dc.description.abstract
[eng] During critical periods of development, psychosocial stress experiences may alter
key neural networks of the human brain, with long-lasting effects on behavior and
mental health. However, the specific biological mechanisms through which early life
stress impacts on present and future mental health are still not well understood.
Hypothalamic-pituitary-adrenal (HPA) axis is the principal sensor and regulator
of stress response. Its modulation begins early in development through fetus-placental
dialogue and continues during postnatal life, from childhood to adolescence, being
especially sensitive to early life’s adversities. Thus, HPA axis programming during prepostnatal
developmental periods is proposed as a plausible mechanism of early
sensitization that undermine future HPA axis functioning and associated mental
disorders. Moreover, it should not be forgotten that the HPA axis dialogues with the
immune system, exhibiting a bidirectional interaction.
In this framework, the present dissertation aimed to disentangle the impact of
psychosocial stress exposure during early sensitive periods of pre-postnatal brain
development on HPA axis and immunity system. Cortisol (the HPA axis ultimate
effector) and secretory immunoglobulin A (s-IgA) (an immunoglobulin of the mucosal
surfaces) were selected in this thesis, respectively, as putative biomarkers of the
endocrine and immune response to early psychosocial stress exposure in early life.
The study of two mother/infant dyad cohorts, the Intramural_Maternal_Epi_project
cohort and the COGESCOV-19 cohort, enable us to explore the respectively effects of
the maternal distress and SARS-CoV-2 infection during pregnancy on the newborn’s
early stress reactivity.
In Intramural_Maternal_Epi_project, we observed that the presence of depressive
symptoms flattened the maternal cortisol circadian pattern, especially during the second
trimester of pregnancy. Furthermore, elevated maternal cortisol levels in mid-late
pregnancy were associated with poor birth outcomes, including prematurity and low
weight percentile at birth. These results underscore the importance of early detection of
depressive symptoms, which are often manifested as a subclinical condition during
pregnancy.
Another hypothesis we tested with this cohort was based on the premise that
maternal distress during pregnancy could influence DNA methylation patterns in
placenta. Specifically, we studied the DNA methylation of FKBP5, NR3C1 and
HSD11B2 genes in two different placental layers: maternal decidua and chorionic villi.
We observed that while maternal cortisol levels in early pregnancy were associated with
an increase in DNA methylation of CpG islands of NR3C1 gene and a decrease in DNA
methylation of CpG islands of FKBP5 gene in the chorionic villi, at the level of the
maternal decidua it was the increase in DNA methylation (at specific CpG sites of
FKBP5 gene) that was strongly associated with the lower gestational age of the newborn
at birth. Thus, stress during the pregnancy, and its associated cortisol levels could
influence placental epigenetic signatures differently depending on the time of exposure,
the placental layer, and the gene of study.
Complementarily, we could explore the putative consequences of maternal
exposure to SARS-CoV-2 during pregnancy in the neurodevelopmental outcomes of
offspring, thanks to the COGESCOV-19 cohort. In this regard, we observed that infants
born to mothers exposed to SARS-CoV-2 (serologically positive) showed poorer
responses in items related to regulation and motor system domains (NBAS-Brazelton
scale) at seven weeks old. This effect was especially evident in infants whose mothers
were infected in the third trimester. Considering the magnitude of COVID-19 pandemic,
children born to mothers infected during pregnancy, particularly in late pregnancy,
should undergo additional longitudinal screening for neurodevelopmental milestones.
On the other hand, in this thesis, we had the opportunity to explore the effect of
the most severe psychosocial stress condition for a child, such as exposure to
maltreatment during their early years of life. Our research was made possible thanks to
Epi_young_stress cohort, which consists of a representative number of children and
adolescents from the general population (aged between 7 and 17 years). This cohort has
been recruited through the collaboration of various child and adolescent psychiatry units
nationwide and includes both children with a current psychiatric diagnosis and a control
group. For all subjects, the history of childhood maltreatment was thoroughly examined,
and the Trier Social Stress Test for children (TSST-C) was also administered to assess
the reactivity of the HPA axis to acute stress in this population.
Regarding the functioning of the HPA axis in this young population, although
children with maltreatment showed higher basal cortisol levels compared to those not
exposed to maltreatment, when subjected to the acute stressor (TSST-C), they exhibited
a flattened cortisol response but higher perceived anxiety. Noticeably, we also observed
a dose-response relationship between the frequency and severity of the maltreatment
and cortisol dysregulation. Furthermore, and in relation with putative immunity
biomarkers in front psychosocial stress, we described that the acute exposure to the
stress test was able to stimulate the secretion of s-IgA in young subjects after puberty.
Additionally, concerning immune markers in response to acute stress, we found that
exposure to the acute stressor (TSST-C) was able to stimulate the secretion of s-IgA in
young subjects, but only after puberty. However, although s-IgA reactivity to acute stress
was not observed in prepubescent children, when the presence of maltreatment was
observed, these children had developed this immune response capability, suggesting that
complex trauma could anticipates the immune maturation.
Finally, considering our previous result that salivary s-IgA quickly rises after acute
stress exposure, we wanted to know if salivary s-IgA could be a new promising
biomarker of psychosocial stress reactivity in young population. A systematic review of
the available scientific literature revealed that s-IgA can be considered a reliable
biomarker of acute stress in under 18 population. However, further research is needed
to specifically determine how psychosocial stress impacts on s-IgA circadian rhythm and
basal levels.
Together, the results of this thesis support the notion that psychosocial stress
during prenatal and child-juvenile periods could alter endocrine and immune systems
regulation, modifying early behavioral dimensions and the reactivity to stress, which
might increase the risk of future mental health problems.
ca
dc.description.abstract
[spa] Durante los periodos más precoces y sensibles del desarrollo del sistema nervioso
central (SNC), la exposición al estrés psicosocial puede alterar los sistemas biológicos
para el futuro funcionamiento adaptativo del sujeto. El cortisol (último efector del eje
Hipotalámico Hipofisario Adrenal (HHA)) y la inmunoglobulina A secretora (s-IgA) se
seleccionaron en esta tesis, respectivamente, como posibles biomarcadores de respuesta
al estrés psicosocial en las primeras etapas de la vida.
Se pudo estudiar el papel del distrés materno durante el embarazo, y su posible
asociación con en el comportamiento y la reactividad ante el estrés del recién nacido,
gracias a dos cohortes de diadas madre/niño seguidas durante el embarazo y hasta las
primeras semanas postnatales: la cohorte del Intramural_Maternal_Epi_project y la cohorte
COGESTCOV-19.
En primer lugar, pudimos constatar que el patrón diurno de cortisol estaba
desregulado en mujeres con síntomas de depresión, especialmente durante en el segundo
trimestre del embarazo. Así mismo se observó que altos niveles de cortisol en esta etapa
del embarazo se asociaban con prematuridad y bajo peso al nacer. Por otra parte, se pudo
comprobar que los niveles altos de cortisol materno al principio del embarazo podrían
asociarse con un perfil de metilación del ADN específico en genes placentarios
implicados en la regulación del cortisol, incrementando el riesgo de un parto adelantado.
Finalmente, se estudiaron las consecuencias de la infección materna por SARS-COV-2
durante el embarazo en las respuestas motoras y de regulación ante los estímulos del test
de Brazelton en los niños a las 7 semanas de vida, constatando un mayor efecto si la
infección afectaba al último trimestre de embarazo.
Por otro lado, el estudio de una cohorte de niños/as y adolescentes con y sin
patología mental (cohorte del proyecto Epi_young_stress) nos permitió analizar el papel
del maltrato infantil en la posible sensibilización temprana del eje HHA y del sistema
inmunitario de los sujetos expuestos. Para testar esta posible sensibilización, en este
estudio se indujo estrés psicosocial agudo a todos los sujetos de la cohorte, mediante un
protocolo de laboratorio cuasi experimental: el test de estrés psicosocial Trier para niños
(TSST-C).
Los niños/as y adolescentes expuestos a maltrato mostraron mayores niveles de
cortisol basales y una hiporreactividad del eje HHA al TSST-C, a pesar de mostrar una
mayor percepción de ansiedad ante estrés psicosocial agudo comparados con los niños
no expuestos a maltrato. También se observó una relación dosis-efecto entre la
exposición y severidad del maltrato y la desregulación del eje HHA. Además, el estrés
psicosocial estimuló la secreción de s-IgA, pero sólo después de la pubertad. Sin
embargo, los niños/as expuestos a maltrato infantil mostraron secreción de la s-IgA ante
estrés psicosocial de forma similar a los adolescentes, sugiriendo una anticipación de la
maduración del sistema inmune en los niños maltratados. El uso de la s-IgA como
posible biomarcador de estrés agudo y crónico en etapas tempranas de la vida fue
estudiado y discutido mediante una revisión sistemática.
En conjunto, los resultados de esta tesis sostienen que la exposición al estrés
psicosocial durante los periodos tempranos del desarrollo del SNC (prenatal, infancia y
adolescencia) podrían alterar la respuesta al estrés de los sistemas endocrino e inmune,
modificando algunos rasgos de la conducta temprana en el recién nacido y aumentando
el riesgo de futuros problemas de salud mental.
ca
