. Therefore, the sample of this study comprises all quartiles of distribution of SCARED anxiety scale (i.e., no anxiety, mild anxiety, moderate anxiety and severe anxiety). Socioeconomic Status was defined through the Brazilian Association of Research Companies (ABEP) questionnaire (2013). The study was approved by the Hospital de Clínicas de Porto Alegre Research Ethics Committee (GPPG/HCPA, project number 08-481). We collected separate informed consent from primary caretakers and assent from adolescents. 2.2. Early life trauma evaluation Early life stress was assessed through the Childhood Trauma Questionnaire (CTQ) that is a self-reported instrument containing 28 questions in a five points scale. It investigates traumatic experiences using 5 domains: physical, emotional and sexual abuse, physical and emotional neglect (Grassi-Oliveira et al., 2006). The CTQ domains were separated into low, intermediate or high according to the CTQ Manual (Bernstein and Fink, 1998). As explained in the Introduction, in this study we focused on the physical abuse domain, which was used as a proxy of early life trauma, but data on the other domains is presented. 2.3. Nutritional evaluation Anthropometric measurements were performed in duplicate and taken through standard techniques and calibrated equipment following WHO recommendation (1995). The adolescents were barefoot and with minimum clothing. Body weight was measured with portable digital electronic scales (Marte® , SR Sapucaí, MG, Brazil). Height was measured with an extensible portable stadiometer (Alturexata® , BH, MG, Brazil), with the individuals standing still, feet in parallel, ankles together, arms extended along

the body, and the head positioned on the Frankfurt Plan (Jelliffe, 1968). Weight and height were used to calculate BMI. Sexual maturation stage was determined by self-assessment, according to Tanner’s criteria using secondary sexual characteristics’ pictures (Tanner, 1962). 2.4. Biochemical analysis Blood samples were collected between 07:00 and 10:00 h after a fasting period of 10–12 h, centrifuged for 5 min at 4500 rpm, and plasma was stored at −80 ◦ C until analysis; hormones were measured by immunoassay direct chemiluminescence (assay limits T3: 0.15–12.3 nmol/l and T4: 3.9–387 nmol/l). 2.5. Statistical analyses Quantitative normal data were expressed by mean and standard deviation. T3 and T4 were tested for normal distribution by One-Sample Kolmogorov–Smirnov Test. T3 and T4 measurements were evaluated using Student’s t test or one-way analysis of variance (ANOVA) followed by the Bonferroni post hoc test. Pearson’s correlation was calculated to assess the relationship between BMI and T3 and T4. ANCOVA were used to evaluate the influence of the Physical Abuse domain of the Childhood Trauma Questionnaire as the early life stress variable in T3 and T4 separately, adjusted for potential confounders such as pubertal status, gender, socioeconomic status and BMI. Similar analysis were done for the other domains. Statistical significance was assumed if the p value was ≤5%. 3. Results As shown in Table 1, there was a significant difference between levels of T3 among groups of subjects differing in levels of physical abuse. Post hoc tests revealed that differences in T3 levels

T.D. Machado et al. / Int. J. Devl Neuroscience 47 (2015) 304–308

were between subjects with low or intermediate vs. high levels of physical abuse. We also detected differences in the post-puberty group if compared to pre-puberty and puberty groups (p = 0.002). Also, individuals with high socioeconomic status had high levels of T3 hormone (p = 0.036). There were no differences in T4 levels concerning the presence of physical abuse (p = 0.539), the pubertal stage (p = 0.127) or the socioeconomic status (p = 0.512) of the subjects. Gender was also no associated with differences in T3 (p = 0.292) and T4 levels (p = 0.931). ANCOVA, adjusting for pubertal status, gender, socioeconomic status and BMI demonstrated that ELS, as measured by physical abuse was found to be associated with T3 levels (p = 0.013), with differences between high and intermediate groups, but not T4 levels (p = 0.625), Fig. 1. In Table 2 we demonstrated data for the others domains of the CTQ, in which no differences or associations were found. 4. Discussion Our study suggests that early life trauma is associated with reduced T3 levels in adolescents, but not with T4 levels. Our findings are in agreement with results described in rodents showing that early life trauma and T3 are an important player in the epigenetic mechanisms by which the early environment persistently impacts on the individual’s responses to stress. The hypothalamic–pituitary–thyroid axis plays an important role in development and growth (Roelfsema and Veldhuis, 2013), and a critical event happening during a critical period such as childhood could persistently program its functioning, leading to altered T3 secretion throughout life. Patients with psychiatric disorders who have attempted suicide have lower levels of plasma T3 as compared to non-attempters (Pompili et al., 2012) and this is also true for depressed patients (Hage and Azar, 2012; Premachandra et al., 2006). Given the association between early life trauma and depression, it is interesting that both conditions are associated with decreased T3 levels. This may suggest that, similarly to the rat model, thyroid hormones may be involved in the molecular mechanisms by which early trauma leads to persistent alterations in stress responses (Mitchell et al., 1990b) and consequently to higher vulnerability to psychopathology (MacMillan et al., 2001) (Mello et al., 2009), (Heim and Nemeroff, 2001; Kunugi et al., 2010). In agreement with this hypothesis, an experimental study in male and female mice shows that T3 administration is able to decrease depression-like behavior in specific tasks such as the novelty suppressed feeding and tail suspension tests (Lifschytz et al., 2010). Our findings are in agreement with Bunevicius et al. (2012) that showed that women without menstrually related mood disorder (MRMD) with a history of sexual abuse during childhood had lower T3 levels (Bunevicius et al., 2012). Similar results are seen in a experimental study using inescapable tail-shock describing lower levels of T4 and T3, without differences at reverse triiodothyronine (rT3) and type II deiodinase (Helmreich and Tylee, 2011). Bordeline personality disorder women’s exposed to ELS at childhood also demonstrate altered thyroid regulation (FT3/FT4) (Sinai et al., 2014). In this study we have some limitations, such as the small sample size, a recruitment that favored the inclusion of individuals having anxiety symptoms and the use of a retrospective questionnaire to evaluate the exposure to childhood trauma. Our strengths reside on the communitarian profile of our sample as well as the translational and innovative aspects of the study. 5. Conclusions In conclusion, we observed that early life trauma (physical abuse) is associated with reduced T3 levels in adolescents according

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