Are there epigenetic causes for sexual orientation and gender identity?

This US 2018 review lead author was a gynecologic oncologist in private practice:

“Sexual orientation is biologically conferred in the first trimester of pregnancy. Gender identity is biologically conferred during the middle trimester of pregnancy.

Since the genitals differentiate in the first trimester, and the brain becomes imprinted in the latter half of gestation, it is possible for the fetal brain to be imprinted differently than the genitals. As children mature, this innate imprinting expresses as genital anatomy, gender identity, sexual orientation and other physiologic capabilities and natural preferences along a continuum, between masculine and feminine.

The evidence shows that both orientation and identity are biologic features that co-vary with a very large number of other biologic sexually dimorphic traits.”


A fetus’ development is influenced by survival reactions to their environment. Although fetal and placental responses to environmental stressors are relevant to sexual orientation and gender identity, the subject wasn’t explored.

Epigenetic adaptations to the prenatal environment involving microRNA were mentioned in a small subsection. But the review didn’t cite relevant studies involving DNA methylation, chromatin and histone modifications for epigenetic causes of and effects on sexual orientation and gender identity.

The authors included a half-dozen anecdotal quotations from personal correspondence that promoted their narrative. These came across as appeals to authority rather than evidence for scientific understanding of the subject.

It was insufficient for the review to note “a continuum between masculine and feminine” without also exploring evidence for an individual’s placement on the continuum, including possible epigenetic causes for sexual orientation and gender identity.

https://www.sciencedirect.com/science/article/pii/S009082581731510X “Biological origins of sexual orientation and gender identity: Impact on health” (not freely available)

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Parental lying thwarted both their children and researchers

This 2017 German human study explored the relationship between birth stress and handedness. The authors summarized previous research which, among other points, estimated epigenetic contributions to handedness as great as 75%.

The research hypothesis itself was worthwhile based on the prior studies cited and elsewhere such as Is what’s true for a population what’s true for an individual?. But the study hit a snag in its reliance on the sixty participants (average age 24) completing, with the assistance of their parents and medical records, a 24-item questionnaire of maternal health problems during pregnancy, substance use during pregnancy, and birth complications.

The subjects didn’t provide accurate information. For example:

  • Only one of the subjects reported maternal alcohol use during pregnancy. An expected number would have been twenty-six!
  • None of the subjects reported maternal mental illness during pregnancy. An expected number would have been at least seven!

The subjects’ parents willingly misled their children about facts of their child’s important earliest development periods. Their lies and omissions were not only unethical to the children, but also, whenever they became recognized, diminished or destroyed the society among family members.

As mentioned on the Welcome page, lies and omissions ruin the standard scientific methodology of surveying parents and caregivers. The absence of evidence greatly increased the difficulty for researchers to determine causes of epigenetic effects still present in the subjects’ lives.

The parental lying was again unethical in that it diminished or destroyed the society between the sources of information – the research subjects – and the users of the information. It adversely affected anyone who valued evidence-based research.

http://www.tandfonline.com/doi/full/10.1080/1357650X.2017.1377726 “DNA methylation in candidate genes for handedness predicts handedness direction” (not freely available)

Epigenetic stress effects in preterm infants

This 2017 Italian review selected 9 human studies on the epigenetic effects of:

“One of the major adverse events in human development. Preterm infants are hospitalized in the Neonatal Intensive Care Unit where they are exposed to life-saving yet pain-inducing procedures and to protective care.”

Highlights of the referenced studies included:

  • “Early exposure to adverse events during the third trimester of pregnancy is capable to alter the epigenetic status of imprinted and placenta-related genes which have relevant implications for fetal development and preterm infants’ HPA [hypothalamic–pituitary–adrenal] stress reactivity during infancy.”
  • “There was an association between DNAm [DNA methylation] and white matter tract tissue integrity and shape inferred from dMRI [diffusion MRI], suggesting that epigenetic variation may contribute to the cerebral phenotype of preterm birth.”

Limitations of the referenced studies included:

  • “A multiple sampling design that includes parental samples, placental tissue, cord blood and extends across the life-course would be required to investigate the relative contributions of in utero and postnatal exposures to changes in DNAm, and the extent to which preterm birth leaves a legacy on the methylome.”
  • Saliva, blood, and other tissues’ DNA methylation may not produce valid links to brain tissue DNA methylation of the same gene, which may hamper conclusive inferences about behavior, etc.

http://www.sciencedirect.com/science/article/pii/S0149763417302117 “Preterm Behavioral Epigenetics: A systematic review” (not freely available)

http://www.nature.com/tp/journal/v6/n1/full/tp2015210a.html “Epigenomic profiling of preterm infants reveals DNA methylation differences at sites associated with neural function” (one of the studies selected, quoted above)

The effects of imposing helplessness

This 2016 New York rodent study found:

“By using unbiased and whole-brain imaging techniques, we uncover a number of cortical and subcortical brain structures that have lower activity in the animals showing helplessness than in those showing resilience following the LH [learned helplessness] procedure. We also identified the LC [locus coeruleus] as the sole subcortical area that had enhanced activity in helpless animals compared with resilient ones.

Some of the brain areas identified in this study – such as areas in the mPFC [medial prefrontal cortex], hippocampus, and amygdala – have been previously implicated in clinical depression or depression-like behavior in animal models. We also identified novel brain regions previously not associated with helplessness. For example, the OT [olfactory tubercle], an area involved in odor processing as well as high cognitive functions including reward processing, and the Edinger–Westphal nucleus containing centrally projecting neurons implicated in stress adaptation.

The brains of helpless animals are locked in a highly stereotypic pathological state.”

Concerning the study’s young adult male subjects:

“To achieve a subsequent detection of neuronal activity related to distinct behavioral responses, we used the c-fosGFP transgenic mice expressing c-FosGFP under the control of a c-fos promoter. The expression of the c-fosGFP transgene has been previously validated to faithfully represent endogenous c-fos expression.

Similar to wild-type mice, approximately 22% (32 of 144) of the c-fosGFP mice showed helplessness.”

The final sentence of the Introduction section:

“Our study..supports the view that defining neuronal circuits underlying stress-induced depression-like behavior in animal models can help identify new targets for the treatment of depression.”


Helplessness is both a learned behavior and a cumulative set of experiences during every human’s early life. Therapeutic approaches to detrimental effects of helplessness can be different with humans than with rodents in that we can address causes.

The researchers categorized activity in brain circuits as causal in the Discussion section:

“Future studies aimed at manipulating these identified neural changes are required for determining whether they are causally related to the expression of helplessness or resilience.”

Studying whether or not activity in brain circuits induces helplessness in rodents may not inform us about causes of helplessness in humans. Our experiences are often the ultimate causes of helplessness effects. Many of our experiential “neural changes” are only effects, as demonstrated by this and other studies’ induced phenotypes such as “Learned Helplessness” and “Prenatally Restraint Stressed.”

Weren’t the researchers satisfied that the study confirmed what was known and made new findings? Why attempt to extend animal models that only treat effects to humans, as implied in the Introduction above and in the final sentence of the Discussion section:

“Future studies aimed at elucidating the specific roles of these regions in the pathophysiology of depression as well as serve as neural circuit-based targets for the development of novel therapeutics.”

http://journal.frontiersin.org/article/10.3389/fncir.2016.00003/full “Whole-Brain Mapping of Neuronal Activity in the Learned Helplessness Model of Depression” (Thanks to A Paper a Day Keeps the Scientist Okay)

Where do our beliefs about our children come from? An autism example

A 2015 case study by Ohio physicians highlighted:

“Although only a small minority of patients with autism have a mitochondrial disease, many patients with mitochondrial myopathies have autism spectrum disorder symptoms.

These symptoms may be the presenting symptoms, which presents a diagnostic challenge for clinicians.

The case of a 15-year-old boy with a history of autism spectrum disorder and neurocardiogenic syncope, admitted to the inpatient unit for self-injury, whose young mother, age 35, was discovered to suffer from mitochondrial myopathy, dysautonomia, neurocardiogenic syncope, Ehler-Danlos syndrome, and other uncommon multisystem pathologies likely related to mitochondrial dysfunction.”

I was somewhat taken aback by the Abstract and Introduction statements:

“All autism spectrum disorders are known to be heritable, via genetic and/or epigenetic mechanisms, but specific modes of inheritance are not well characterized.

This form of ASD is known to be heritable, as are all forms of ASD, despite the previous belief to the contrary, though the mechanisms of inheritance, both genetic and epigenetic, are not well characterized.”

The definition of heritable as used was “able to be passed from parent to child before birth.” The reference provided for the statements was a 2014 French review Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms.

I didn’t see the “known to be heritable” phrase mentioned in the referenced review. However, I also didn’t see anything stated in the review or cited from its 217 references that disproved the phrase.


I shouldn’t have been surprised by “despite the previous belief to the contrary” in the above quotation. I’d guess that the physicians frequently encountered parents who needed such beliefs when faced with their child’s condition.

A relevant hypothesis of Dr. Arthur Janov’s Primal Therapy is: a major function that our cerebrums have evolutionarily adapted is to use ideas and beliefs to repress pain and make us more comfortable.

I value this inference as an empathetic method of interpreting people’s behaviors and expressions of thoughts and feelings.

When a “known to be heritable” phrase can unleash pain, it likely won’t be understood in its appropriate context. Among the physicians’ challenges was a barrier that kept the parent’s pain from being felt – the belief.

http://innovationscns.com/autism-in-the-son-of-a-woman-with-mitochondrial-myopathy-and-dysautonomia-a-case-report/ “Autism in the Son of a Woman with Mitochondrial Myopathy and Dysautonomia: A Case Report”

Do strong emotions cause our brain hemispheres to interact more closely?

This 2015 human/macaque study found:

“The functional coordination between the two hemispheres of the brain is maintained by strong and stable interactions.

These findings suggest a notable role for the corpus callosum in maintaining stable functional communication between hemispheres.”

The human subjects were asked to:

“Generate four negative autobiographical memories and create word cues that reminded them of each event. Participants then underwent a 6-min IR fMRI scan during which they were cued with the words they had created to recall the two most negative autobiographic memories generated outside the scanner.”

However, the study’s supplementary material didn’t address why the researchers used this particular technique.

Does recalling strong emotional memories that engage our limbic systems cause our brain hemispheres to interact more closely than do cerebral exercises?


This study demonstrated that including emotional content in brain studies was essential. It may have provided additional information had the researchers also used the two least-negative emotional memories.

As noted in Agenda-driven research on emotional memories, one hypothesis of Dr. Arthur Janov’s Primal Therapy is that recalling an emotional memory engages one’s brain differently than does re-experiencing an emotional memory. Asking the subjects to attempt to re-experience the two least-negative emotional memories may have provided data relevant to the study.


I didn’t understand why macaques were used as subjects. The researchers didn’t provide any tasks for the monkeys during the scans. The information this study gained only duplicated other studies.

Also, the monkeys were anesthetized throughout the experiments. An assumption that wasn’t addressed: fMRI scan data on anesthetized macaques provided comparable evidence to fMRI scan data on normal non-anesthetized humans who were recalling emotional memories?

Did the researchers use macaques simply because they were available?

http://www.pnas.org/content/112/20/6473.full “Stable long-range interhemispheric coordination is supported by direct anatomical projections”

What causes disconnection between the limbic system and the cerebrum?

This 2014 Swedish human study with 339 subjects aged 25-80 years old found that as the subjects’ age increased, their hippocampus became less connected to their cerebrums:

“Age-related cortico–hippocampal functional connectivity disruption leads to a more functionally isolated hippocampus at rest, which translates into aberrant hippocampal decoupling and deficits in active mnemonic processing.”

The lead researcher said:

“What we can now show is that memory problems that come with increased age are most likely due to a process where the interaction among different regions of the hippocampus increases in response to less inhibitory cortical input. This in turn means that the hippocampus risks being more isolated from other important networks in the brain which impacts our ability to actively engage the hippocampus, for example to remember different events.”

Like other researchers commonly do, they excluded emotional content from the study. See another Swedish study Emotional memories and out-of-body–induced hippocampal amnesia as an example of why emotional memories are necessary in order to properly study the hippocampus.


1) As a result of excluding emotional content and other aspects of the study’ design such as using 25 as the beginning age of the subjects, all the researchers could muster as a explanatory factor was age. However, they had to couch their findings as “age-related” because age in and of itself wasn’t a causal explanation for the observed effects.

2) The findings weren’t even truly “age-related”  because, for example, the study didn’t necessarily apply to people below the age of 25. Had the study included 10-18 year old subjects, the researchers may have found that “less inhibitory cortical input” may also be present before puberty, as The prefrontal cortex develops more repressive function at puberty study indicated.

3) Had the study design included neurochemicals, the researchers may have found that “cortico–hippocampal functional connectivity disruption” was due to factors that influenced dopamine and glutamate levels, as A mechanistic study of neurotransmitters in the hippocampus indicated.

4) A finding that “cortico–hippocampal functional connectivity disruption” was influenced by other factors may also have been made had the study design included the subjects’ histories. Per my Welcome page, the findings of much of the recent research I’ve curated on this blog, and the references in those studies show that when basic needs aren’t met, especially early in people’s lives, and the painful conditions persist, enduring physiological changes may occur.

5) What the researchers noted in the study’s limitation paragraph were references to fMRI scans rather than limitations such as those mentioned above regarding the study design. The study provided unconvincing evidence for causes of “cortico–hippocampal functional connectivity disruption” and it wasn’t because of fMRI limitations.

http://www.pnas.org/content/111/49/17654.full “Elevated hippocampal resting-state connectivity underlies deficient neurocognitive function in aging”


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