“Females Are Not Just ‘Protected’ Males”: Sex-Specific Vulnerabilities in Placenta and Brain after Prenatal Immune Disruption

Abstract

Current perceptions of genetic and environmental vulnerabilities in the developing fetus are biased toward male outcomes. An argument is made that males are more vulnerable to gestational complications and neurodevelopmental disorders, the implication being that an understanding of disrupted development in males is sufficient to understand causal mechanisms that are assumed to be similar but attenuated in females. Here we examine this assumption in the context of immune-driven alterations in fetal brain development and related outcomes in female and male mice. Pregnant C57BL/6 mice were treated with low-dose lipopolysaccharide at embryonic day 12.5. Placental pathology, acute fetal brain inflammation and hypoxia, long-term changes in adult cortex cytoarchitecture, altered densities and ratio of excitatory (Satb2 ϩ ) to inhibitory (parvalbumin ϩ ) neuronal subtypes, postnatal growth, and behavior outcomes were compared between male and female offspring. We find that while males experience more pronounced placental pathology, fetal brain hypoxia, depleted PV and Satb2 ϩ densities, and social and learning-related behavioral abnormalities, females exhibit unique acute inflammatory signaling in fetal brain, postnatal growth delay, opposite alterations in cortical PV densities, changes in juvenile behavior, delayed postnatal body growth, and elevated anxiety-related behavior as adults. While males are more severely impacted by prenatal immune disruption by several measures, females exposed to the same insult exhibit a unique set of vulnerabilities and developmental consequences that is not present in males. Our results clearly outline disparate Significance StatementGiven the common practice of excluding female animals from studies of maternal immune activation during pregnancy, it appears to be widely assumed that female outcomes are simply attenuated versions of more severe male outcomes. However, when female fetuses and offspring are closely examined in a model of lipopolysaccharide-induced maternal inflammation during pregnancy, we find that sex confers selective vulnerabilities and outcomes that impact the placenta, fetal brain, adult brain, and behavior in ways that are categorically distinct and in some cases opposite between females and males. Therefore, the effect of maternal immune activation on female offspring cannot be inferred from male outcomes and must be studied independently to fully understand the mechanisms that underlie prenatal vulnerability to maternal insults.

Controlling litter effects to enhance rigor and reproducibility with rodent models of neurodevelopmental disorders

“…For example, male placenta weight was significantly greater than female placenta weight (Table 2 , Fig. 3 ), consistent with prior studies [ 19 – 21 ]. Importantly, the statistical significance of this measure increased after correcting for litter-to-litter variation.…”

Alteration in the time and/or mode of delivery differentially modulates early development in mice

“…Indeed, epidemiological studies on perinatal adverse outcomes [60][61][62] or the emergence of psychiatric disorders such as ASD [63], schizophrenia [64,65], and attention deficit hyperactivity disorder [66] have revealed an imbalanced male-tofemale ratio with stronger symptoms in males. However, recent work also revealed that females have their own plethora of deleterious manifestations [67][68][69], warning against the extrapolation of male disease mechanisms to females. Interestingly, our results are in accordance with this view, with males exhibiting stronger symptoms than females, and males and females having dissimilar deficits following birth modifications in behavioral patterns such as the ultrasonic vocalizations.…”

Alterations in Tau Protein Level and Phosphorylation State in the Brain of the Autistic-Like Rats Induced by Prenatal Exposure to Valproic Acid

“…Autism spectrum disorders (ASD) is a behaviourally defined heterogeneous complex of neurodevelopmental conditions characterized by persistent deficient social interaction, impaired communication as well as restricted or stereotyped patterns of behaviours, interests and activities, and abnormalities in sensory reactivity [ 1 , 2 ]. Epidemiological studies estimate that roughly 1% of the world’s population is thought to have an ASD, but exact numbers are highly dependent upon the still-evolving methodology [ 3 , 4 , 5 ]. A significant rise in the prevalence of the condition in recent years has increased the importance of clarifying its pathogenesis.…”