In support of the placental programming hypothesis: Placental endocrine insufficiency programs atypical behaviour in mothers and their offspring

Abstract

New Findings What is the topic of this review?More than half of all pregnancies in the UK are exposed to adversity linked to increased problems in pregnancy for mothers and adverse outcomes for their children, but we do not know the mechanism(s) underpinning these relationships. What advances does it highlight?Studies in mice prove that placental endocrine insufficiency driven by genetic manipulation of imprinted genes in the offspring can concurrently drive fetal growth restriction, alterations in maternal caregiving and aberrant behaviour in wild‐type offspring exposed to an adverse environment. This suggests that placental endocrine insufficiency might contribute to the co‐morbidity of low birth weight, maternal depression and neurodevelopmental disorders observed in human populations. Abstract Prenatal adversity, which is estimated to impact more than half of all pregnancies in the UK, compromises fetal growth and increases the chances of stillbirth, prematurity and infant mortality. Beyond these immediate and highly visible problems, infants that survive carry the invisible burden of increased risk of some of the most common and pervasive diseases that impact human populations. In utero exposure to depression and anxiety is one adversity that has been linked to these poorer outcomes, suggesting that maternal mood disorders drive the outcomes. However, recent studies in animal models suggest that both the maternal mood disorders and the detrimental outcomes for children could be the result of the same underlying placental pathology. In these studies, genetically wild‐type rodent mothers exposed to placental endocrine insufficiency engaged in less pup‐focused behaviours and less self‐care. Genetically wild‐type rodent offspring raised in this abnormal environment exhibited increased anxiety‐like behaviours, with male offspring additionally exhibiting deficits in cognition and atypical social behaviour, with some evidence of depressive‐like symptoms. This work establishes experimentally that placental endocrine insufficiency alone is sufficient to drive atypical behaviour in both mothers and their offspring. Although there are some data to suggest that this phenomenon is relevant to human pregnancy, considerably more work is required.

High fat diet‐induced maternal obesity in mice impairs peripartum maternal behaviour

“…24 Recent evidence shows that maternal obesity in humans is associated with marked suppression of hPL production. 56,57 It also results in diminished prolactin secretory response to suckling and impaired lactation in the early post-partum period. 7 In mice, a high fat/high sugar diet during pregnancy leads to reduced expression of placental lactogen-related genes in the placenta on Day 16 of pregnancy.…”

“…Placental lactogen and prolactin are hypothesized to play a key role in adapting the maternal body to the new demands of pregnancy and lactation 24 . Recent evidence shows that maternal obesity in humans is associated with marked suppression of hPL production 56,57 . It also results in diminished prolactin secretory response to suckling and impaired lactation in the early post‐partum period 7 .…”

The role of the placenta-brain axis in psychoneuroimmune programming

“…Inflammatory placental conditions may drive fetal and neonatal brain damage and neuroinflammation relevant to clinical conditions in humans ( Spinillo et al, 2014 ). Multiple convergent offspring brain endophenotypes have been described in clinical and preclinical work on placental inflammation: increased phagocytic or activated microglia; increased pro-inflammatory cytokine production by pericytes, astrocytes, and neurons themselves; loss of oligodendrocytes and/or increased astroglia ( John, 2022 ); and disruption of immune modulatory signaling pathways (e.g., proteasome pathway, interferon response) ( Gutierrez-Exposito et al, 2020 ; Ohyu et al, 1999 ; Ganguli et al, 2021 ). Patterns of injury may differ by etiology.…”

“…A variety of placentally-mediated endocrine factors impact fetal brain development and immune status ( John, 2022 ). Placental monoamine metabolism, signaling, and production are implicated in neuropsychiatric disorders from ASD to anxiety ( Hendricks et al, 2003 ; Sato, 2013 ; Yang et al, 2014 ).…”

Physiological resilience across the lifecourse: in utero and beyond

“…The requirement to interrogate the mechanisms determining lifecourse health, and their regulation and integration over time, speaks loudly to the interests of physiologists and the role of physiology: our curiosity to unravel the molecular mechanisms enabling our cells, Rosalind John describes research investigating the cross-talk between feto-placental and maternal environments during pregnancy and discusses the relevance for longer-term maternal and neonatal health and behaviour (John, 2022). It is well-established that the placenta plays a crucial role in pregnancy success by modulating the maternal environment (e.g., via structural and functional alterations of the uterine vasculature to facilitate maternal blood flow to the intervillous space) and facilitating nutrient exchange between the maternal and placental circulations to support gestationally appropriate fetal growth.…”