Table 2.

Recommendations for future research on placental-fetal development, its utility in prenatal screening for environmental exposures, and ideas for targeted intervention.

N	Molecular pathway	Recommendations for future studies	Candidates for prenatal screening for environmental risks to fetus	Safe method for modulation, post conception
1	hCG	Measure hCG as alpha and beta subunits, and as heterodimer (intact, hyperglycosylated). Investigate female corollary to male placental hCG-fetal LHCGR model: measure candidate mRNAs (NPY, LEP, WNT2B, ETV5 and relevant receptors and proteins) in matched female placental and fetal tissues. Measure and model hCGα in the placental-fetal and in the maternal neuroendocrine-placental axes, along with other ‘neuroactive’ molecules (CSH1, PRL, CRF, Leptin, GDF15, Serotonin). Include maternal and child health outcomes. Combine measures of hCG and the GNRH pathways (placental, fetal) to evaluate the presence of an epigenetically regulated human ‘epiclock’ between the placenta and the fetal brain (analogous to finding in mouse). Analyze ratio of serum hCG to sex steroids as a global indicator of HPA and HPG development that can carry over into postnatal health. Study more hCG biomarkers in the context of cerebral palsy to identify the mechanism by which placental hCG can be neuroprotective in setting of hypoxic injury.	Serum hCG is already in use in prenatal screening for fetal aneuploidies.	None identified.
2	TH	MCT8, MCT10, LAT1, LAT2, ABCB1, NIS may be specific transporters to study in the human placenta to quantify the hCG-TH-fetal brain relationship. Measure D2 and D3 expression to determine regulation of bioactive TH availability.	A combined measured of serum hCG and thyroid hormone, normalized for gestational age, could be informative.	Iodine and selenium supplementation
3	PPARγ	Evaluate sex differences in PPARγ regulation. Evaluate PPARγ (jointly with ABCB1 and P-glycoprotein) as transport mechanism of xenobiotics into placental and fetal tissues. Consider genotypic differences in PPARG, measured and analyzed jointly with placental biomarkers of PPARG expression. Include biomarkers of epigenetic regulation of the PPARγ pathway. Identify role of the placenta in obesogenic effects.	It is not measured in maternal circulation.	Quality and quantity of fats in maternal diet.
4	Leptin	Measure and model in tandem with adiponectin; analyze the two biomarkers as a ratio. Include placental epigenetic and transcriptional biomarkers to identify placenta-specific regulation and production. Adjust maternal serum levels for circulating leptin receptor levels.	It is not possible to distinguish maternal and fetal serum levels.	Diet and exercise
5	TGFβ	Develop theory and methods to distinguish placental TGFβ from maternal and fetal sources. Evaluate microRNA epigenetic regulation.	The evidence is not strong.	None identified
6	Epiregulin	Minimal evidence of placental expression. No evidence of role in fetal development.	There is no evidence to support.	None identified
7	GDF15	Highly promising given strong correlation with hCG. GDF15 and hCGα together may offer a specific panel of placental-maternal endocrine disruption. In non-pregnant individuals, it is being studied as a therapeutic target for dementia and hence may have specific effects on cells in fetal and/or maternal brain.	A potential screening analyte for health risks that are specific to the maternal neuroendocrine-placental axis.	None identified
8	snoRNA	Potentially a type of epigenetic regulation of placental-fetal endocrine disruption. Placental expression and its association with Prader Willi syndrome offer support for relevance to theory. Unclear how to measure and relate to other molecules (coding RNAs and proteins).	It may have potential as a screening analyte for risk of Prader-Willi Syndrome, and related phenotypes.	None identified
9	Serotonin	Literature on placental serotonin, like leptin, has exploded in recent years. It has exceptional appeal given its potential role in DoHAD and the difficulties in directly measuring fetal brain development. Still unclear what is the most salient molecule to measure that is representative of the placental serotonin system.	5-HIAA was proposed as a urinary biomarker of miscarriage and potentially other outcomes.	Tryptophan Maternal diet (triglycerides)
10	Vitamin D	Most important in the first trimester. Requires multiple measures. Challenging to tease apart maternal and fetal measures.	The evidence is not strong.	Supplementation Maternal diet