Parental factors, such as mental health, stress exposures, advanced age, socioeconomic status, and cognitive performance are associated with child neuroendocrine development. While it is well accepted that early-life exposure to maternal stress alters the programming of the developing neuroendocrine axes leading to lasting cognitive, behavioral, and physical effects in the offspring in childhood and into adulthood (Bergman et al., 2007, 2010; DiPietro, 2012; O’Donnell et al., 2013; Duchesne et al., 2017; Nguyen et al., 2018) the role of paternal factors has received much less attention. Paternal mental health symptoms including perceived stress (Challacombe et al., 2023), paternal anxiety (Möller et al., 2015) and paternal depression (Ramchandani et al., 2005; Wanless et al., 2008; Paulson et al., 2009; Gentile and Fusco, 2017; Cui et al., 2020), during the prenatal period and in childhood, are associated with child social, cognitive and behavioral outcomes. One possible link between paternal mental health and child outcomes could be via biological mechanisms including the child’s own neuroendocrine systems.

The prenatal period is critical in the structural development of neuroendocrine systems which develop in a sex-specific manner under the influence of steroid hormones, as shown in a classic and paradigm shifting study in rodents (Phoenix et al., 1959). That study proposed what is known as the organizational-activational hypothesis which is well-supported to this day and integrated into new conceptual frameworks of sexual differentiation (Arnold and Cahill, 2016). In brief, the organizational-activational hypothesis posits that prenatal testosterone released from the fetal testes (due to the testes-determining gene Sry located on the Y chromosome) (Goodfellow and Lovell-Badge, 1993) is critical for the structural organization of the sexually-dimorphic nucleus of the preoptic area of the hypothalamus resulting in a larger structure in males than in females. At puberty, gonadal steroid hormones activate those prenatally organized structures to elicit sex-specific hormone-dependent behaviors. Factors that alter the prenatal steroid hormone environment can disrupt the structural organization and function of the offspring’s hypothalamic–pituitary–adrenal and gonadal axes (HPA and HPG, respectively) (Glover et al., 2010; Gerecke et al., 2012; Jones et al., 2020). The consequence of this is altered behavioral expression that is dependent on the activation of those systems as shown in animal models (Ng, 2000; Welberg and Seckl, 2001; Austin et al., 2005; Kapoor and Matthews, 2008; Xiong and Zhang, 2013; Jones et al., 2015; McGowan and Matthews, 2017; Matthews and McGowan, 2019). Human observational studies suggest that prenatal factors such as parental stress may disrupt the prenatal steroid hormone environment resulting in altered physical and cognitive-behavioral outcomes in the offspring during childhood (Barrett et al., 2013, 2014).

Animal and human studies suggest that parental preconception and prenatal stress/mental health symptoms are associated with child neuroendocrine development and mental health outcomes (for reviews see, Glover et al., 2010; Chan et al., 2018; Tan et al., 2023). These associations may occur through maternal or paternal pathways, or some combination of both. For instance, during the preconception and prenatal periods, paternal stress or glucocorticoid administration in rodents (Dietz et al., 2011; Rodgers et al., 2013; Gapp et al., 2014; Short et al., 2016) or mental health problems (e.g., anxiety, depression, post-traumatic stress disorder in humans; Yehuda et al., 2014; Ayano et al., 2021) are associated with numerous offspring outcomes. Outcomes include higher anxiety symptoms in offspring that persist into adulthood (Ayano et al., 2021), disrupted epigenetic regulation of the glucocorticoid receptor gene in humans (Yehuda et al., 2014), impaired neurodevelopment in animals and humans (Chan et al., 2018), and altered steroid hormone levels in animals (Moisiadis et al., 2017) and humans (Black et al., 2019), as well as associations between steroid hormones and childhood internalizing problems as shown in humans (Black et al., 2019). In fact, paternal mental health status has been shown to alter sperm epigenetics, in turn influencing development of the offspring (Marcho et al., 2020). This may occur via paternal sperm epigenetics, and placental development (Crespi, 2020; Dini et al., 2021). Thus, paternal factors may play a role in child neuroendocrine and cognitive-behavioral development via sperm epigenetics or placental gene expression.

After birth, paternal psychosocial factors (e.g., parenting, perceived stress, the quality of the father-child relationship and engagement with childcare; De Cock et al., 2017; Challacombe et al., 2023; Wu et al., 2023) may also influence the child. Alternatively, associations between paternal stress or mental health and child development may also occur through maternal mental health, maternal stress, or the couple’s relationship quality. It has previously been shown that maternal stress during pregnancy disrupts typical associations between steroid hormones that are regulated by the HPA and HPG axes (Nguyen et al., 2018) and predicts earlier menarche in offspring (Duchesne et al., 2017). As such, paternal factors may interact with those of the mother, for example via increased stress levels, in turn predicting disrupted neuroendocrine development and function in the offspring.

A key developmental period for testing associations between paternal factors and the child’s neuroendocrine and behavioral development may become particularly important during middle childhood. During this time, children begin puberty while also gaining further independence from the parents, as they transition into elementary school. School transition is associated with increased morning salivary cortisol, suggesting it is a normative environmental stressor that activates the HPA axis (Parent et al., 2019; Leblond et al., 2022). For children who do not show an adaptive cortisol recovery, lower morning cortisol predicts higher anxiety symptoms 1.5 years later (Leblond et al., 2023), which supports the importance of considering associations between the HPA axis and mental health symptoms in childhood. Adrenarche, the first phase of puberty which begins around 6–8 years of age, is a neuroendocrine event, unique to humans and the great apes, characterized by enhanced secretion of adrenal hormones that are important for cognitive and behavioral development (Campbell, 2006). During this period, hypothalamic secretion of corticotropin-releasing factor (CRF) stimulates adrenocorticotropic hormone (ACTH) release from the anterior pituitary gland (PG). This triggers dehydroepiandrosterone (DHEA) and its sulfate DHEA-S production in the zona reticularis of the adrenal glands (Endoh et al., 1996); and it is during adrenarche that DHEA and DHEA-S become the most abundant hormones in the body (Adams, 1985; Campbell, 2006). The blood brain barrier is highly permeable to DHEA, while its sulfated DHEA-S metabolite is actively transported out of the central nervous system (Nguyen, 2018; Greaves et al., 2019; Cumberland et al., 2021). Higher DHEA levels during childhood and adolescence have been associated with better attention, working memory, reading, and writing abilities through alterations of structural brain networks (Nguyen et al., 2013, 2016, 2017, 2018; Nguyen, 2018). On the other hand, disruptions in the timing or rate at which adrenarche proceeds in a particular child is associated with adverse mental health problems (e.g., internalizing, externalizing problems; Dorn et al., 2008). Any DHEA-related optimization of cognitive skills may come at an emotional cost, with lower levels of social and affective functioning, particularly in vulnerable children with externalizing disorders, as previously proposed (Nguyen et al., 2013, 2016, 2017, 2018; Nguyen, 2018).

Thus, paternal factors including paternal stress, anxiety, and depressive symptoms during the prenatal and postnatal childhood periods (including concurrent symptoms assessed during childhood) may be associated with child neuroendocrine, cognitive and behavioral development, which may be particularly evident during middle childhood. However, studies in support of this neuroendocrine intergenerational transmission are limited by cross-sectional and retrospective data or were not specifically designed to examine the associations between parental factors, including paternal mental health, and child neuroendocrine and cognitive-behavioral development. Moreover, most of these studies do not account for the more specific roles of paternal mental health measured prenatally and into childhood.

Using data from a longitudinal birth cohort, the Design, Develop, and Discover (3D) Study (Fraser et al., 2016), we designed a follow-up study to examine whether paternal mental health symptoms assessed during the prenatal period and during childhood are associated with altered development of neuroendocrine structure (PG volume) and function (DHEA/DHEA-S levels) in middle childhood (6–8 years old), while controlling for maternal mental health. We hypothesized that paternal mental health symptoms would be associated with neuroendocrine structure (PG volume) and function (DHEA/DHEA-S levels) during adrenarche, though the predicted direction of those associations was unclear. We also hypothesized that the identified neuroendocrine factors would act as intermediates linking paternal mental health and child cognitive and behavioral development, given the role of adrenarche hormones on child brain and cognitive-behavioral development. Finally, we hypothesized that any associations between paternal mental health and child neuroendocrine outcomes would be more strongly predicted by prenatal mental health symptoms than symptoms assessed concurrently at the childhood assessment, given that neuroendocrine structural development is particularly sensitive to the prenatal period (Xiong and Zhang, 2013; Arnold and Cahill, 2016).

To our knowledge, this is the first study investigating paternal programming of stress, anxious, or depressive symptoms on their offspring’s pituitary structure and function, and their relationship with child cognitive-behavioral outcomes. We found that prenatal paternal self-reported anxiety symptoms were associated with child HPA function as measured by DHEA levels. Higher paternal anxiety symptoms during pregnancy were associated with lower DHEA levels 6–8 years later in their children, controlling for prenatal maternal anxiety symptoms. Although these findings are based on the 61 families recruited for the ancillary study from a larger longitudinal birth cohort, we note that this association had a consistent effect size (r_p ~ −0.3) in all models controlling for potential covariates, including maternal and paternal education and annual household income measured during pregnancy, as well as the time of day and season of salivary hormone sampling. In turn, using an indirect-effect analysis, we found that lower child DHEA levels were an intermediate factor explaining an indirect relationship between paternal prenatal anxiety symptoms and higher levels of internalizing symptoms (particularly emotional difficulties) in the child during middle childhood. Interestingly, findings appeared to be specific to paternal anxiety symptoms during the prenatal period, as opposed to the middle childhood period, given that only the prenatal anxiety model was significant. Moreover, post-hoc power analyses suggest that we were adequately powered to detect potential associations between concurrent paternal anxiety symptoms and child DHEA levels, if the sample effect size is a good estimate of the population effect size (observed power = 0.829; Supplementary Table S2). This finding is consistent with our hypothesis that mental health assessments during the prenatal period, as opposed to the childhood period, would be more strongly associated with child neuroendocrine outcomes, given that the neuroendocrine system development is programmed prenatally. These results suggest that paternal mental health may be an important modifiable risk factor for child mental health, and that paternal mental health should be given consideration for targeted interventions, as for mothers, as early as the prenatal period.

These findings highlight the importance, in the field of developmental neuroendocrinology, of: (1) obtaining biopsychosocial data on the family unit (mother–father-child triad); (2) measuring neuroendocrine intergenerational risk transmission in a prospective manner; (3) distinguishing paternal vs. maternal influences; and (4) identifying modifiable parental factors as early as possible, in order to optimize developmental trajectories.

We find evidence partially consistent with the organizational-activational hypothesis of neuroendocrine development. The first tenet posits that the intra-uterine environment, including exposures to psychological or physical stress, can result in lasting alterations in the organization and hence the function of the central nervous system (CNS) (Schulz et al., 2009). This early developmental process preferentially affects neuroendocrine brain structures such as the hypothalamic–pituitary axes, thereby resulting in what is commonly referred to as HPA and HPG “programming” (Rulli et al., 2018; Matthews and McGowan, 2019). The second tenet posits that the brain’s sensitivity to the organizational effects of steroid hormones decreases as the child matures, i.e., exposure to steroid hormones earlier in life would tend to have a more lasting impact on brain organization and structure while later developmental exposures would result in more reversible changes in brain function and activation. As such, prenatal and postnatal (enduring into childhood) exposures to symptoms of anxiety and depression via the parents can serve to differentially organize neural substrates, as well as impact the activation of various endocrine functions later in life (Schulz et al., 2009).

In relation to these frameworks, our study finds evidence to suggest that: (1) prenatal paternal factors can predict the child’s hormonal function during adrenarche and are distinct from that of maternal factors; and (2) prenatal paternal mental health factors may have stronger associations with the child’s hormonal function compared to postnatal (childhood) paternal mental health factors measured in middle childhood. In contrast, our data do not support stable or lasting paternal organizational effects detectable during middle childhood, given that we did not detect an association between prenatal paternal symptoms of stress, anxiety, or depression and pituitary structure as measured by its volume. This may be due to methodological limitations of structural MRI, as only macroscopic changes in pituitary structure can be detected by MRI. We thus cannot exclude whether paternal organizational effects occurred at a more microscopic, cellular, or molecular level. We also note that the effect size was small, and the observed power was also small to medium, possibly suggesting that our sample size might not have been sufficiently large to detect structural differences. Relatedly, we note that no sex difference was detected in pituitary volume, which we largely attribute to the age and pre-pubertal stage of the children, given that pituitary volume is reportedly larger in girls, beginning around age 10 and throughout adolescence due to HPG-axis hormones (Peper et al., 2010; Wong et al., 2014; Whittle et al., 2020), even after correction for total brain volume (Wong et al., 2014; Whittle et al., 2020). It is also possible that paternal mental health symptoms may be associated with other brain structures of the HPA axis. For example, hypothalamic nuclei or the zona reticularis of the adrenal cortex (via increased adrenocorticotropic hormone secretion stimulating activation of the 17,20 lyase enzyme, resulting in subsequent zona reticularis growth; Majzoub and Topor, 2018). Unfortunately, it was not possible to measure these neuroendocrine structures in our current sample, or, as far as we know, with existing structural MRI using a 3 T research scanner. Moreover, our single assessment of paternal mental health (during the first trimester) or more generally a history of mental health (as with the STR questionnaire) precluded our ability to consider the timing and potentially the fluctuating chronicity of paternal mental health symptoms during pregnancy. As it has been found for maternal mental health problems (Rees et al., 2019), we cannot rule out the possibility that chronic paternal mental health symptoms may have had a more important effect on child brain structure organization over time.

Our findings suggest the need to further consider a potential timing effect of the exposure to paternal mental health symptoms and its sequelae. The relation with timing is suggested by the specificity of the relationship between prenatal paternal anxiety symptoms and child internalizing symptoms, which were indirectly associated via child DHEA levels, in contrast to the concurrent/postnatal paternal anxiety symptoms, which was not (see Figure 2). We note that in a related study from the same sample (Jones et al., 2023b) associations between paternal mental health and child cognitive and behavioral outcomes were not explained by parental relationship quality or paternal self-perceived parenting measured in infancy. In the present study, prenatal paternal mental health was measured as early as possible during the 1^st trimester, and it is plausibly correlated with paternal mental health pre-conception. Thus, one potential mechanism for the association between paternal mental health symptoms and child neuroendocrine and behavioral outcomes may be related to direct biological pathways via sperm epigenetics (Lombó and Herráez, 2021). It has been shown that mental health status can alter sperm epigenetics, in turn influencing development of the offspring (Marcho et al., 2020), which may occur via paternal gene expression that programs placental development (Crespi, 2020; Dini et al., 2021). As such, one preconception pathway may occur via paternal gene expression which drives placental development, the maternal-fetal interface which is necessary for fetal growth and survival (Crespi, 2020; Dini et al., 2021). The field of genomic imprinting has revealed that sperm predominantly controls the growth and differentiation of extraembryonic tissues such as the placenta and yolk sac (Bhadsavle and Golding, 2022). Studies have consistently shown that preconception paternal exposures such as age (Denomme et al., 2020), obesity (Mitchell et al., 2017; Jazwiec et al., 2022), toxicants (Ding et al., 2018), cannabis (Innocenzi et al., 2019) and alcohol (De Cock et al., 2017; Thomas et al., 2022) result in sex-specific alterations of placental imprinted gene expression, as well as reduced placental weights and disruptions in placental histology. Importantly, the placenta is essential for regulating transport of nutrients and by-products, including maternal hormones between the fetal and maternal circulation, for protecting the fetus from the maternal immune system, and for producing hormones to support fetal development (Rossant and Cross, 2001; Adamson et al., 2002). Although direct evidence linking preconception paternal mental health factors and placental gene expression remains limited, both human and rodent models of intergenerational effects of trauma and chronic stress experience have reported epigenetic changes to sperm DNA methylation and subsequent associations with increased susceptibility to mental health conditions and disease risk in the offspring (Chan et al., 2018). Consistent with previous findings, one study in mice showed paternal preconception stress drives sex-specific transcriptional changes in the placenta, specifically tied to an upregulation in expression of gene sets involved in metabolic signaling and immunity in the placenta of female offspring (Cissé et al., 2020). Unfortunately, a preconception impact on the sperm epigenome could not be tested in our study since sperm were not collected from the fathers. The design of future birth cohort studies would benefit from collecting preconception data from the fathers to prospectively test whether mental health status influences sperm epigenetics, placental gene expression, the intra-uterine environment, and in turn influence child neuroendocrine and cognitive-behavioral development, building on other birth cohort studies and epigenetic inheritance (Pembrey and Team, 2004; Gapp et al., 2014; Fraser et al., 2016).

While existing literature suggests that higher DHEA levels during childhood and adolescence may support cognitive functions such as attention and working memory (Campbell, 2006; Nguyen et al., 2013, 2016, 2017; Nguyen, 2018; Witchel et al., 2020), there are also studies suggesting that DHEA is adversely associated with behavior, increasing the risk of developing both internalizing and externalizing symptoms (Mundy et al., 2015). These associations seem to be stronger in children with a predisposition for conduct and other externalizing disorders (Goodyer et al., 2003; Sontag-Padilla et al., 2012). Our findings further highlight the complexity of endocrine-behavioral relationships, as they indicate that any association between prenatal paternal mental health and DHEA levels in the offspring may preferentially be associated with internalizing (rather than externalizing) behaviors, in particular emotional problems during middle childhood.

Strengths of this study include the use of data from a longitudinal birth cohort, the 3D Study, and a prospective follow-up specifically designed to assess the potential associations between paternal factors on child neuroendocrine and cognitive-behavioral development. The 3D team collected biopsychosocial measures from mother–father-child triads during the prenatal and postnatal periods (up to 2 years) and encourages follow-up developmental studies on the cohort. In the context of our prospective follow-up study, when the children were aged 6–8 years, we collected maternal-paternal-child mental health data, as well as child salivary hormones, structural MRI, behavioral and cognitive outcomes. We evaluated predictive contributions of each parent while controlling for the other due to the availability of equivalent prenatal and childhood assessments of anxiety and depression. We also collected adrenarcheal hormones during a critical period of neural and social development, which is unique to humans and the great apes. We performed gold-standard manual segmentation of the PG from MRI, as well as parsed the anterior from the posterior PG, which is rarely done despite them being structurally and functionally distinct. In this way, we were able to assess individual relationships between pre- and postnatal (i.e., into middle childhood) paternal mental health, organizational (i.e., PG structure) and activational (i.e., hormone levels) measures, as well as cognitive and behavioral outcomes in the child. This allowed us to disentangle associations between parental mental health factors during the prenatal and childhood periods, and child neuroendocrine and behavioral development.

Limitations of our study include the small sample size, based on 61 children and their parents, and generalizability to vulnerable populations, rural and low socio-economic groups (Fraser et al., 2016). Moreover, mean parental self-reported scores of anxious and depressive symptoms for both mothers and fathers were low, indicating minimal presence of symptoms associated with mental health issues in parents participating in the paternal sub-study, and a more conservative test of our hypotheses. As such, our findings may not be generalizable to a population of parents experiencing clinical levels of anxiety or depression. Similarly, children in our sample scored within normal ranges on all SDQ subscales, including emotional symptoms (Shojaei et al., 2008), albeit this was a parental self-report measure. Thus, it is possible that fathers who reported higher mental health symptoms may have been more in-tune with these slightly higher, yet mild symptoms if they also provided the parental report of their child on the SDQ; particularly since the association seems to be driven by the emotional subscale. Unfortunately, we did not systematically collect data to determine which parent completed the SDQ, and could not account for this in our analyses. It is nonetheless interesting that even mild symptoms of prenatal paternal mental health may be associated with later child neuroendocrine and behavioral outcomes at subclinical levels, thus increasing the generalizability of our findings to subclinical populations. Future studies could address the associations between a greater range of symptoms of parental mental health and child outcomes, and should include assessment of current child stressors and family unit factors and the social environment as important factors to consider, as planned in the 3D transition study (Leblond et al., 2023). In addition, our findings could be due, at least in part, to the use of different instruments to measure paternal anxiety during the prenatal (STR) vs. concurrent childhood (BAI) periods. Still, both scales show a significant degree of overlap over several years in the self-reported items they measure, with STR screening for the presence/absence of symptoms suggestive of a clinically significant anxiety disorder as defined by DSM-V, whereas BAI measures levels of anxious symptomatology with a higher focus on somatic symptoms of stress. Regardless of this limitation, our results support screening for anxiety disorders in both parents as early as possible during pregnancy to prevent adverse developmental effects in the offspring. The results also suggest the potential added advantage of using a risk assessment for clinically significant signs of impairment and of social and occupational dysfunction due to anxiety (as in this study, the STR), rather than overall scores of self-reported levels of anxiety (BAI). Our findings suggest that future research should consider the inclusion of multiple parental assessments, including the preconception period, throughout pregnancy (i.e., prenatal - first, second, third trimester), and across childhood, while including varying components of both maternal and paternal mental health (e.g., stressors, anxiety, and depressive symptoms), and in particular, a screening measure for anxiety. Moreover, considering these factors in a single statistical model would make it possible to examine unique or compound effects of maternal and paternal mental health more comprehensively on child developmental outcomes (Black et al., 2019). Another limitation of this study is the lack of altered neuroendocrine function between the father and child across time. Addressing this in future studies would require collecting paternal sperm to conduct epigenetic analyses of relevant hormone promoter genes (e.g., methylation), at the time of conception and in the offspring cells (e.g., blood). In summary, our data highlight the importance of future birth cohort studies to gather pre-conception paternal data in addition to maternal data to assess potential biological pathways of child development more reliably, for example via sperm epigenetics.

From a sample of 61 children and their parents recruited as part of a larger longitudinal birth cohort study, this study found that prenatal paternal self-reported anxiety symptoms predicted lower salivary DHEA in children during adrenarche and that DHEA levels were an intermediate factor that accounted for associations between prenatal paternal anxiety symptoms and child internalizing symptoms. These data suggest that more research is needed to determine whether prenatal paternal factors could be important for offspring hormonal programming during a critical neuroendocrine event -adrenarche- and suggest an indirect association with increased child internalizing symptomatology. These data highlight the need for additional research between modifiable prenatal paternal factors and child developmental outcomes, and build a foundation for future studies to collect epigenetic measures in the father and child to address intergenerational transmission.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. The data are under the jurisdiction of the CHU Sainte-Justine Research Ethics Committee and subject to current provincial and national privacy laws guiding their ethical use in Québec. To submit a request, please visit http://www.irnpqeo.ca/en/researchers/ or contact the corresponding author.

The studies involving humans were approved by Research Institute of the McGill University Health Center Research Ethics Board and the CHU Ste-Justine Research Center Ethics Board. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin.

T-VN, JRS, JT, SD, WF, CH, GM, SP, and NC-R conceived and designed the paternal study. SLJ and T-VN conceived this sub-analysis study and oversaw trainees. CC and JL performed paternal study data collection and data entry. SLJ processed all MRI images. SLJ and VB segmented the pituitary glands. SLJ, T-VN, and JL oversaw hormone analyses and data entry. GE managed the database with input from SLJ, T-VN, JL, and CC. GE performed imputations and statistical consultation. SLJ and VB performed statistical analyses. VB wrote the first draft of the manuscript in consultation with SLJ and T-VN. SLJ and TCM led the revisions of the article through to submission and publication. TCM oversees all ongoing aspects of the paternal study database. All authors contributed to the article and approved the final accepted version for publication version.