Genome editing technologies promise therapeutic advances for genetic diseases. We discuss the ethical and societal issues raised by these technologies, including their use in preclinical research, their potential to address mutations in somatic cells, and their potential to make germ line alterations that may be passed to subsequent generations. We call for a proportionate response from health leaders based on a realistic assessment of benefits, risks, and timelines for clinical translation.

Prenatal iron-deficiency (ID) is known to alter fetal developmental trajectories, which predisposes the offspring to chronic disease in later life, although the underlying mechanisms remain unclear. Here, we sought to determine whether varying degrees of maternal anaemia could induce organ-specific patterns of hypoxia in the fetuses. Pregnant female Sprague Dawley rats were fed iron-restricted or iron-replete diets to induce a state of moderate (M-ID) or severe ID (S-ID) alongside respective controls. Ultrasound biomicroscopy was performed on gestational day (GD)20 to assess uterine and umbilical artery blood flow patterns. On GD21, tissues were collected and assessed for hypoxia using pimonidazole staining. Compared to controls, maternal haemoglobin (Hb) in M- and S-ID were reduced 17%(P < 0.01) and 48% (P < 0.001), corresponding to 39% (P < 0.001) and 65% (P < 0.001) decreases in fetal Hb. Prenatal ID caused asymmetric fetal growth restriction, which was most pronounced in S-ID. In both severities of ID, umbilical artery resistive index was increased (P < 0.01), while pulsatility index only increased in S-ID (P < 0.05). In both M- and S-ID, fetal kidneys and livers showed evidence of hypoxia (P < 0.01 vs. controls), whereas fetal brains and placentae remained normoxic. These findings indicate prenatal ID causes organ-specific fetal hypoxia, even in the absence of severe maternal anaemia.

Les technologies de modification du génome promettent des avancées dans le traitement des maladies génétiques. Les auteurs abordent les enjeux éthiques et sociaux que soulèvent ces technologies, y compris leur utilisation dans des recherches précliniques, leur potentiel à résoudre les mutations somatiques et leur potentiel à modifier les lignées germinales qui peuvent être transmises aux prochaines générations. Ils demandent une réponse modérée de la part des leaders en santé, reposant sur une évaluation réaliste des avantages, des risques et des délais d’application clinique.

Iron deficiency (ID) is the most prevalent nutritional deficiency worldwide, and affects populations across the socio‐economic spectrum. The incidence of ID anemia in pregnant women is of chief concern, with rates as high as 80 % in developing countries, and a prevalence of 23 % in Canada. Maternal ID during pregnancy has been shown to impact fetal iron status and growth trajectories, although the precise mechanisms underlying this intrauterine growth restriction are unknown. We hypothesized that maternal ID causes fetal hypoxia, resulting in asymmetric growth restriction in more severe ID. Female rats (initial age 6 weeks for severe (S‐ID), 9 weeks for moderate (M‐ID)) were fed iron restricted diets throughout pregnancy. Dams were treated with pimonidazole on gestational day (GD)20 to assess hypoxia (<10 mm Hg O2). Maternal and fetal hemoglobin (Hb) levels and body weights were assessed on GD21. Pup organs were excised and weighed to assess degree of asymmetric growth restriction. Tissue immunofluorescence was carried out on GD21 pup tissues with fluorescent probes to detect covalent pimonidazole adducts. Both M‐ and S‐ID groups caused fetal anemia ( fetal Hb reduced 30.9 % and 63.8 %, respectively, compared to control of 9.27 g/dL, P<0.01), despite only S‐ID dams becoming anemic (reduction in Hb 10.9 % and 50.3 % for M‐ and S‐ID, respectively, compared to 13.60 g/dL control Hb, P<0.001). Both M‐ and S‐ID caused fetal growth restriction (reduced weight by 9.1 % and 34.9 %, respectively, compared to control weight of 5.45 g, P<0.001). S‐ID, but not M‐ID, caused asymmetrical growth restriction, wherein relative heart and brain weights increased (60 % and 9.8 %, respectively, compared to control weights of 0.005 g/g and 0.041 g/g, P<0.01), and kidney and liver size decreased (20 % and 15 %, respectively, compared to control weights of 0.005 g/g and 0.067 g/g, P<0.01). M‐ID was associated with increased staining for pimonidazole in fetal livers (P=0.01) and kidneys (P=0.01), but not in brains and placentae, versus respective controls; hypoxia staining is S‐ID fetuses is ongoing. Fetal anemia and growth restriction can occur in the absence of maternal anemia, emphasizing the need for new methods of assessment in the clinical setting. Elucidation of the mechanisms through which ID impacts fetal growth and development will enable us to develop a platform with which we can test novel therapeutics.Support or Funding InformationAW held an Alberta Innovates Health Solutions Summer Studentship. SB Holds grants from the Canadian Institute of Health Research (CIHR), and the Women and Children's Health Research Institute (WCHRI).

Prenatal hypoxia can alter the growth trajectory of the fetus and cause lasting health complications including vascular dysfunction. We hypothesized that offspring that were intrauterine growth restricted (IUGR) because of prenatal hypoxia would exhibit altered vascular endothelin-1 (ET-1) signaling in later life. Isolated mesenteric artery responses to big ET-1 (bET-1) and ET-1 were assessed by using wire myography. Male IUGR offspring had 3-fold greater bET-1- induced vasoconstriction compared with controls (n=7 per group; P<0.001); NO synthase inhibition with L-N-G-nitro-arginine- methyl ester potentiated bET-1-induced vasoconstriction, albeit this effect was 2-fold greater (P<0.05) in male control compared with IUGR offspring. Vascular responses to bET-1 were similar between female IUGR and control offspring (n= 9-11 per group). In the presence of L-N-G-nitro-arginine-methyl ester, pretreatment with the chymase inhibitor chymostatin, the gelatinase inhibitor GM6001, or the neutral endopeptidase inhibitor thiorphan did not alter responses to bET-1; however, the ET-converting enzyme inhibitor CGS35066 almost completely abolished vascular responses to bET-1 in control and IUGR groups. Systolic blood pressure in IUGR male offspring was more responsive to ET-1 antagonism in vivo compared with controls (-9 versus -4 mm Hg; n= 5 per group; P=0.02); no such differences were observed in female offspring (n= 5-6 per group). These results demonstrate that vascular ET-1 function is programmed by prenatal hypoxia and provide further insights into the sex differences in the long-term vascular effects of developmental stressors.