The gestational foundation of sex differences in development and vulnerability
Introduction
The morphological differentiation of sex commences early in embryogenesis and unfolds in a well-known sequence. Less well-understood are the functional consequences of sex on physiological, metabolic, and hormonal systems and, in turn, their influence on the developing nervous system before birth and ramifications for postnatal life. Here we explore the gestational origins of sex as a moderator of development. In keeping with the focus of this special issue on early adversity, we will also examine how sex modulates vulnerability to prenatal exposures and consider models that have been developed to account for these observations. Scientific interest in the role of sex in human development has waxed and waned over time in tandem with societal forces that emphasized either biological or social influences on observed differences. Currently, the role of sex as a biological variable is of rising academic significance, illustrated by a call from leaders of the National Institutes of Health for investigators to both identify and include animals and cell lines of both sexes (Clayton and Collins, 2014). This is the result of converging evidence for sexual dimorphisms that include findings as diverse as differential immunological responsiveness to vaccine challenges and variation in sensitivity of neurons to stimulation depending on sex of cell origin.
The construct of differential sex-based vulnerability to adversity has been well-identified. In 1985, a section of The Behavioral and Brain Sciences (Gualtieri and Hicks, 1985) was devoted to consideration of an immunoreactive theory to explain greater vulnerability of male offspring to obstetric, pediatric, psychiatric and developmental disorders. This theory posited that maternal immunological response to an antigenic factor found on the Y chromosome conferred long-lasting deleterious influence on multiple developing systems within the fetus, including the nervous system. In doing so, it summarized the existing empirical data supportive of greater male vulnerability, termed “selective male affliction”, available at the time. These findings have been largely confirmed and expanded in the 30 years since, along with new theories afforded by new assays and methodologies available to research.
The current literature on sex-related variation with relevance to neuroscience is too large and diverse for a single article. Instead we focus on the foundational role of the period before birth and examine the origins of sex differences in function and on prenatal exposures that differentially affect development in boys and girls. From a statistical standpoint, the former observation can be viewed as a main effect, while the latter is more traditionally detected as an interaction.
Section snippets
Male vulnerability and the continuum of reproductive casualty
That adversities experienced during the prenatal and perinatal period have consequences that persist through life, independent of fetal sex, was promulgated in the 1960’s as the “continuum of reproductive casualty” (Pasamanick and Knobloch, 1964). Until very recently, it has been scientific dogma that there is an excess of male conceptions but greater loss in male pregnancies throughout gestation. However, based on a comprehensive study of multiple sources of data, it appears that the ratio of
Fetal sex as a moderator of prenatal exposures
So far, we have illustrated instances of perinatal risk in which there is both heightened male exposure as well as potentiated consequences. However, when male infants exhibit poorer developmental outcomes following perinatal risks, such as preterm birth, it is not possible to disambiguate cause from effect. That is, it is unclear whether the greater incidence of shortened gestation should be viewed simply as a main effect or as a differential response to undetected intrauterine adversity which
Sex differences before birth
The antepartum constitutes the most rapid developmental period, a time where structural development occurs in tandem with functional gains (DiPietro et al., 2010). In this section, we describe current knowledge regarding the development of sex differences in indicators of nervous system maturation prior to birth.
On the origins of male vulnerability
So far we have presented evidence the there is both greater exposure and greater vulnerability to many prenatal and perinatal adversities for male fetuses than for female fetuses. In contrast, there are relatively few well-documented sex differences expressive of neurological development before birth. When significant differences are detected, as illustrated in Fig. 2, Fig. 3, they are accompanied by highly overlapping distributions. This finding echoes the long-standing conclusion of others
Conclusion
The review consolidated empirical information regarding prenatal sex differentials in vulnerability from a variety of diverse sources and literatures. We found converging evidence that developmental outcomes of male fetuses and infants exposed to prenatal and perinatal adversities are more highly impaired than those of female fetuses and infants. Although sex differences in vulnerability are most often found for male offspring, there are reports of female vulnerability, particularly with
Acknowledgments
This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) award 5R01 HD27592 to the first author.
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