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. 2016 Oct 5:6:33822.
doi: 10.1038/srep33822.

Risk of prenatal depression and stress treatment: alteration on serotonin system of offspring through exposure to Fluoxetine

Siran Pei  1   2   3 , Li Liu  1   2 , Zhaomin Zhong  4 , Han Wang  4 , Shuo Lin  3 , Jing Shang  1   2
Affiliations

Risk of prenatal depression and stress treatment: alteration on serotonin system of offspring through exposure to Fluoxetine

Siran Pei et al. Sci Rep. .

Erratum in

Abstract

Fluoxetine is widely used to treat depression, including depression in pregnant and postpartum women. Studies suggest that fluoxetine may have adverse effects on offspring, presumably through its action on various serotonin receptors (HTRs). However, definitive evidence and the underlying mechanisms are largely unavailable. As initial steps towards establishing a human cellular and animal model, we analyzed the expression patterns of several HTRs through the differentiation of human induced pluripotent stem (hiPS) cells into neuronal cells, and analyzed expression pattern in zebrafish embryos. Treatment of zebrafish embryos with fluoxetine significantly blocked the expression of multiple HTRs. Furthermore, fluoxetine gave rise to a change in neuropsychology. Embryos treated with fluoxetine continued to exhibit abnormal behavior upto 12 days post fertilization due to changes in HTRs. These findings support a possible long-term risk of serotonin pathway alteration, possibly resulting from the "placental drug transfer".

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Dual SMAD inhibition allows for a highly efficient neural induction of neuron and neural crest (NC) cells from hiPS cells.
(A) Differentiation scheme used for neural induction can be achieved with the combination of Noggin, a BMP inhibitor and SB431542, an ALK inhibitor; (B) By day 10, the cells appear dramatically thicker with densely packed nuclei and phase-bright ridges; (C) By day 20 the typical cell morphology of neuron under light field (LF); (D–I) By day 20, the neuron-like cells showed positive for mature neuron marker MAP2 (red) and Tuj1 (red) by immunocytochemistry; (J–R) By day 10, the hiPS cells could be selectively directed toward neural crest cells if neural induction began at lower densities. In this case more cells are observed expressing NC markers, p75 (red), HNK-1 (red) and AP-2α (red), but without expressing Pax6 (green), an early marker of neurectodermal differentiation. Nuclei were stained with DAPI (blue). Bars = 200 mm (B,D–F, J–R), 400 mm (C,G–I).
Figure 2
Figure 2. Expression patterns of serotonin receptors from hiPS cells to CNS neurons.
Normalized expression tested for pet-1 (A), htr1a (B), htr1b (C), htr1d (D), htr1f (E), htr2a (F), htr2b (G) and htr5a (H) by qPCR. ***p < 0.005, **p < 0.01, *p < 0.05, one-way analysis of variance (ANOVA) with Tukey’s post-hoc test was used between the hiPS cells group and each time point follow. All error bars show mean ± s.e.m.
Figure 3
Figure 3. Expression patterns of serotonin receptors from hiPS cells to NC cells.
Normalized expression tested for pet-1 (A), htr1a (B), htr1b (C), htr1d (D), htr1f (E), htr2a (F), htr2b (G) and htr5a (H) by qPCR. ***p < 0.005, **p < 0.01, one-way ANOVA with Tukey’s post-hoc test was used between the hiPS cells group and each time point follow. All error bars show mean ± s.e.m.
Figure 4
Figure 4. Quantitative changes of the expression of serotonin receptors during the early development of zebrafish embryos under fluoxetine administration.
Real-time PCR was performed to confirm the relative expression level changes of htr1aa (A), htr1ab (B), htr1b (C), htr2a (D) and htr5a (E) with or without the treatment of fluoxetine in two doses. Two-way ANOVA with Tukey’s multiple comparisons test was used for analysis; n ≥ 20 per group, ***p < 0.005, **p < 0.01, *p < 0.05, manes the statistically significance between different doses in each of six time points, †††p < 0.005, ††p < 0.01, †p < 0.05 manes the statistically significance between different time points of control groups. All error bars show mean ± s.e.m.
Figure 5
Figure 5. Normal Expression patterns of serotonin receptors during early development of zebrafish embryos.
Expression of htr1aa (A), htr1ab (B), htr1b (C), htr2a (D) and htr5a (E) on 7 developmental phases of zebrafish early development: 4-cell, 75% Epiboly, Bud, 6 Somite, 24 hpf, 36 hpf and 48 hpf (i–vii) in both lateral and dorsal whole mount views. Embryos were positioned anterior left and viewed laterally.
Figure 6
Figure 6. Expression patterns of serotonin receptors during the early development of zebrafish embryos under fluoxetine administration.
Expression of htr1aa (A), htr1ab (B), htr1b (C), htr2a (D) and htr5a (E) on 3 developmental phases of zebrafish early development: 24 hpf, 36 hpf and 48 hpf (i–iii) in both lateral and dorsal whole mount views under 1 μM and 10 μM fluoxetine administration. Embryos were positioned anterior left and viewed laterally.
Figure 7
Figure 7. The hypolocomotor behavior of zebrafish larva induced by fluoxetine.
(A,D) Recorded swimming tracks of 3 groups zebrafish. Each red line represents the swimming track of 1 minute recording randomly selected from the 2-hour experiment on both 6 dpf and 12 dpf. (B,E) The locomotor activities of each minute for all zebrafish larva in 3 groups on 6 dpf and 12 dpf. (C,F) The statistic analysis of the average locomotor activities, n ≥ 20 per group, ***p < 0.005, **p < 0.01, *p < 0.05, one-way ANOVA with Tukey’s post-hoc test was used between the control group and each dose fluoxetine group. All error bars show mean ± s.e.m.
Figure 8
Figure 8. Potential mechanism offspring depression induced by SSRIs.
(A) The natural level of both serotonin quantity and HTRs expression ensure the normal serotonin signal. (B) During embryo early development, to maintain the regular serotonin signal, fewer HTRs express reply more available serotonin resulting from SSRIs that are taken by depressed pregnant. (C) Lower serotonin signal appears after the stop using of SSRIs as the fewer HTRs expression.
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